Next Article in Journal
Glucosinolate Profiling and Expression Analysis of Glucosinolate Biosynthesis Genes Differentiate White Mold Resistant and Susceptible Cabbage Lines
Next Article in Special Issue
Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?
Previous Article in Journal
DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia
Previous Article in Special Issue
Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 19
Issue 12
10.3390/ijms19124036
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Targeting Cancer Stem Cells to Overcome Chemoresistance

by
Toni Nunes
1,2,†,
Diaddin Hamdan
1,3,†,
Christophe Leboeuf
1,2,
Morad El Bouchtaoui
1,2,
Guillaume Gapihan
1,2,
Thi Thuy Nguyen
1,
Solveig Meles
1,
Eurydice Angeli
1,
Philippe Ratajczak
1,2,
He Lu
1,2,
Mélanie Di Benedetto
1,2,4,
Guilhem Bousquet
1,2,4,5,*,‡ and
Anne Janin
1,2,6,*,‡
1
Institut National de la Santé et de la Recherche Médicale (INSERM), U1165, F-75010 Paris, France
2
Laboratoire de Pathologie, Université Paris Diderot, Sorbonne Paris Cité, UMR_S1165, F-75010 Paris, France
3
Hôpital de La Porte Verte, F-78004 Versailles, France
4
Université Paris 13, F-93430 Villetaneuse, France
5
Service d’Oncologie Médicale, AP-HP-Hôpital Avicenne, F-93008 Bobigny, France
6
Service de Pathologie, AP-HP-Hôpital Saint-Louis, F-75010 Paris, France
*
Authors to whom correspondence should be addressed.
†
These authors are co-premier authors.
‡
These authors are co-senior authors.
Int. J. Mol. Sci. 2018, 19(12), 4036; https://doi.org/10.3390/ijms19124036
Submission received: 20 November 2018 / Revised: 8 December 2018 / Accepted: 10 December 2018 / Published: 13 December 2018
(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer)
Browse Figure
Review Reports Versions Notes

Abstract

:
Cancers are heterogeneous at the cell level, and the mechanisms leading to cancer heterogeneity could be clonal evolution or cancer stem cells. Cancer stem cells are resistant to most anti-cancer treatments and could be preferential targets to reverse this resistance, either targeting stemness pathways or cancer stem cell surface markers. Gold nanoparticles have emerged as innovative tools, particularly for photo-thermal therapy since they can be excited by laser to induce hyperthermia. Gold nanoparticles can be functionalized with antibodies to specifically target cancer stem cells. Preclinical studies using photo-thermal therapy have demonstrated the feasibility of targeting chemo-resistant cancer cells to reverse clinical chemoresistance. Here, we review the data linking cancer stem cells and chemoresistance and discuss the way to target them to reverse resistance. We particularly focus on the use of functionalized gold nanoparticles in the treatment of chemo-resistant metastatic cancers.

1. Introduction

Cancer heterogeneity was demonstrated on clear-cell renal-cell carcinoma, using whole-genome analyses of multiple samples from the same primary tumor [1,2]. The mechanisms leading to cancer heterogeneity could be cancer stem cells or clonal evolution. According to the cancer stem cell theory, cancer stem cells, capable of self-renewal and differentiation, can generate mature differentiated cancer cells with genetic and epigenetic differences [3].
For 20 years, innovative medical treatments, including targeted therapies, anti-angiogenic drugs, and immunotherapies, have notably improved the prognosis of most metastatic cancers. However, secondary resistances almost constantly occur, and cancer stem cells are suggested as a potential source of this chemoresistance which has an increased risk of metastases and a lower survival rate [4,5,6,7,8].
In this narrative review, we analyze the recent literature on the role of cancer stem cells in chemoresistance to anti-cancer agents. We also provide a synthesis on how to target these cancer stem cells to reverse chemoresistance, for translational purposes.

2. Cancer Stem Cells and Chemoresistance

Two theoretical models are intended to explain the presence of cancer stem cells within a tumor. In the stochastic model, each cancer cell has the capability to dedifferentiate into a cancer stem cell, whereas in the hierarchical model cancer stem cells are the progenitors of differentiated tumor cells. According to this hierarchical model, cancer stem cells are able to self-renew and expand the cancer stem cell pool. They can also differentiate into heterogeneous cancer cell types to form the bulk of the tumor [9,10].
There is growing evidence that cancer stem cells are resistant to different types of stresses, including those generated by anti-cancer treatments [4,5,6,7,8,11], and, thus, could be associated with an increased metastatic risk and a lower survival rate [12].
Chemoresistance of cancer stem cells may be linked to:
  • Their frequent quiescent state with a low proliferation rate, since most conventional cytotoxic agents target proliferating cells [7,13,14,15]. Cancer stem cells niches have been identified, where cancer stem cells may be quiescent and chemo-resistant. Depending on the cancer stem cell type, these niches may be hypoxic areas [6,7] or perivascular areas [16,17]. An innovative therapeutic perspective might be the use of hyperoxia to resensitize cancer stem-cells in the resistant metastases [18]. In chemoresistant glioblastoma cells, hyperoxia restores sensitivity to drugs [19]. In a murine model of breast cancer, hyperbaric oxygen treatment induced the mesenchymal-to-epithelial transition of cancer cells, restoring a more differentiated phenotype [20].
  • The activation of drug-efflux mechanisms like ATP binding cassette (ABC) family transporters, especially ABCG2 [21] or the multidrug resistance P-glycoprotein (P-gp) namely ABCB1 (Table 1) [15,22,23]. Exposition to anti-cancer drugs, including taxanes, anthracyclines or antiangiogenic drugs, induces the expression of efflux pumps in cancer cells [24,25] and also in cancer stem cells leading to chemoresistance [26,27,28].
    The membrane expression of ABC transporters in cancer stem cells, especially ABCG2 and ABCB1, is currently used to identify them in the side population compartment [29,30]. A side population has been identified in many cancer types, based on their ability to efflux the lipophilic dye Hoechst 3342 [31,32,33,34]. To refine the selection of cancer stem cells within the side population, other stemness markers have been used. For example, in a preclinical model of ovarian cancer, side population and aldehyde dehydrogenase (ALDH)-expressing cancer stem cells have a greater tumorigenicity and are more resistant to cisplatin than the side population alone [35].
  • The overexpression of DNA-repair mechanisms, including homologous recombination, non-homologous end joining [36,37], base-excision repair through increased poly (ADP-ribose) polymerase 1 (PARP1) activity [38], and decreased activity of programmed cell death [39,40,41]. These mechanisms are currently involved in resistance to anti-cancer drugs and radiation therapy. The concomitant inhibition of at least two DNA repair pathways is required to reverse chemo or radio-resistance. Typically, Breast Cancer BRCA1 and 2 genes mutations lead to constitutive inactivation of homologous recombination. In metastatic ovarian and breast cancers with BRCA mutations, PARP inhibition with olaparib has been approved [42,43,44,45] and is associated with very high response rates when combined with cisplatin [46]. In a phase I study of radioresistant melanomas, concomitant inhibition of multiple DNA repair pathways restored sensitivity to radiotherapy [47]. To date, there are promising pre-clinical data on the benefit of specifically targeting DNA repair mechanisms in cancer stem cells [38,45,48,49,50].
  • The acquisition of an epithelial-to-mesenchymal transition (EMT) phenotype. Cancer stem cells located at the invasive front of a tumor, contrary to quiescent cancer stem cells, have invasive and metastatic capabilities linked to an epithelial-to-mesenchymal transition phenotype [51]. In a large series of skin cancers, we have demonstrated that some cancer cells with an EMT phenotype also had stemness features and that they were preferentially distributed in the invasive front of the tumors [52]. In pre-clinical models, targeting epithelial-to-mesenchymal transition induces differentiation of cancer stem cells, reduces stemness and restores chemo and radiosensitivity [53,54,55,56,57].
Metastatic renal cancer samples offer the opportunity to study cancer heterogeneity and the role of cancer stem cells in resistance to treatments [1,2,6,58].
In pre-clinical studies, sunitinib, a leading anti-angiogenic drug, has been shown to mainly target neo-angiogenic micro-vessels, thus, inducing necrosis [6,59,60]. In clinical settings, there is also radiological evidence of necrosis induced by anti-angiogenic drugs among patients with metastatic renal cell carcinoma [61]. On cancer samples from patients with metastatic renal cell carcinoma, we showed that the numbers of cancer stem cells increased after treatment with sunitinib, but only in peri-necrotic hypoxic areas [6]. Using patient-derived xenografts from clear-cell renal cell carcinomas, we demonstrated that sunitinib was able to induce its own resistance by increasing the numbers of cancer stem cells in peri-necrotic hypoxic areas [6].
Our results are consistent with the clinical experience of cancer relapses after treatment with sunitinib [62], and with the identified two sub-types of renal cell carcinoma associated with resistance to sunitinib in patients. These sub-types are characterized by an activation of hypoxia pathways and a stem-cell signature [63]. So, sunitinib increases renal cancer stem cells numbers and contributes to its own resistance by its effects on endothelial tumor cells and the increase in cancer stem cells.
Regardless of tumor type, targeting tumor vessels could increase cancer stem cell numbers, because neo-angiogenesis is a mechanism common to all tumors [64].
We applied our experience on renal cancer stem cells to triple-negative breast cancers, a poor prognosis form of breast cancer in young women. On pre-treatment tumor biopsies of women with triple negative breast cancers, we have demonstrated that the numbers of breast cancer stem cells that were inversely correlated to response to chemotherapy were more numerous. We have also shown that these cancer stem cells were hypoxic, preferentially distributed in peri-necrotic areas, and in an autophagic quiescent state with autophagy features. Then, with our patient-derived xenograft models of triple-negative breast cancers, we demonstrated that drug resistance of autophagic cancer stem cells increased under hypoxic conditions, and we showed that inhibition of the autophagic pathway, and so cancer stem cells, was able to reverse the chemoresistance [7]. Our results present innovative therapeutic strategies to target cancer stem cells, and to overcome acquired resistance to anti-cancer drugs using multiple targets pathways simultaneously, namely autophagy and hypoxia.
Targeting cancer stem cells to reverse chemoresistance, thus, adds a new dimension to anti-cancer treatments, particularly for metastatic patients in resort situations.

3. Targeting Stemness Pathways to Overcome Chemoresistance

There are signaling pathways preferentially associated with cancer stem cells [65,66,67], including HEDGEHOG, NOTCH, STAT3, WNT/β-catenin, and NF-κB pathways that regulate stemness properties in many cancers (Table 2) [68].
The activation of the HEDGEHOG pathway is associated with cancer progression, acquisition of an EMT phenotype and cancer stem cell survival [69]. In tumor samples from patients with skin carcinoma, glioblastoma or colon cancers, HEDGEHOG is preferentially activated in cancer stem cells [69,70,71,72].
Janus Kinase/signal transducer and activator of transcription (JAK/STAT) are constitutively activated in tumor-initiating cells of patient-derived acute myeloid leukemia, and JAK inhibitors reduce their survival in vitro and their engraftment capability [73]. In patient-derived glioblastoma stem cells, STAT3 is strongly overexpressed and its inhibition decreases stemness properties and increases cell differentiation [74].
The NOTCH pathway is often implicated in tumorigenesis by promoting cell cycle progression, epithelial-to-mesenchymal transition, and apoptosis inhibition [75]. In patient-derived pancreatic xenografts, NOTCH genes are highly expressed in cancer stem cells. NOTCH inhibition decreases the numbers of pancreatic cancer stem cells in vitro and delays tumor engraftment and tumor growth [76]. In another model of the oesophageal cancer cell line and xenografts, NOTCH activity is correlated with stemness, tumor progression, and chemoresistance [77]. NOTCH inhibition restores radio-sensitivity of patient-derived glioma stem cells in vitro and impairs xenograft formation [78].
In addition to its role in maintaining stemness, WNT/β-catenin pathway is involved in EMT transition and metastatic process in many different cancers [76], including medulloblastoma, breast, gastric, and colorectal cancers [79]. In pre-clinical models of squamous cell carcinoma and breast cancer xenografts, blocking the WNT/β-catenin pathway decreases the numbers of cancers stem cells and enables treatment resistance to be overcome [80,81]. Cancer stem cell chemoresistance may be linked to the overexpression of ATP-binding cassette drug transporters, known as transcriptional targets of WNT/β-catenin [15,82].
NF-κB pathway constitutive activation is involved in many cancers and is also associated with aggressiveness features and cancer stem cell survival [88,89]. Pre-clinical studies using hematopoietic stem cells have demonstrated that loss of NF-κB activity impairs their stemness properties and their engraftment potential [90,91]. In breast cancer, cancer stem cells express higher NF-κB activity, and blocking NF-κB reduces stemness and metastatic potential in vitro and in vivo [92,93].
Targeting these stemness pathways in patients may thus be a way to reverse chemoresistance. It has provided some clinical benefit [94], but data are still lacking to make the link between response to an anti-cancer drug and the specific targeting of cancer stem cells [95].
Vismodegib is an inhibitor of the HEDGEHOG pathway, approved for the treatment of inoperable basal cell carcinoma of the skin [86,96]. In patients with metastatic gastric cancer, vismodegib did not lead to any clinical benefit except in a subgroup of patients with high levels of CD44 expressing cancer stem cells within the primary tumors [67,95]. In a phase II study of patients with progressive glioblastoma, vismodegib monotherapy was also disappointing, although it was able to decrease self-renewal capacities of glioblastoma-derived CD133-expressing stem cells [97].
Napabucasin is a STAT3 inhibitor with anti-tumor activity in vitro and in vivo in various cancers [98,99]. In association with paclitaxel, napabucasin did not lead to any benefit for the treatment of metastatic gastric cancer, probably due to the lack of patient selection. Subgroup analyses are ongoing to detect a benefit for patients with high levels of cancer cells expressing STAT3 [100,101]. In patients with advanced colorectal cancer, napabucasin led to a survival benefit, only in patients with tumors expressing phospho-STAT3 [102].
A limitation of targeting stemness pathways is that they are not specific of cancer stem cells and may particularly be activated in normal cells, leading to limiting toxic effects on normal tissues. Another limitation is the potential cross-talk between these pathways, an adaptive mechanism to maintain cancer stem cell survival. In a pre-clinical model of breast cancer, the inhibition of the PI3K pathway, another stemness pathway, increased the number of cancer stem cells through NOTCH activation [86,87]. Dual or multiple inhibitions of stemness pathways could be a way to overcome this limitation.

4. Targeting Cancer Stem Cell Surface Markers

Cancer stem cells can be identified by non-specific surface markers, usually dependent on the cancer type. Some markers have been proposed as preferential stemness markers (Table 3).
CD44, a hyaluronic acid receptor, is involved in numerous biological processes including cell adhesion, migration, drug resistance and apoptosis [150,151,152]. It has been identified as a stem cell marker in most cancer types, where it is associated with an invasive phenotype, metastatic potential [27,104,105,153,154,155,156], and chemoresistance [157]. In preclinical models of ovarian cancer, CD44-expressing cancer stem cells are more resistant to platinum salts and to paclitaxel than CD44-negative cells [27,106]. Knockdown of CD44 expression restores drug sensitivity to paclitaxel [158].
CD44 also has several isoforms of different functional significance. In pre-clinical models of colorectal cancer and in patient’s tumor samples, the variant 6 is highly expressed by cancer stem cells and interacts with WNT/β-catenin pathway leading to more aggressive tumors [159].
CD117 is the stem cell growth factor receptor, encoded by the c-KIT gene [114]. In preclinical studies, patient-derived CD117-expressing ovarian cancer stem cells have a high tumorigenic potential with features of chemoresistance to platinum salts and to paclitaxel. Using imatinib, a c-KIT/CD117 inhibitor, or anti-CD117 siRNA, enables the reversal of chemoresistance through Wnt/β-catenin pathway inhibition [27,82,115]. Unfortunately, in a phase II study of patients with metastatic recurrent and platinum-resistant ovarian cancer, imatinib alone did not lead to any benefit. This might be explained by the non-specificity of stem-cell markers within the same tumor [160].
CD133 is a common marker of cancer stem cells in patients, associated with a poor prognosis and resistance to conventional treatments [161,162,163]. In 131 patients with cancers of different types, a high level of CD133 mRNA expression in circulating mononuclear cells, including cancer stem cells, is associated with metastatic disease and worse survival [164]. In pre-clinical studies, patient-derived CD133-expressing ovarian cancer stem cells have increased engraftment capacities with chemoresistance to cisplatin [117,118]. In vivo, targeting CD133 efficiently inhibits the engraftment rate of various types of cancer stem cells [165,166,167]. In a pre-clinical model of glioblastoma, drug-conjugate bi-specific antibodies targeting CD133 increase drug delivery to glioblastoma stem cells with enhanced anti-tumor activity [168].
CD24 has also been largely studied as a cancer stem cell marker in many different types of cancers [104,111,126]. However, its role remains complex since both tumor-derived CD24-positive and CD24-negative cells may be chemoresistant with stemness properties, depending on the cancer type [126,169,170]. For example, in patients with ovarian cancer, CD24 expression is independently associated with an increased metastatic potential and a decreased survival [171]. By contrast, in patient-derived ovarian tumor samples, CD24-negative cells were more aggressive than CD24-positive cells, with stemness features and resistance to carboplatin and paclitaxel [172]. In hepatocellular carcinoma derived-xenografts, using a humanized monoclonal anti-CD24 antibody had anti-tumor effects, while there was no data on the eradication of the pool of cancer stem cells [173].
In patients, cancer stem cells usually have high levels of aldehyde dehydrogenase (ALDH) activity. This enzyme, by way of oxidizing aldehydes to carboxylic acids, may protect cancer stem cells and increase their chemoresistance by detoxification of anti-cancer drugs [174]. In a meta-analysis on 1258 patients with ovarian cancers, high ALDH expression in tumors is associated with decreased survival [129,175]. In preclinical models, ALDH-expressing ovarian cancer stem cells are chemo-resistant, and silencing ALDH gene expression enables chemoresistance to be reversed [176].
Epithelial cell adhesion molecule (EpCAM) is expressed in many types of cancer stem cells. EpCAM is involved in proliferation, migration, and invasion through WNT pathway activation [177]. In ovarian cancer xenografts, cancer cells co-expressing EpCAM and CD44 or CD24 had stemness properties with resistance to doxorubicin and cisplatin [137]. In patients with ovarian cancer, EpCAM expression correlates with aggressiveness and metastatic extent [178,179]. Using an anti-EpCAM therapeutic antibody showed promising results in xenografts models of colon and head and neck cancers [180].
Targeting cancer stem cells using monoclonal antibodies against surface markers still have limited clinical developments.
Schlaak et al. reported the case of a patient with chemoresistant metastatic melanoma. He was successfully treated with an association of a cytotoxic agent and an anti-CD20 monoclonal humanized antibody to eradicate the CD20-expressing cancer stem cells in the melanoma metastases [181].
For renal cell carcinoma, several potential markers have been discussed, including CXCR4, CD105 or endoglin, and CD133 which correlate with poor prognosis [182,183]. Endoglin or CD105 is a membrane marker of tumor endothelial cells but has also been described as a potential cancer stem cell marker in renal cell carcinoma as well as other cancers [138,139,140]. Targeting CD105-expressing renal cancer stem cell inhibited tumor growth [141]. A phase I trial using an anti-CD105 antibody showed promising results, restoring sensitivity to anti-angiogenic agents in patients with metastatic renal cell carcinoma [184]. Various phase I trials have also been conducted in other cancer types with clinical benefits [185,186,187,188]. However, there is no published data regarding the effect of the anti-CD105 antibody on the pool of cancer stem cells.
One limitation in targeting cancer stem cell markers is linked to the negative expression of some makers. Typically, breast cancer stem cells are CD44-positive and CD24-negative [112]. Anti-CD24 antibodies cannot, thus, be used as therapeutic agents.
Cancer stem cells with different surface markers in a given tumor also contribute to tumor heterogeneity. We studied an exceptional clinical situation that of cancers in transplant patients. In a large series of skin cancers occurring in female patients with male kidney transplants, we studied donor-derived male cells using laser microdissection on tissue samples. An identical TP53 mutation in the tumor cells of a skin cancer and in tubular epithelial cells of the corresponding grafted kidney enabled us to demonstrate the participation of donor epithelial cells to the malignant epithelial proliferation in the recipient [189]. We also found that some epithelial cells, of male or female genotypes, had a cancer stem cell phenotype [52,190], thus, demonstrating the heterogeneity of cancer stem-cells within one and the same tumor.
To overcome this limitation, antibodies capable of dual or multiple inhibitions could be proposed.

5. Nanotechnologies to Overcome Chemoresistance

With cancer stem cells being more resistant to drugs than differentiated cancer cells, higher doses are required to kill them. Due to the need to limit toxicities on normal organs, this is not usually possible. Active drug delivery to cancer cells, including cancer stem cells, has thus been proposed using nanovectors.
Nanoparticles have been used for more than twenty years to deliver drugs to target cells, protecting them from degradation, with enhanced absorption, and improved distribution [191]. Targeting can be active, through recognition ligands, or passive as a result of enhanced permeability and retention in tumors, and the release of the drug in tumor cells by internalization [192].
A few nanovectors have been successfully developed for translational applications in cancer treatment, including liposomal doxorubicin for metastatic ovarian and breast cancers [193,194], and nanoparticle albumin-bound paclitaxel for metastatic breast and pancreatic cancers [195,196]. Liposomes were first described in the early seventies [197,198,199]. They are made of a copolymer of polylactic acid and polyglycolic acid [200,201], covered with polyethylene glycol (PEG) to decrease their captation by the reticuloendothelial system and, thus, increase their serum half-life [202]. In vitro, liposomal doxorubicin had a higher sensitivity than doxorubicin in chemoresistant CH LZ cells [203]. In patients with platinum-resistant ovarian cancer, liposomal doxorubicin had a low cardiac toxicity, enabling the use of very high doses, and, thus, delaying the occurrence of resistance to doxorubicin [204].
Active targeting of cancer cells can enhance drug delivery. This is done by functionalization of nanoparticles with specific antibodies [205,206,207,208,209,210]. One of the most explored targets is carcinoembryonic antigen (CEA) [210,211,212]. For active targeting of cancer stem cells and chemoresistance reversion, drug-loaded liposomes can be conjugated with a specific antibody, as successfully demonstrated in a pre-clinical model of glioblastoma [168].
Gold nanoparticles are promising nanovectors for translational purposes. Pure gold has two important properties. It is an inert bio-compatible chemical element, and so can be used for biomedical application; gold nanoparticles are non-toxic in pre-clinical models [213,214]. It has a unique optical and p lasmon surface resonance property, shifting the plasmonic resonance from 520 to 800–1200 nm wavelength, thus, converting light into heat [215]. Near infra-red radiation, with its peak absorbance wavelength in the 450 to 600 nm range, is transmitted through normal tissue with minimal absorption and can excite gold nanoparticles [216]. This produces focal hyperthermia [217].
Heating at supra-physiological temperatures from 40 to 47 °C leads to direct cell death in a time- and temperature-dependent manner [218]. This can be used to destroy cancer cells, and also cancer stem cells, thus, increasing the sensitivity of cancer to chemotherapy/radiotherapy-based treatments [11].
Hyperthermia, as an anticancer treatment, has already been discussed since the eighties [219]. Actually, it is used combined with intraperitoneal chemotherapy, at temperatures ranging from 40 to 45 °C, for the treatment of diffuse peritoneal carcinomatosis of ovarian or colon origin [220]. It is also used in radiofrequency ablation of metastases; its combination with chemotherapy, in colorectal liver metastases, results in a better overall control [221]. However, in these technologies, hyperthermia can be toxic due to heating of surrounding normal tissues. In photo-thermal therapy using plasmon surface resonance properties of gold nanoparticles, only irradiated cancer cells are heated [222], with no effect on surrounding normal tissues. In addition, the intense localized heat generated by irradiated carbon nanoparticles overcomes chemotherapy resistance in breast cancer cells [5].
Gold nanoparticles can be used in another promising application. They can be loaded with cytotoxic drugs for efficient delivery to cancer cells by passive distribution as malignant tumors have enhanced permeability and retention effect [223,224,225,226].
Active targeting can also enhance drug delivery. It was demonstrated by Pitsillides et al. that gold nanoparticles functionalized with an anti-CD8 can efficiently target T lymphocytes in vitro, and kill them after laser irradiation [222]. Functionalizing gold nanoparticles with cetuximab, an anti-EGFR therapeutic antibody, was able to enhance their internalization in cancer cells, while non-functionalized nanoparticles remained within the tumor stroma [208].
Another way to functionalize nanoparticles is with an anti-HER2 antibody; HER2 receptor is overexpressed in 15 to 20% of breast cancers [227] and usually maintained in resistance situations [228]; there are already three efficient anti-HER2 therapeutic antibodies trastuzumab, pertuzumab [229], and trastuzumab emtansine, a cytotoxic drug conjugated with trastuzumab to target resistant cancer cells [230]. Recently, it was shown, by Kubota et al., that gold nanoparticles conjugated with trastuzumab had a cytotoxic effect on HER2-overexpressing cancer cell lines, which was not the case for gold nanoparticles alone. They showed, in vivo, using HER2-overexpressing tumor xenografts, that tumor growth inhibition was linked to an autophagic state [231]. We have engineered a hybrid iron-gold nanoparticle conjugated with an anti-HER2 antibody for theranostic purposes. Active targeting of our hybrid gold nanoparticles on HER2-overexpressing breast cancer cells, in patient-derived xenografts of HER2-overexpressing breast cancer, increased gold delivery to cancer cells. Then the bulk of the cancer regressed, after pulsed-laser near-infrared irradiation, as a result of an anti-angiogenic effect alongside a direct cytotoxic effect on cancer cells [232].

6. Gold Nanoparticles Targeting Cancer Stem Cells to Reverse Chemoresistance

Functionalized nanoparticles with peptides or antibodies are currently being developed to actively target cancer stem cells, with translational relevance [233,234,235,236,237,238]. Gold nanoparticles coupled with a peptide recognizing CD133 have been used to target glioblastoma cancer stem cells, and as a contrast agent in a preclinical study [235]. Hyaluronic acid, a biocompatible linear polysaccharide with a high affinity to the CD44 receptor, is able to target cancer stem cells [233,239,240] since some CD44v isoforms are stemness markers [241]. PEGylated gold nanoparticles functionalized with an anti-CD44 antibody efficiently target breast or gastric cancer stem cells. Under electron microscopy, they are found in the cytoplasm of targeted cells within a few hours [234,236]. After intravenous injection of gold, nanostars conjugated with CD44v6 antibody in human gastric xenografts, near infra-red laser-irradiation significantly inhibits tumor growth [236].
The functionalization of gold nanoparticles with specific antibodies could enhance local drug delivery, and, combined with photothermal therapy, eradicate targeted chemo-resistant cancer stem cells (Figure 1).
A limitation of this approach could be the intrinsic resistance of cancer stem cells to hyperthermia, possibly related to the up-regulation of some heat-shock proteins. The fact that breast cancer stem cells are resistant to conventional hyperthermia in vitro, and to temperatures up to 47 °C [5], could explain the local recurrences of liver metastases following treatment by radiofrequency ablation [242]. According to mathematical modeling, the level of electromagnetic heat is limited at the interface between cancer and normal tissue [243]. To spare normal adjacent tissues, temperatures should not exceed 50 °C. Heating cancer stem-cells with carbon nanoparticle-mediated hyperthermia makes it possible to overcome resistance by generating intense sub-cellular localized heat [5], possibly above 50 °C [244]. Further experiments are required to check that targeting of normal stem cells within normal tissues adjacent to a tumor does not induce significant damages to these normal tissues.
Nanoparticles functionalized with molecules capable of dual or multiple inhibitions could be a way to overcome the problem of non-specificity of stem cell markers. For example, Zaimy et al. engineered complex nanoparticles to target hematopoietic stem cells in acute myeloid leukemia subtype 2. Their nanoparticles, loaded with five antisense oligonucleotides, are functionalized with an aptamer recognizing both CD33 and CD34 and are able to target AML-M2 cells in vitro [245].
In conclusion, the emergence of gold nanoparticle technology in the field of cancer biology will lead to significant theranostic progress with translational applications, particularly for metastatic patients in resort situation.

Author Contributions

Conceptualization, T.N., D.H., A.J. and G.B.; writing—original draft preparation, T.N., D.H., A.J. and G.B.; writing—review and editing, C.L., M.E.B., G.G., T.T.N., S.M., E.A., P.R., H.L. and M.D.B.; project administration, A.J. and G.B.; funding acquisition, A.J. and G.B.

Acknowledgments

We would like to thank A. Swaine for revising the English language.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ABCATP binding cassette
PARPPoly (ADP-ribose) polymerase 1
EMTEpithelial-to-mesenchymal transition
JAK/STATJanus Kinase/signal transducer and activator of transcription
ALDHAldehyde dehydrogenase
EpCAMEpithelial cell adhesion molecule
PEGPolyethylene glycol
CEACarcinoembryonic antigen

References

  1. Gerlinger, M.; Rowan, A.J.; Horswell, S.; Math, M.; Larkin, J.; Endesfelder, D.; Gronroos, E.; Martinez, P.; Matthews, N.; Stewart, A.; et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 2012, 366, 883–892. [Google Scholar] [CrossRef] [PubMed]
  2. Gerlinger, M.; Horswell, S.; Larkin, J.; Rowan, A.J.; Salm, M.P.; Varela, I.; Fisher, R.; McGranahan, N.; Matthews, N.; Santos, C.R.; et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 2014, 46, 225–233. [Google Scholar] [CrossRef] [Green Version]
  3. Ren, S.C.; Qu, M.; Sun, Y.H. Investigating intratumour heterogeneity by single-cell sequencing. Asian J. Androl. 2013, 15, 729–734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Carey, L.A.; Dees, E.C.; Sawyer, L.; Gatti, L.; Moore, D.T.; Collichio, F.; Ollila, D.W.; Sartor, C.I.; Graham, M.L.; Perou, C.M. The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin. Cancer Res. 2007, 13, 2329–2334. [Google Scholar] [CrossRef] [PubMed]
  5. Burke, A.R.; Singh, R.N.; Carroll, D.L.; Wood, J.C.; D’Agostino, R.B., Jr.; Ajayan, P.M.; Torti, F.M.; Torti, S.V. The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated photothermal therapy. Biomaterials 2012, 33, 2961–2970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Varna, M.; Gapihan, G.; Feugeas, J.P.; Ratajczak, P.; Tan, S.; Ferreira, I.; Leboeuf, C.; Setterblad, N.; Duval, A.; Verine, J.; et al. Stem cells increase in numbers in perinecrotic areas in human renal cancer. Clin. Cancer Res. 2015, 21, 916–924. [Google Scholar] [CrossRef] [PubMed]
  7. Bousquet, G.; El Bouchtaoui, M.; Sophie, T.; Leboeuf, C.; de Bazelaire, C.; Ratajczak, P.; Giacchetti, S.; de Roquancourt, A.; Bertheau, P.; Verneuil, L.; et al. Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer. Oncotarget 2017, 8, 35205–35221. [Google Scholar] [CrossRef]
  8. Hu, J.; Guan, W.; Liu, P.; Dai, J.; Tang, K.; Xiao, H.; Qian, Y.; Sharrow, A.C.; Ye, Z.; Wu, L.; et al. Endoglin Is Essential for the Maintenance of Self-Renewal and Chemoresistance in Renal Cancer Stem Cells. Stem Cell Rep. 2017, 9, 464–477. [Google Scholar] [CrossRef] [PubMed]
  9. Clarke, M.F.; Dick, J.E.; Dirks, P.B.; Eaves, C.J.; Jamieson, C.H.; Jones, D.L.; Visvader, J.; Weissman, I.L.; Wahl, G.M. Cancer stem cells—Perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006, 66, 9339–9344. [Google Scholar] [CrossRef] [PubMed]
  10. Dick, J.E. Looking ahead in cancer stem cell research. Nat. Biotechnol. 2009, 27, 44–46. [Google Scholar] [CrossRef]
  11. Atkinson, R.L.; Zhang, M.; Diagaradjane, P.; Peddibhotla, S.; Contreras, A.; Hilsenbeck, S.G.; Woodward, W.A.; Krishnan, S.; Chang, J.C.; Rosen, J.M. Thermal enhancement with optically activated gold nanoshells sensitizes breast cancer stem cells to radiation therapy. Sci. Transl. Med. 2010, 2. [Google Scholar] [CrossRef] [PubMed]
  12. Li, M.; Zhang, B.; Zhang, Z.; Liu, X.; Qi, X.; Zhao, J.; Jiang, Y.; Zhai, H.; Ji, Y.; Luo, D. Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer. Biomed. Res. Int. 2014, 2014, 981261. [Google Scholar] [CrossRef] [PubMed]
  13. Kwon, M.J.; Shin, Y.K. Regulation of ovarian cancer stem cells or tumor-initiating cells. Int. J. Mol. Sci. 2013, 14, 6624–6648. [Google Scholar] [CrossRef] [PubMed]
  14. Dalerba, P.; Cho, R.W.; Clarke, M.F. Cancer stem cells: Models and concepts. Annu. Rev. Med. 2007, 58, 267–284. [Google Scholar] [CrossRef] [PubMed]
  15. Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005, 5, 275–284. [Google Scholar] [CrossRef] [PubMed]
  16. Lathia, J.D.; Heddleston, J.M.; Venere, M.; Rich, J.N. Deadly teamwork: Neural cancer stem cells and the tumor microenvironment. Cell Stem Cell 2011, 8, 482–485. [Google Scholar] [CrossRef] [PubMed]
  17. Charles, N.; Ozawa, T.; Squatrito, M.; Bleau, A.M.; Brennan, C.W.; Hambardzumyan, D.; Holland, E.C. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 2010, 6, 141–152. [Google Scholar] [CrossRef] [PubMed]
  18. Schito, L.; Semenza, G.L. Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends Cancer 2016, 2, 758–770. [Google Scholar] [CrossRef] [PubMed]
  19. Lee, D.; Sun, S.; Ho, A.S.; Kiang, K.M.; Zhang, X.Q.; Xu, F.F.; Leung, G.K. Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response. Anticancer Res. 2014, 34, 2957–2966. [Google Scholar] [PubMed]
  20. Moen, I.; Oyan, A.M.; Kalland, K.H.; Tronstad, K.J.; Akslen, L.A.; Chekenya, M.; Sakariassen, P.O.; Reed, R.K.; Stuhr, L.E. Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model. PLoS ONE 2009, 4, e6381. [Google Scholar] [CrossRef]
  21. Bleau, A.M.; Hambardzumyan, D.; Ozawa, T.; Fomchenko, E.I.; Huse, J.T.; Brennan, C.W.; Holland, E.C. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 2009, 4, 226–235. [Google Scholar] [CrossRef] [PubMed]
  22. Begicevic, R.R.; Falasca, M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int. J. Mol. Sci. 2017, 18, 2362. [Google Scholar] [CrossRef] [PubMed]
  23. Kathawala, R.J.; Gupta, P.; Ashby, C.R., Jr.; Chen, Z.S. The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist. Updates 2015, 18, 1–17. [Google Scholar] [CrossRef] [PubMed]
  24. Huang, L.; Hu, C.; Di Benedetto, M.; Varin, R.; Liu, J.; Jin, J.; Wang, L.; Vannier, J.P.; Janin, A.; Lu, H.; et al. Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells. Oncol. Lett. 2015, 9, 1287–1292. [Google Scholar] [CrossRef] [PubMed]
  25. Huang, L.; Perrault, C.; Coelho-Martins, J.; Hu, C.; Dulong, C.; Varna, M.; Liu, J.; Jin, J.; Soria, C.; Cazin, L.; et al. Induction of acquired drug resistance in endothelial cells and its involvement in anticancer therapy. J. Hematol. Oncol. 2013, 6, 49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ricci, F.; Bernasconi, S.; Perego, P.; Ganzinelli, M.; Russo, G.; Bono, F.; Mangioni, C.; Fruscio, R.; Signorelli, M.; Broggini, M.; et al. Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype. Cell Cycle 2012, 11, 1966–1976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Zhang, S.; Balch, C.; Chan, M.W.; Lai, H.C.; Matei, D.; Schilder, J.M.; Yan, P.S.; Huang, T.H.; Nephew, K.P. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008, 68, 4311–4320. [Google Scholar] [CrossRef] [PubMed]
  28. Kruger, J.A.; Kaplan, C.D.; Luo, Y.; Zhou, H.; Markowitz, D.; Xiang, R.; Reisfeld, R.A. Characterization of stem cell-like cancer cells in immune-competent mice. Blood 2006, 108, 3906–3912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Chang, H.L.; MacLaughlin, D.T.; Donahoe, P.K. Somatic stem cells of the ovary and their relationship to human ovarian cancers. In StemBook; Harvard Stem Cell Institute: Cambridge, MA, USA, 2008. [Google Scholar]
  30. Boesch, M.; Zeimet, A.G.; Reimer, D.; Schmidt, S.; Gastl, G.; Parson, W.; Spoeck, F.; Hatina, J.; Wolf, D.; Sopper, S. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics. Oncotarget 2014, 5, 7027–7039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Szotek, P.P.; Pieretti-Vanmarcke, R.; Masiakos, P.T.; Dinulescu, D.M.; Connolly, D.; Foster, R.; Dombkowski, D.; Preffer, F.; Maclaughlin, D.T.; Donahoe, P.K. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc. Natl. Acad. Sci. USA 2006, 103, 11154–11159. [Google Scholar] [CrossRef] [Green Version]
  32. Haraguchi, N.; Utsunomiya, T.; Inoue, H.; Tanaka, F.; Mimori, K.; Barnard, G.F.; Mori, M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006, 24, 506–513. [Google Scholar] [CrossRef] [PubMed]
  33. Kondo, T.; Setoguchi, T.; Taga, T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc. Natl. Acad. Sci. USA 2004, 101, 781–786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Seigel, G.M.; Campbell, L.M.; Narayan, M.; Gonzalez-Fernandez, F. Cancer stem cell characteristics in retinoblastoma. Mol. Vis. 2005, 11, 729–737. [Google Scholar] [PubMed]
  35. Yasuda, K.; Torigoe, T.; Morita, R.; Kuroda, T.; Takahashi, A.; Matsuzaki, J.; Kochin, V.; Asanuma, H.; Hasegawa, T.; Saito, T.; et al. Ovarian cancer stem cells are enriched in side population and aldehyde dehydrogenase bright overlapping population. PLoS ONE 2013, 8, e68187. [Google Scholar] [CrossRef] [PubMed]
  36. Lim, Y.C.; Roberts, T.L.; Day, B.W.; Harding, A.; Kozlov, S.; Kijas, A.W.; Ensbey, K.S.; Walker, D.G.; Lavin, M.F. A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells. Mol. Cancer Ther. 2012, 11, 1863–1872. [Google Scholar] [CrossRef] [PubMed]
  37. Yuan, M.; Eberhart, C.G.; Kai, M. RNA binding protein RBM14 promotes radio-resistance in glioblastoma by regulating DNA repair and cell differentiation. Oncotarget 2014, 5, 2820–2826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Venere, M.; Hamerlik, P.; Wu, Q.; Rasmussen, R.D.; Song, L.A.; Vasanji, A.; Tenley, N.; Flavahan, W.A.; Hjelmeland, A.B.; Bartek, J.; et al. Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 2014, 21, 258–269. [Google Scholar] [CrossRef]
  39. Srivastava, A.K.; Han, C.; Zhao, R.; Cui, T.; Dai, Y.; Mao, C.; Zhao, W.; Zhang, X.; Yu, J.; Wang, Q.E. Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells. Proc. Natl. Acad. Sci. USA 2015, 112, 4411–4416. [Google Scholar] [CrossRef] [Green Version]
  40. Yang-Hartwich, Y.; Soteras, M.G.; Lin, Z.P.; Holmberg, J.; Sumi, N.; Craveiro, V.; Liang, M.; Romanoff, E.; Bingham, J.; Garofalo, F.; et al. p53 protein aggregation promotes platinum resistance in ovarian cancer. Oncogene 2015, 34, 3605–3616. [Google Scholar] [CrossRef]
  41. Vitale, I.; Manic, G.; De Maria, R.; Kroemer, G.; Galluzzi, L. DNA Damage in Stem Cells. Mol. Cell 2017, 66, 306–319. [Google Scholar] [CrossRef]
  42. Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011, 12, 852–861. [Google Scholar] [CrossRef]
  43. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 2012, 366, 1382–1392. [Google Scholar] [CrossRef] [PubMed]
  44. Robson, M.; Im, S.A.; Senkus, E.; Xu, B.; Domchek, S.M.; Masuda, N.; Delaloge, S.; Li, W.; Tung, N.; Armstrong, A.; et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med. 2017, 377, 523–533. [Google Scholar] [CrossRef] [PubMed]
  45. Shimo, T.; Kurebayashi, J.; Kanomata, N.; Yamashita, T.; Kozuka, Y.; Moriya, T.; Sonoo, H. Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells. Breast Cancer 2014, 21, 75–85. [Google Scholar] [CrossRef] [PubMed]
  46. Balmana, J.; Tung, N.M.; Isakoff, S.J.; Grana, B.; Ryan, P.D.; Saura, C.; Lowe, E.S.; Frewer, P.; Winer, E.; Baselga, J.; et al. Phase, I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann. Oncol. 2014, 25, 1656–1663. [Google Scholar] [CrossRef] [PubMed]
  47. Le Tourneau, C.; Dreno, B.; Kirova, Y.; Grob, J.J.; Jouary, T.; Dutriaux, C.; Thomas, L.; Lebbe, C.; Mortier, L.; Saiag, P.; et al. First-in-human phase, I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. Br. J. Cancer 2016, 114, 1199–1205. [Google Scholar] [CrossRef] [PubMed]
  48. Nieborowska-Skorska, M.; Sullivan, K.; Dasgupta, Y.; Podszywalow-Bartnicka, P.; Hoser, G.; Maifrede, S.; Martinez, E.; Di Marcantonio, D.; Bolton-Gillespie, E.; Cramer-Morales, K.; et al. Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J. Clin. Investig. 2017, 127, 2392–2406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Karpel-Massler, G.; Pareja, F.; Aime, P.; Shu, C.; Chau, L.; Westhoff, M.A.; Halatsch, M.E.; Crary, J.F.; Canoll, P.; Siegelin, M.D. PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. PLoS ONE 2014, 9, e114583. [Google Scholar] [CrossRef]
  50. Gilabert, M.; Launay, S.; Ginestier, C.; Bertucci, F.; Audebert, S.; Pophillat, M.; Toiron, Y.; Baudelet, E.; Finetti, P.; Noguchi, T.; et al. Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS ONE 2014, 9, e104302. [Google Scholar] [CrossRef]
  51. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454. [Google Scholar] [CrossRef]
  52. Verneuil, L.; Leboeuf, C.; Bousquet, G.; Brugiere, C.; Elbouchtaoui, M.; Plassa, L.F.; Peraldi, M.N.; Lebbe, C.; Ratajczak, P.; Janin, A. Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients. Oncotarget 2015, 6, 41497–41507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Pattabiraman, D.R.; Weinberg, R.A. Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy. Cold Spring Harb. Symp. Quant. Biol. 2016, 81, 11–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Du, B.; Shim, J.S. Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules 2016, 21, 965. [Google Scholar] [CrossRef] [PubMed]
  55. Polireddy, K.; Dong, R.; McDonald, P.R.; Wang, T.; Luke, B.; Chen, P.; Broward, M.; Roy, A.; Chen, Q. Targeting Epithelial-Mesenchymal Transition for Identification of Inhibitors for Pancreatic Cancer Cell Invasion and Tumor Spheres Formation. PLoS ONE 2016, 11, e0164811. [Google Scholar] [CrossRef] [PubMed]
  56. Lee, S.Y.; Jeong, E.K.; Ju, M.K.; Jeon, H.M.; Kim, M.Y.; Kim, C.H.; Park, H.G.; Han, S.I.; Kang, H.S. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol. Cancer 2017, 16, 10. [Google Scholar] [CrossRef] [PubMed]
  57. Jayachandran, A.; Dhungel, B.; Steel, J.C. Epithelial-to-mesenchymal plasticity of cancer stem cells: Therapeutic targets in hepatocellular carcinoma. J. Hematol. Oncol. 2016, 9, 74. [Google Scholar] [CrossRef]
  58. Bousquet, G.; El Bouchtaoui, M.; Leboeuf, C.; Battistella, M.; Varna, M.; Ferreira, I.; Plassa, L.F.; Hamdan, D.; Bertheau, P.; Feugeas, J.P.; et al. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma. Oncotarget 2015, 6, 19279–19289. [Google Scholar] [CrossRef] [Green Version]
  59. Mendel, D.B.; Laird, A.D.; Xin, X.; Louie, S.G.; Christensen, J.G.; Li, G.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B.; et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 2003, 9, 327–337. [Google Scholar]
  60. Bousquet, G.; Varna, M.; Ferreira, I.; Wang, L.; Mongiat-Artus, P.; Leboeuf, C.; de Bazelaire, C.; Faivre, S.; Bertheau, P.; Raymond, E.; et al. Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis. Cancer Chemother. Pharmacol. 2013, 72, 1183–1193. [Google Scholar] [CrossRef]
  61. Fournier, L.S.; Oudard, S.; Thiam, R.; Trinquart, L.; Banu, E.; Medioni, J.; Balvay, D.; Chatellier, G.; Frija, G.; Cuenod, C.A. Metastatic renal carcinoma: Evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT. Radiology 2010, 256, 511–518. [Google Scholar] [CrossRef]
  62. Motzer, R.J.; Hutson, T.E.; Tomczak, P.; Michaelson, M.D.; Bukowski, R.M.; Oudard, S.; Negrier, S.; Szczylik, C.; Pili, R.; Bjarnason, G.A.; et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 2009, 27, 3584–3590. [Google Scholar] [CrossRef] [PubMed]
  63. Beuselinck, B.; Job, S.; Becht, E.; Karadimou, A.; Verkarre, V.; Couchy, G.; Giraldo, N.; Rioux-Leclercq, N.; Molinie, V.; Sibony, M.; et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin. Cancer Res. 2015, 21, 1329–1339. [Google Scholar] [CrossRef] [PubMed]
  64. Folkman, J.; Shing, Y. Angiogenesis. J. Biol. Chem. 1992, 267, 10931–10934. [Google Scholar] [PubMed]
  65. Xiao, W.; Gao, Z.; Duan, Y.; Yuan, W.; Ke, Y. Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma. J. Exp. Clin. Cancer Res. 2017, 36, 41. [Google Scholar] [CrossRef] [PubMed]
  66. Mohammed, M.K.; Shao, C.; Wang, J.; Wei, Q.; Wang, X.; Collier, Z.; Tang, S.; Liu, H.; Zhang, F.; Huang, J.; et al. Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis. 2016, 3, 11–40. [Google Scholar] [CrossRef] [PubMed]
  67. Bekaii-Saab, T.; El-Rayes, B. Identifying and targeting cancer stem cells in the treatment of gastric cancer. Cancer 2017, 123, 1303–1312. [Google Scholar] [CrossRef] [Green Version]
  68. Matsui, W.H. Cancer stem cell signaling pathways. Medicine 2016, 95 (Suppl. S1), S8–S19. [Google Scholar] [CrossRef]
  69. Merchant, A.A.; Matsui, W. Targeting Hedgehog—A cancer stem cell pathway. Clin. Cancer Res. 2010, 16, 3130–3140. [Google Scholar] [CrossRef]
  70. Hutchin, M.E.; Kariapper, M.S.; Grachtchouk, M.; Wang, A.; Wei, L.; Cummings, D.; Liu, J.; Michael, L.E.; Glick, A.; Dlugosz, A.A. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: Conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005, 19, 214–223. [Google Scholar] [CrossRef]
  71. Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; I Altaba, A.R. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 2007, 17, 165–172. [Google Scholar] [CrossRef]
  72. Varnat, F.; Duquet, A.; Malerba, M.; Zbinden, M.; Mas, C.; Gervaz, P.; I Altaba, A.R. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol. Med. 2009, 1, 338–351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Cook, A.M.; Li, L.; Ho, Y.; Lin, A.; Li, L.; Stein, A.; Forman, S.; Perrotti, D.; Jove, R.; Bhatia, R. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells. Blood 2014, 123, 2826–2837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Sherry, M.M.; Reeves, A.; Wu, J.K.; Cochran, B.H. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009, 27, 2383–2392. [Google Scholar] [CrossRef] [PubMed]
  75. Ranganathan, P.; Weaver, K.L.; Capobianco, A.J. Notch signalling in solid tumours: A little bit of everything but not all the time. Nat. Rev. Cancer 2011, 11, 338–351. [Google Scholar] [CrossRef]
  76. Abel, E.V.; Kim, E.J.; Wu, J.; Hynes, M.; Bednar, F.; Proctor, E.; Wang, L.; Dziubinski, M.L.; Simeone, D.M. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS ONE 2014, 9, e91983. [Google Scholar] [CrossRef]
  77. Wang, Z.; Da Silva, T.G.; Jin, K.; Han, X.; Ranganathan, P.; Zhu, X.; Sanchez-Mejias, A.; Bai, F.; Li, B.; Fei, D.L.; et al. Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res. 2014, 74, 6364–6374. [Google Scholar] [CrossRef]
  78. Wang, J.; Wakeman, T.P.; Lathia, J.D.; Hjelmeland, A.B.; Wang, X.F.; White, R.R.; Rich, J.N.; Sullenger, B.A. Notch promotes radioresistance of glioma stem cells. Stem Cells 2010, 28, 17–28. [Google Scholar] [CrossRef]
  79. Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 2012, 4. [Google Scholar] [CrossRef]
  80. Malanchi, I.; Peinado, H.; Kassen, D.; Hussenet, T.; Metzger, D.; Chambon, P.; Huber, M.; Hohl, D.; Cano, A.; Birchmeier, W.; et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 2008, 452, 650–653. [Google Scholar] [CrossRef]
  81. Jang, G.B.; Kim, J.Y.; Cho, S.D.; Park, K.S.; Jung, J.Y.; Lee, H.Y.; Hong, I.S.; Nam, J.S. Blockade of Wnt/beta-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci. Rep. 2015, 5, 12465. [Google Scholar] [CrossRef]
  82. Chau, W.K.; Ip, C.K.; Mak, A.S.; Lai, H.C.; Wong, A.S. c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/beta-catenin-ATP-binding cassette G2 signaling. Oncogene 2013, 32, 2767–2781. [Google Scholar] [CrossRef] [PubMed]
  83. Duan, L.; Ye, L.; Wu, R.; Wang, H.; Li, X.; Li, H.; Yuan, S.; Zha, H.; Sun, H.; Zhang, Y.; et al. Inactivation of the phosphatidylinositol 3-kinase/Akt pathway is involved in BMP9-mediated tumor-suppressive effects in gastric cancer cells. J. Cell. Biochem. 2015, 116, 1080–1089. [Google Scholar] [CrossRef] [PubMed]
  84. Yuzugullu, H.; Baitsch, L.; Von, T.; Steiner, A.; Tong, H.; Ni, J.; Clayton, L.K.; Bronson, R.; Roberts, T.M.; Gritsman, K.; et al. A PI3K p110beta-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat. Commun. 2015, 6, 8501. [Google Scholar] [CrossRef] [PubMed]
  85. Bahena-Ocampo, I.; Espinosa, M.; Ceballos-Cancino, G.; Lizarraga, F.; Campos-Arroyo, D.; Schwarz, A.; Garcia-Lopez, P.; Maldonado, V.; Melendez-Zajgla, J. MiR-10b expression in breast cancer stem cells supports self-renewal through negative PTEN regulation and sustained AKT activation. EMBO Rep. 2016, 17, 1081. [Google Scholar] [CrossRef] [PubMed]
  86. Takebe, N.; Miele, L.; Harris, P.J.; Jeong, W.; Bando, H.; Kahn, M.; Yang, S.X.; Ivy, S.P. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: Clinical update. Nat. Rev. Clin. Oncol. 2015, 12, 445–464. [Google Scholar] [CrossRef] [PubMed]
  87. Bhola, N.E.; Jansen, V.M.; Koch, J.P.; Li, H.; Formisano, L.; Williams, J.A.; Grandis, J.R.; Arteaga, C.L. Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population. Cancer Res. 2016, 76, 440–452. [Google Scholar] [CrossRef]
  88. Hayden, M.S.; Ghosh, S. Shared principles in NF-kappaB signaling. Cell 2008, 132, 344–362. [Google Scholar] [CrossRef]
  89. Prasad, S.; Ravindran, J.; Aggarwal, B.B. NF-kappaB and cancer: How intimate is this relationship. Mol. Cell. Biochem. 2010, 336, 25–37. [Google Scholar] [CrossRef]
  90. Stein, S.J.; Baldwin, A.S. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood 2013, 121, 5015–5024. [Google Scholar] [CrossRef]
  91. Zhao, C.; Xiu, Y.; Ashton, J.; Xing, L.; Morita, Y.; Jordan, C.T.; Boyce, B.F. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 2012, 30, 709–718. [Google Scholar] [CrossRef]
  92. Chen, C.; Cao, F.; Bai, L.; Liu, Y.; Xie, J.; Wang, W.; Si, Q.; Yang, J.; Chang, A.; Liu, D.; et al. IKKbeta Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis. Cancer Res. 2015, 75, 1725–1735. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, M.; Sakamaki, T.; Casimiro, M.C.; Willmarth, N.E.; Quong, A.A.; Ju, X.; Ojeifo, J.; Jiao, X.; Yeow, W.S.; Katiyar, S.; et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010, 70, 10464–10473. [Google Scholar] [CrossRef] [PubMed]
  94. Von Hoff, D.D.; LoRusso, P.M.; Rudin, C.M.; Reddy, J.C.; Yauch, R.L.; Tibes, R.; Weiss, G.J.; Borad, M.J.; Hann, C.L.; Brahmer, J.R.; et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 2009, 361, 1164–1172. [Google Scholar] [CrossRef] [PubMed]
  95. Yoon, C.; Park, D.J.; Schmidt, B.; Thomas, N.J.; Lee, H.J.; Kim, T.S.; Janjigian, Y.Y.; Cohen, D.J.; Yoon, S.S. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin. Cancer Res. 2014, 20, 3974–3988. [Google Scholar] [CrossRef] [PubMed]
  96. Sekulic, A.; Migden, M.R.; Oro, A.E.; Dirix, L.; Lewis, K.D.; Hainsworth, J.D.; Solomon, J.A.; Yoo, S.; Arron, S.T.; Friedlander, P.A.; et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 2012, 366, 2171–2179. [Google Scholar] [CrossRef] [PubMed]
  97. Sloan, A.E.; Nock, C.J.; Ye, X.; Kerstetter, A.; Supko, J.; Lamborn, K.; Rich, J.N.; Miller, R.; Takebe, N.; Prados, M.; et al. Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway. J. Clin. Oncol. 2014, 32 (Suppl. S15), 2026. [Google Scholar] [CrossRef]
  98. Li, Y.; Rogoff, H.A.; Keates, S.; Gao, Y.; Murikipudi, S.; Mikule, K.; Leggett, D.; Li, W.; Pardee, A.B.; Li, C.J. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc. Natl. Acad. Sci. USA 2015, 112, 1839–1844. [Google Scholar] [CrossRef] [Green Version]
  99. Zhang, Y.; Jin, Z.; Zhou, H.; Ou, X.; Xu, Y.; Li, H.; Liu, C.; Li, B. Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin. Cancer Med. 2016, 5, 1251–1258. [Google Scholar] [CrossRef] [Green Version]
  100. Shah, M.A.; Muro, K.; Shitara, K.; Tebbutt, N.C.; Bang, Y.-J.; Lordick, F.; Borodyansky, L.; Li, C. The BRIGHTER trial: A phase III randomized double-blind study of BBI608 + weekly paclitaxel versus placebo (PBO) + weekly paclitaxel in patients (pts) with pretreated advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma. J. Clin. Oncol. 2015, 33 (Suppl. S15), TPS4139. [Google Scholar] [CrossRef]
  101. Sonbol, M.B.; Bekaii-Saab, T. A clinical trial protocol paper discussing the BRIGHTER study. Future Oncol. 2018, 14, 901–906. [Google Scholar] [CrossRef]
  102. Jonker, D.J.; Nott, L.; Yoshino, T.; Gill, S.; Shapiro, J.; Ohtsu, A.; Zalcberg, J.; Vickers, M.M.; Wei, A.; Gao, Y.; et al. A randomized phase III study of napabucasin [BBI608] (NAPA) vs. placebo (PBO) in patients (pts) with pretreated advanced colorectal cancer (ACRC): The CCTG/AGITG CO.23 trial. Ann. Oncol. 2016, 27 (Suppl. S6). [Google Scholar] [CrossRef]
  103. Takaishi, S.; Okumura, T.; Tu, S.; Wang, S.S.; Shibata, W.; Vigneshwaran, R.; Gordon, S.A.; Shimada, Y.; Wang, T.C. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009, 27, 1006–1020. [Google Scholar] [CrossRef] [PubMed]
  104. Li, C.; Heidt, D.G.; Dalerba, P.; Burant, C.F.; Zhang, L.; Adsay, V.; Wicha, M.; Clarke, M.F.; Simeone, D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67, 1030–1037. [Google Scholar] [CrossRef] [PubMed]
  105. Prince, M.E.; Sivanandan, R.; Kaczorowski, A.; Wolf, G.T.; Kaplan, M.J.; Dalerba, P.; Weissman, I.L.; Clarke, M.F.; Ailles, L.E. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 2007, 104, 973–978. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Alvero, A.B.; Chen, R.; Fu, H.H.; Montagna, M.; Schwartz, P.E.; Rutherford, T.; Silasi, D.A.; Steffensen, K.D.; Waldstrom, M.; Visintin, I.; et al. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 2009, 8, 158–166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Nguyen, P.H.; Giraud, J.; Staedel, C.; Chambonnier, L.; Dubus, P.; Chevret, E.; Boeuf, H.; Gauthereau, X.; Rousseau, B.; Fevre, M.; et al. All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene 2016, 35, 5619–5628. [Google Scholar] [CrossRef] [PubMed]
  108. Chen, P.; Huang, H.F.; Lu, R.; Wu, Y.; Chen, Y.Z. Prognostic significance of CD44v6/v7 in acute promyelocytic leukemia. Asian Pac. J. Cancer Prev. 2012, 13, 3791–3794. [Google Scholar] [CrossRef] [PubMed]
  109. Bao, B.; Ali, S.; Ahmad, A.; Li, Y.; Banerjee, S.; Kong, D.; Aboukameel, A.; Mohammad, R.; Van Buren, E.; Azmi, A.S.; et al. Differentially expressed miRNAs in cancer-stem-like cells: Markers for tumor cell aggressiveness of pancreatic cancer. Stem Cells Dev. 2014, 23, 1947–1958. [Google Scholar] [CrossRef]
  110. Vermeulen, L.; Todaro, M.; de Sousa Mello, F.; Sprick, M.R.; Kemper, K.; Perez Alea, M.; Richel, D.J.; Stassi, G.; Medema, J.P. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl. Acad. Sci. USA 2008, 105, 13427–13432. [Google Scholar] [CrossRef] [Green Version]
  111. Yang, C.H.; Wang, H.L.; Lin, Y.S.; Kumar, K.P.; Lin, H.C.; Chang, C.J.; Lu, C.C.; Huang, T.T.; Martel, J.; Ojcius, D.M.; et al. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. PLoS ONE 2014, 9, e99412. [Google Scholar] [CrossRef]
  112. Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983–3988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Yu, L.; Liu, S.; Guo, W.; Zhang, B.; Liang, Y.; Feng, Q. Upregulation of Mad2 facilitates in vivo and in vitro osteosarcoma progression. Oncol. Rep. 2012, 28, 2170–2176. [Google Scholar] [CrossRef] [PubMed]
  114. Miettinen, M.; Lasota, J. KIT (CD117): A review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl. Immunohistochem. Mol. Morphol. 2005, 13, 205–220. [Google Scholar] [CrossRef]
  115. Luo, L.; Zeng, J.; Liang, B.; Zhao, Z.; Sun, L.; Cao, D.; Yang, J.; Shen, K. Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome. Exp. Mol. Pathol. 2011, 91, 596–602. [Google Scholar] [CrossRef] [PubMed]
  116. Chiou, S.H.; Yu, C.C.; Huang, C.Y.; Lin, S.C.; Liu, C.J.; Tsai, T.H.; Chou, S.H.; Chien, C.S.; Ku, H.H.; Lo, J.F. Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin. Cancer Res. 2008, 14, 4085–4095. [Google Scholar] [CrossRef] [PubMed]
  117. Baba, T.; Convery, P.A.; Matsumura, N.; Whitaker, R.S.; Kondoh, E.; Perry, T.; Huang, Z.; Bentley, R.C.; Mori, S.; Fujii, S.; et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 2009, 28, 209–218. [Google Scholar] [CrossRef] [PubMed]
  118. Curley, M.D.; Therrien, V.A.; Cummings, C.L.; Sergent, P.A.; Koulouris, C.R.; Friel, A.M.; Roberts, D.J.; Seiden, M.V.; Scadden, D.T.; Rueda, B.R.; et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells 2009, 27, 2875–2883. [Google Scholar] [CrossRef] [PubMed]
  119. Vander Griend, D.J.; Karthaus, W.L.; Dalrymple, S.; Meeker, A.; DeMarzo, A.M.; Isaacs, J.T. The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 2008, 68, 9703–9711. [Google Scholar] [CrossRef] [PubMed]
  120. Jiang, Y.; He, Y.; Li, H.; Li, H.N.; Zhang, L.; Hu, W.; Sun, Y.M.; Chen, F.L.; Jin, X.M. Expressions of putative cancer stem cell markers ABCB1, ABCG2, and CD133 are correlated with the degree of differentiation of gastric cancer. Gastric Cancer 2012, 15, 440–450. [Google Scholar] [CrossRef]
  121. Hashimoto, K.; Aoyagi, K.; Isobe, T.; Kouhuji, K.; Shirouzu, K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2014, 17, 97–106. [Google Scholar] [CrossRef]
  122. Chen, X.L.; Chen, X.Z.; Wang, Y.G.; He, D.; Lu, Z.H.; Liu, K.; Zhang, W.H.; Wang, W.; Li, C.C.; Xue, L.; et al. Clinical significance of putative markers of cancer stem cells in gastric cancer: A retrospective cohort study. Oncotarget 2016, 7, 62049–62069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Nguyen, P.H.; Giraud, J.; Chambonnier, L.; Dubus, P.; Wittkop, L.; Belleannee, G.; Collet, D.; Soubeyran, I.; Evrard, S.; Rousseau, B.; et al. Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma. Clin. Cancer Res. 2017, 23, 1586–1597. [Google Scholar] [CrossRef] [PubMed]
  124. Chiou, S.H.; Kao, C.L.; Chen, Y.W.; Chien, C.S.; Hung, S.C.; Lo, J.F.; Chen, Y.J.; Ku, H.H.; Hsu, M.T.; Wong, T.T. Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor. PLoS ONE 2008, 3, e2090. [Google Scholar] [CrossRef] [PubMed]
  125. Velpula, K.K.; Dasari, V.R.; Tsung, A.J.; Dinh, D.H.; Rao, J.S. Cord blood stem cells revert glioma stem cell EMT by down regulating transcriptional activation of Sox2 and Twist1. Oncotarget 2011, 2, 1028–1042. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Gao, M.Q.; Choi, Y.P.; Kang, S.; Youn, J.H.; Cho, N.H. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene 2010, 29, 2672–2680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Katsuno, Y.; Ehata, S.; Yashiro, M.; Yanagihara, K.; Hirakawa, K.; Miyazono, K. Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-beta. J. Pathol. 2012, 228, 391–404. [Google Scholar] [CrossRef] [PubMed]
  128. Deng, Y.; Zhou, J.; Fang, L.; Cai, Y.; Ke, J.; Xie, X.; Huang, Y.; Huang, M.; Wang, J. ALDH1 is an independent prognostic factor for patients with stages II-III rectal cancer after receiving radiochemotherapy. Br. J. Cancer 2014, 110, 430–434. [Google Scholar] [CrossRef] [PubMed]
  129. Silva, I.A.; Bai, S.; McLean, K.; Yang, K.; Griffith, K.; Thomas, D.; Ginestier, C.; Johnston, C.; Kueck, A.; Reynolds, R.K.; et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011, 71, 3991–4001. [Google Scholar] [CrossRef]
  130. Satar, N.A.; Fakiruddin, K.S.; Lim, M.N.; Mok, P.L.; Zakaria, N.; Fakharuzi, N.A.; Abd Rahman, A.Z.; Zakaria, Z.; Yahaya, B.H.; Baharuddin, P. Novel triplepositive markers identified in human nonsmall cell lung cancer cell line with chemotherapy-resistant and putative cancer stem cell characteristics. Oncol. Rep. 2018, 40, 669–681. [Google Scholar]
  131. Cherciu, I.; Barbalan, A.; Pirici, D.; Margaritescu, C.; Saftoiu, A. Stem cells, colorectal cancer and cancer stem cell markers correlations. Curr. Health Sci. J. 2014, 40, 153–161. [Google Scholar]
  132. Fujita, T.; Chiwaki, F.; Takahashi, R.U.; Aoyagi, K.; Yanagihara, K.; Nishimura, T.; Tamaoki, M.; Komatsu, M.; Komatsuzaki, R.; Matsusaki, K.; et al. Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells. PLoS ONE 2015, 10, e0130808. [Google Scholar] [CrossRef] [PubMed]
  133. Sun, L.Y.; Hsieh, D.K.; Syu, W.S.; Li, Y.S.; Chiu, H.T.; Chiou, T.W. Cell proliferation of human bone marrow mesenchymal stem cells on biodegradable microcarriers enhances in vitro differentiation potential. Cell Prolif. 2010, 43, 445–456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Yasumoto, K.; Koizumi, K.; Kawashima, A.; Saitoh, Y.; Arita, Y.; Shinohara, K.; Minami, T.; Nakayama, T.; Sakurai, H.; Takahashi, Y.; et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 2006, 66, 2181–2187. [Google Scholar] [CrossRef] [PubMed]
  135. Taichman, R.S.; Cooper, C.; Keller, E.T.; Pienta, K.J.; Taichman, N.S.; McCauley, L.K. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002, 62, 1832–1837. [Google Scholar] [PubMed]
  136. Jager, M.; Schoberth, A.; Ruf, P.; Hess, J.; Hennig, M.; Schmalfeldt, B.; Wimberger, P.; Strohlein, M.; Theissen, B.; Heiss, M.M.; et al. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Res. 2012, 72, 24–32. [Google Scholar] [CrossRef] [PubMed]
  137. Meirelles, K.; Benedict, L.A.; Dombkowski, D.; Pepin, D.; Preffer, F.I.; Teixeira, J.; Tanwar, P.S.; Young, R.H.; MacLaughlin, D.T.; Donahoe, P.K.; et al. Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proc. Natl. Acad. Sci. USA 2012, 109, 2358–2363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Bussolati, B.; Bruno, S.; Grange, C.; Ferrando, U.; Camussi, G. Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J. 2008, 22, 3696–3705. [Google Scholar] [CrossRef]
  139. Hu, D.; Wang, X.; Mao, Y.; Zhou, L. Identification of CD105 (endoglin)-positive stem-like cells in rhabdoid meningioma. J. Neurooncol. 2012, 106, 505–517. [Google Scholar] [CrossRef]
  140. Ziebarth, A.J.; Nowsheen, S.; Steg, A.D.; Shah, M.M.; Katre, A.A.; Dobbin, Z.C.; Han, H.D.; Lopez-Berestein, G.; Sood, A.K.; Conner, M.; et al. Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer. Clin. Cancer Res. 2013, 19, 170–182. [Google Scholar] [CrossRef]
  141. Zhang, X.F.; Weng, D.S.; Pan, K.; Zhou, Z.Q.; Pan, Q.Z.; Zhao, J.J.; Tang, Y.; Jiang, S.S.; Chen, C.L.; Li, Y.Q.; et al. Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells. Mol. Carcinog. 2017, 56, 2499–2511. [Google Scholar] [CrossRef]
  142. Chen, T.; Yang, K.; Yu, J.; Meng, W.; Yuan, D.; Bi, F.; Liu, F.; Liu, J.; Dai, B.; Chen, X.; et al. Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients. Cell Res. 2012, 22, 248–258. [Google Scholar] [CrossRef] [PubMed]
  143. Fan, C.W.; Chen, T.; Shang, Y.N.; Gu, Y.Z.; Zhang, S.L.; Lu, R.; OuYang, S.R.; Zhou, X.; Li, Y.; Meng, W.T.; et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis. 2013, 4, e828. [Google Scholar] [CrossRef] [PubMed]
  144. Ohkuma, M.; Haraguchi, N.; Ishii, H.; Mimori, K.; Tanaka, F.; Kim, H.M.; Shimomura, M.; Hirose, H.; Yanaga, K.; Mori, M. Absence of CD71 transferrin receptor characterizes human gastric adenosquamous carcinoma stem cells. Ann. Surg. Oncol. 2012, 19, 1357–1364. [Google Scholar] [CrossRef] [PubMed]
  145. Gong, X.; Azhdarinia, A.; Ghosh, S.C.; Xiong, W.; An, Z.; Liu, Q.; Carmon, K.S. LGR5-Targeted Antibody-Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence. Mol. Cancer Ther. 2016, 15, 1580–1590. [Google Scholar] [CrossRef] [PubMed]
  146. Zheng, Z.X.; Sun, Y.; Bu, Z.D.; Zhang, L.H.; Li, Z.Y.; Wu, A.W.; Wu, X.J.; Wang, X.H.; Cheng, X.J.; Xing, X.F.; et al. Intestinal stem cell marker LGR5 expression during gastric carcinogenesis. World J. Gastroenterol. 2013, 19, 8714–8721. [Google Scholar] [CrossRef] [PubMed]
  147. Yang, D.R.; Ding, X.F.; Luo, J.; Shan, Y.X.; Wang, R.; Lin, S.J.; Li, G.; Huang, C.K.; Zhu, J.; Chen, Y.; et al. Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer. J. Biol. Chem. 2013, 288, 16476–16483. [Google Scholar] [CrossRef] [PubMed]
  148. Chen, Z.; Xu, W.R.; Qian, H.; Zhu, W.; Bu, X.F.; Wang, S.; Yan, Y.M.; Mao, F.; Gu, H.B.; Cao, H.L.; et al. Oct4, a novel marker for human gastric cancer. J. Surg. Oncol. 2009, 99, 414–419. [Google Scholar] [CrossRef] [PubMed]
  149. Kobayashi, Y.; Seino, K.; Hosonuma, S.; Ohara, T.; Itamochi, H.; Isonishi, S.; Kita, T.; Wada, H.; Kojo, S.; Kiguchi, K. Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin. Gynecol. Oncol. 2011, 121, 390–394. [Google Scholar] [CrossRef]
  150. Naor, D.; Wallach-Dayan, S.B.; Zahalka, M.A.; Sionov, R.V. Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin. Cancer Biol. 2008, 18, 260–267. [Google Scholar] [CrossRef]
  151. Ponta, H.; Sherman, L.; Herrlich, P.A. CD44: From adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 2003, 4, 33–45. [Google Scholar] [CrossRef]
  152. Mielgo, A.; van Driel, M.; Bloem, A.; Landmann, L.; Gunthert, U. A novel antiapoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms. Cell Death Differ. 2006, 13, 465–477. [Google Scholar] [CrossRef] [PubMed]
  153. Louderbough, J.M.; Schroeder, J.A. Understanding the dual nature of CD44 in breast cancer progression. Mol. Cancer Res. 2011, 9, 1573–1586. [Google Scholar] [CrossRef] [PubMed]
  154. Yun, E.J.; Zhou, J.; Lin, C.J.; Hernandez, E.; Fazli, L.; Gleave, M.; Hsieh, J.T. Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer. Clin. Cancer Res. 2016, 22, 670–679. [Google Scholar] [CrossRef] [PubMed]
  155. Chu, P.; Clanton, D.J.; Snipas, T.S.; Lee, J.; Mitchell, E.; Nguyen, M.L.; Hare, E.; Peach, R.J. Characterization of a subpopulation of colon cancer cells with stem cell-like properties. Int. J. Cancer 2009, 124, 1312–1321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Chen, D.; Wu, M.; Li, Y.; Chang, I.; Yuan, Q.; Ekimyan-Salvo, M.; Deng, P.; Yu, B.; Yu, Y.; Dong, J.; et al. Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell 2017, 20, 621–634 e626. [Google Scholar] [CrossRef] [PubMed]
  157. Bonneau, C.; Rouzier, R.; Geyl, C.; Cortez, A.; Castela, M.; Lis, R.; Darai, E.; Touboul, C. Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma. Gynecol. Oncol. 2015, 136, 112–120. [Google Scholar] [CrossRef] [PubMed]
  158. Gao, Y.; Foster, R.; Yang, X.; Feng, Y.; Shen, J.K.; Mankin, H.J.; Hornicek, F.J.; Amiji, M.M.; Duan, Z. Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer. Oncotarget 2015, 6, 9313–9326. [Google Scholar] [CrossRef] [Green Version]
  159. Todaro, M.; Gaggianesi, M.; Catalano, V.; Benfante, A.; Iovino, F.; Biffoni, M.; Apuzzo, T.; Sperduti, I.; Volpe, S.; Cocorullo, G.; et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 2014, 14, 342–356. [Google Scholar] [CrossRef]
  160. Alberts, D.S.; Liu, P.Y.; Wilczynski, S.P.; Jang, A.; Moon, J.; Ward, J.H.; Beck, J.T.; Clouser, M.; Markman, M. Phase, I.I. Trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211). Int. J. Gynecol. Cancer 2007, 17, 784–788. [Google Scholar] [CrossRef] [PubMed]
  161. Neuzil, J.; Stantic, M.; Zobalova, R.; Chladova, J.; Wang, X.; Prochazka, L.; Dong, L.; Andera, L.; Ralph, S.J. Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: What’s in the name? Biochem. Biophys. Res. Commun. 2007, 355, 855–859. [Google Scholar] [CrossRef]
  162. Zhang, J.; Guo, X.; Chang, D.Y.; Rosen, D.G.; Mercado-Uribe, I.; Liu, J. CD133 expression associated with poor prognosis in ovarian cancer. Mod. Pathol. 2012, 25, 456–464. [Google Scholar] [CrossRef] [PubMed]
  163. Hueng, D.Y.; Sytwu, H.K.; Huang, S.M.; Chang, C.; Ma, H.I. Isolation and characterization of tumor stem-like cells from human meningiomas. J. Neurooncol. 2011, 104, 45–53. [Google Scholar] [CrossRef] [PubMed]
  164. Mehra, N.; Penning, M.; Maas, J.; Beerepoot, L.V.; van Daal, N.; van Gils, C.H.; Giles, R.H.; Voest, E.E. Progenitor marker CD133 mRNA is elevated in peripheral blood of cancer patients with bone metastases. Clin. Cancer Res. 2006, 12, 4859–4866. [Google Scholar] [CrossRef] [PubMed]
  165. Huang, J.; Li, C.; Wang, Y.; Lv, H.; Guo, Y.; Dai, H.; Wicha, M.S.; Chang, A.E.; Li, Q. Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clin. Immunol. 2013, 149, 156–168. [Google Scholar] [CrossRef]
  166. Chen, W.; Li, F.; Xue, Z.M.; Wu, H.R. Anti-human CD133 monoclonal antibody that could inhibit the proliferation of colorectal cancer cells. Hybridoma 2010, 29, 305–310. [Google Scholar] [CrossRef] [PubMed]
  167. Sato-Dahlman, M.; Miura, Y.; Huang, J.L.; Hajeri, P.; Jacobsen, K.; Davydova, J.; Yamamoto, M. CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer. Oncotarget 2017, 8, 76044–76056. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Kim, J.S.; Shin, D.H.; Kim, J.S. Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells. J. Control. Release 2018, 269, 245–257. [Google Scholar] [CrossRef]
  169. Burgos-Ojeda, D.; Wu, R.; McLean, K.; Chen, Y.C.; Talpaz, M.; Yoon, E.; Cho, K.R.; Buckanovich, R.J. CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis. Mol. Cancer Ther. 2015, 14, 1717–1727. [Google Scholar] [CrossRef] [Green Version]
  170. Gunjal, P.; Pedziwiatr, D.; Ismail, A.A.; Kakar, S.S.; Ratajczak, M.Z. An emerging question about putative cancer stem cells in established cell lines-are they true stem cells or a fluctuating cell phenotype? J. Cancer Stem Cell Res. 2015, 3. [Google Scholar] [CrossRef]
  171. Zhu, J.; Zhang, G.; Lu, H. CD24, COX-2, and p53 in epithelial ovarian cancer and its clinical significance. Front. Biosci. 2012, 4, 2645–2651. [Google Scholar] [CrossRef]
  172. Meng, E.; Long, B.; Sullivan, P.; McClellan, S.; Finan, M.A.; Reed, E.; Shevde, L.; Rocconi, R.P. CD44+/CD24− ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clin. Exp. Metastasis 2012, 29, 939–948. [Google Scholar] [CrossRef] [PubMed]
  173. Sun, F.; Wang, T.; Jiang, J.; Wang, Y.; Ma, Z.; Li, Z.; Han, Y.; Pan, M.; Cai, J.; Wang, M.; et al. Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. Oncotarget 2017, 8, 51238–51252. [Google Scholar] [CrossRef] [PubMed]
  174. Marcato, P.; Dean, C.A.; Giacomantonio, C.A.; Lee, P.W. Aldehyde dehydrogenase: Its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle 2011, 10, 1378–1384. [Google Scholar] [CrossRef] [PubMed]
  175. Liu, S.; Liu, C.; Min, X.; Ji, Y.; Wang, N.; Liu, D.; Cai, J.; Li, K. Prognostic value of cancer stem cell marker aldehyde dehydrogenase in ovarian cancer: A meta-analysis. PLoS ONE 2013, 8, e81050. [Google Scholar] [CrossRef] [PubMed]
  176. Landen, C.N., Jr.; Goodman, B.; Katre, A.A.; Steg, A.D.; Nick, A.M.; Stone, R.L.; Miller, L.D.; Mejia, P.V.; Jennings, N.B.; Gershenson, D.M.; et al. Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol. Cancer Ther. 2010, 9, 3186–3199. [Google Scholar] [CrossRef] [PubMed]
  177. Munz, M.; Baeuerle, P.A.; Gires, O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009, 69, 5627–5629. [Google Scholar] [CrossRef] [PubMed]
  178. Bellone, S.; Siegel, E.R.; Cocco, E.; Cargnelutti, M.; Silasi, D.A.; Azodi, M.; Schwartz, P.E.; Rutherford, T.J.; Pecorelli, S.; Santin, A.D. Overexpression of epithelial cell adhesion molecule in primary, metastatic, and recurrent/chemotherapy-resistant epithelial ovarian cancer: Implications for epithelial cell adhesion molecule-specific immunotherapy. Int. J. Gynecol. Cancer 2009, 19, 860–866. [Google Scholar] [CrossRef]
  179. Deng, J.; Wang, L.; Chen, H.; Hao, J.; Ni, J.; Chang, L.; Duan, W.; Graham, P.; Li, Y. Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer. Oncotarget 2016, 7, 55771–55788. [Google Scholar] [CrossRef] [Green Version]
  180. Liao, M.Y.; Lai, J.K.; Kuo, M.Y.; Lu, R.M.; Lin, C.W.; Cheng, P.C.; Liang, K.H.; Wu, H.C. An anti-EpCAM antibody EpAb2-6 for the treatment of colon cancer. Oncotarget 2015, 6, 24947–24968. [Google Scholar] [CrossRef] [Green Version]
  181. Schlaak, M.; Schmidt, P.; Bangard, C.; Kurschat, P.; Mauch, C.; Abken, H. Regression of metastatic melanoma in a patient by antibody targeting of cancer stem cells. Oncotarget 2012, 3, 22–30. [Google Scholar] [CrossRef]
  182. Corro, C.; Moch, H. Biomarker discovery for renal cancer stem cells. J. Pathol. Clin. Res. 2018, 4, 3–18. [Google Scholar] [CrossRef] [Green Version]
  183. Cheng, B.; Yang, G.; Jiang, R.; Cheng, Y.; Yang, H.; Pei, L.; Qiu, X. Cancer stem cell markers predict a poor prognosis in renal cell carcinoma: A meta-analysis. Oncotarget 2016, 7, 65862–65875. [Google Scholar] [CrossRef]
  184. Choueiri, T.K.; Michaelson, M.D.; Posadas, E.M.; Sonpavde, G.P.; McDermott, D.F.; Nixon, A.B.; Liu, Y.; Yuan, Z.; Seon, B.K.; Walsh, M.; et al. An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma. Oncologist 2018. [Google Scholar] [CrossRef] [PubMed]
  185. Duffy, A.G.; Ma, C.; Ulahannan, S.V.; Rahma, O.E.; Makarova-Rusher, O.; Cao, L.; Yu, Y.; Kleiner, D.E.; Trepel, J.; Lee, M.J.; et al. Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma. Clin. Cancer Res. 2017, 23, 4633–4641. [Google Scholar] [CrossRef]
  186. Karzai, F.H.; Apolo, A.B.; Cao, L.; Madan, R.A.; Adelberg, D.E.; Parnes, H.; McLeod, D.G.; Harold, N.; Peer, C.; Yu, Y.; et al. A phase I. study of TRC105 anti-endoglin (CD105) antibody in metastatic castration-resistant prostate cancer. BJU Int. 2015, 116, 546–555. [Google Scholar] [CrossRef]
  187. Apolo, A.B.; Karzai, F.H.; Trepel, J.B.; Alarcon, S.; Lee, S.; Lee, M.J.; Tomita, Y.; Cao, L.; Yu, Y.; Merino, M.J.; et al. A Phase, II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma. Clin. Genitourin. Cancer 2017, 15, 77–85. [Google Scholar] [CrossRef]
  188. Gordon, M.S.; Robert, F.; Matei, D.; Mendelson, D.S.; Goldman, J.W.; Chiorean, E.G.; Strother, R.M.; Seon, B.K.; Figg, W.D.; Peer, C.J.; et al. An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin. Cancer Res. 2014, 20, 5918–5926. [Google Scholar] [CrossRef] [PubMed]
  189. Verneuil, L.; Varna, M.; Ratajczak, P.; Leboeuf, C.; Plassa, L.F.; Elbouchtaoui, M.; Schneider, P.; Sandid, W.; Lebbe, C.; Peraldi, M.N.; et al. Human skin carcinoma arising from kidney transplant-derived tumor cells. J. Clin. Investig. 2013, 123, 3797–3801. [Google Scholar] [CrossRef]
  190. Verneuil, L.; Varna, M.; Leboeuf, C.; Plassa, L.F.; Elbouchtaoui, M.; Loisel-Ferreira, I.; Bouhidel, F.; Peraldi, M.N.; Lebbe, C.; Ratajczak, P.; et al. Donor-derived keratinocytes in actinic keratosis and squamous cell carcinoma in patients with kidney transplant. J. Investig. Dermatol. 2013, 133, 1108–1111. [Google Scholar] [CrossRef] [PubMed]
  191. Torchilin, V. Nanotechnology in Drugs; Imperial College Press: London, UK, 2008. [Google Scholar]
  192. Wilczewska, A.Z.; Niemirowicz, K.; Markiewicz, K.H.; Car, H. Nanoparticles as drug delivery systems. Pharmacol. Rep. 2012, 64, 1020–1037. [Google Scholar] [CrossRef]
  193. James, N.D.; Coker, R.J.; Tomlinson, D.; Harris, J.R.; Gompels, M.; Pinching, A.J.; Stewart, J.S. Liposomal doxorubicin (Doxil): An effective new treatment for Kaposi’s sarcoma in AIDS. Clin. Oncol. 1994, 6, 294–296. [Google Scholar] [CrossRef]
  194. Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev. 2013, 65, 36–48. [Google Scholar] [CrossRef] [PubMed]
  195. Gradishar, W.J.; Tjulandin, S.; Davidson, N.; Shaw, H.; Desai, N.; Bhar, P.; Hawkins, M.; O’Shaughnessy, J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol. 2005, 23, 7794–7803. [Google Scholar] [CrossRef] [PubMed]
  196. Sun, T.; Zhang, Y.S.; Pang, B.; Hyun, D.C.; Yang, M.; Xia, Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem. Int. Ed. Engl. 2014, 53, 12320–12364. [Google Scholar] [CrossRef] [PubMed]
  197. Deamer, D.W. From “banghasomes” to liposomes: A memoir of Alec Bangham, 1921–2010. FASEB J. 2010, 24, 1308–1310. [Google Scholar] [CrossRef]
  198. Batzri, S.; Korn, E.D. Single bilayer liposomes prepared without sonication. Biochim. Biophys. Acta 1973, 298, 1015–1019. [Google Scholar] [CrossRef]
  199. Gregoriadis, G.; Ryman, B.E. Liposomes as carriers of enzymes or drugs: A new approach to the treatment of storage diseases. Biochem. J. 1971, 124, 58. [Google Scholar] [CrossRef]
  200. Kumari, A.; Yadav, S.K.; Yadav, S.C. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf. B Biointerfaces 2010, 75, 1–18. [Google Scholar] [CrossRef]
  201. Martins, L.G.; Khalil, N.M.; Mainardes, R.M. PLGA Nanoparticles and Polysorbate-80-Coated PLGA Nanoparticles Increase the In vitro Antioxidant Activity of Melatonin. Curr. Drug Deliv. 2018, 15, 554–563. [Google Scholar] [CrossRef]
  202. Veronese, F.M.; Pasut, G. PEGylation, successful approach to drug delivery. Drug Discov. Today 2005, 10, 1451–1458. [Google Scholar] [CrossRef]
  203. Thierry, A.R.; Rahman, A.; Dritschilo, A. A new procedure for the preparation of liposomal doxorubicin: Biological activity in multidrug-resistant tumor cells. Cancer Chemother. Pharmacol. 1994, 35, 84–88. [Google Scholar] [CrossRef] [PubMed]
  204. Blank, N.; Laskov, I.; Kessous, R.; Kogan, L.; Lau, S.; Sebag, I.A.; Gotlieb, W.H.; Rudski, L. Absence of cardiotoxicity with prolonged treatment and large accumulating doses of pegylated liposomal doxorubicin. Cancer Chemother. Pharmacol. 2017, 80, 737–743. [Google Scholar] [CrossRef] [PubMed]
  205. Lopes de Menezes, D.E.; Pilarski, L.M.; Allen, T.M. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res. 1998, 58, 3320–3330. [Google Scholar] [PubMed]
  206. Park, J.W.; Hong, K.; Kirpotin, D.B.; Colbern, G.; Shalaby, R.; Baselga, J.; Shao, Y.; Nielsen, U.B.; Marks, J.D.; Moore, D.; et al. Anti-HER2 immunoliposomes: Enhanced efficacy attributable to targeted delivery. Clin. Cancer Res. 2002, 8, 1172–1181. [Google Scholar] [PubMed]
  207. El-Sayed, I.H.; Huang, X.; El-Sayed, M.A. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett. 2006, 239, 129–135. [Google Scholar] [CrossRef]
  208. Kao, H.W.; Lin, Y.Y.; Chen, C.C.; Chi, K.H.; Tien, D.C.; Hsia, C.C.; Lin, W.J.; Chen, F.D.; Lin, M.H.; Wang, H.E. Biological characterization of cetuximab-conjugated gold nanoparticles in a tumor animal model. Nanotechnology 2014, 25, 295102. [Google Scholar] [CrossRef] [PubMed]
  209. Zhang, M.; Kim, H.S.; Jin, T.; Moon, W.K. Near-infrared photothermal therapy using EGFR-targeted gold nanoparticles increases autophagic cell death in breast cancer. J. Photochem. Photobiol. B 2017, 170, 58–64. [Google Scholar] [CrossRef]
  210. Pereira, I.; Sousa, F.; Kennedy, P.; Sarmento, B. Carcinoembryonic antigen-targeted nanoparticles potentiate the delivery of anticancer drugs to colorectal cancer cells. Int. J. Pharm. 2018, 549, 397–403. [Google Scholar] [CrossRef]
  211. Hammarstrom, S. The carcinoembryonic antigen (CEA) family: Structures, suggested functions and expression in normal and malignant tissues. Semin. Cancer Biol. 1999, 9, 67–81. [Google Scholar] [CrossRef]
  212. Bhatti, I.; Patel, M.; Dennison, A.R.; Thomas, M.W.; Garcea, G. Utility of postoperative CEA for surveillance of recurrence after resection of primary colorectal cancer. Int. J. Surg. 2015, 16, 123–128. [Google Scholar] [CrossRef]
  213. Varna, M.; Ratajczak, P.; Ferreira, I.; Leboeuf, C.; Bousquet, G.; Janin, A. In vivo Distribution of Inorganic Nanoparticles in Preclinical Models. J. Biomater. Nanobiotechnol. 2012, 3, 269–279. [Google Scholar] [CrossRef]
  214. Pannerec-Varna, M.; Ratajczak, P.; Bousquet, G.; Ferreira, I.; Leboeuf, C.; Boisgard, R.; Gapihan, G.; Vérine, J.; Palpant, B.; Bossy, E.; et al. In vivo uptake and cellular distribution of gold nanoshells in a preclinical model of xenografted human renal cancer. Gold Bull. 2013, 46, 257–265. [Google Scholar] [CrossRef] [Green Version]
  215. Singh, P.; Pandit, S.; Mokkapati, V.; Garg, A.; Ravikumar, V.; Mijakovic, I. Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer. Int. J. Mol. Sci. 2018, 19, 1979. [Google Scholar] [CrossRef] [PubMed]
  216. Day, E.S.; Morton, J.G.; West, J.L. Nanoparticles for thermal cancer therapy. J. Biomech. Eng. 2009, 131, 074001. [Google Scholar] [CrossRef] [PubMed]
  217. Dickerson, E.B.; Dreaden, E.C.; Huang, X.; El-Sayed, I.H.; Chu, H.; Pushpanketh, S.; McDonald, J.F.; El-Sayed, M.A. Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer Lett. 2008, 269, 57–66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  218. Roti Roti, J.L. Cellular responses to hyperthermia (40–46 degrees C): Cell killing and molecular events. Int. J. Hyperth. 2008, 24, 3–15. [Google Scholar] [CrossRef] [PubMed]
  219. Kowal, C.D.; Bertino, J.R. Possible benefits of hyperthermia to chemotherapy. Cancer Res. 1979, 39, 2285–2289. [Google Scholar] [PubMed]
  220. Classe, J.M.; Glehen, O.; Decullier, E.; Bereder, J.M.; Msika, S.; Lorimier, G.; Abboud, K.; Meeus, P.; Ferron, G.; Quenet, F.; et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for First Relapse of Ovarian Cancer. Anticancer Res. 2015, 35, 4997–5005. [Google Scholar] [PubMed]
  221. Meijerink, M.R.; Puijk, R.S.; van Tilborg, A.; Henningsen, K.H.; Fernandez, L.G.; Neyt, M.; Heymans, J.; Frankema, J.S.; de Jong, K.P.; Richel, D.J.; et al. Radiofrequency and Microwave Ablation Compared to Systemic Chemotherapy and to Partial Hepatectomy in the Treatment of Colorectal Liver Metastases: A Systematic Review and Meta-Analysis. Cardiovasc. Interv. Radiol. 2018, 41, 1189–1204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  222. Pitsillides, C.M.; Joe, E.K.; Wei, X.; Anderson, R.R.; Lin, C.P. Selective cell targeting with light-absorbing microparticles and nanoparticles. Biophys. J. 2003, 84, 4023–4032. [Google Scholar] [CrossRef]
  223. Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751–760. [Google Scholar] [CrossRef]
  224. Liang, Y.; Gao, W.; Peng, X.; Deng, X.; Sun, C.; Wu, H.; He, B. Near infrared light responsive hybrid nanoparticles for synergistic therapy. Biomaterials 2016, 100, 76–90. [Google Scholar] [CrossRef] [PubMed]
  225. El-Hammadi, M.M.; Delgado, A.V.; Melguizo, C.; Prados, J.C.; Arias, J.L. Folic acid-decorated and PEGylated PLGA nanoparticles for improving the antitumour activity of 5-fluorouracil. Int. J. Pharm. 2017, 516, 61–70. [Google Scholar] [CrossRef] [PubMed]
  226. Dadwal, A.; Baldi, A.; Kumar Narang, R. Nanoparticles as carriers for drug delivery in cancer. Artif. Cells Nanomed. Biotechnol. 2018, 1–11. [Google Scholar] [CrossRef] [PubMed]
  227. Slamon, D.J.; Clark, G.M.; Wong, S.G.; Levin, W.J.; Ullrich, A.; McGuire, W.L. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235, 177–182. [Google Scholar] [CrossRef] [PubMed]
  228. Niikura, N.; Liu, J.; Hayashi, N.; Mittendorf, E.A.; Gong, Y.; Palla, S.L.; Tokuda, Y.; Gonzalez-Angulo, A.M.; Hortobagyi, G.N.; Ueno, N.T. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J. Clin. Oncol. 2012, 30, 593–599. [Google Scholar] [CrossRef] [PubMed]
  229. Baselga, J.; Cortes, J.; Kim, S.B.; Im, S.A.; Hegg, R.; Im, Y.H.; Roman, L.; Pedrini, J.L.; Pienkowski, T.; Knott, A.; et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 2012, 366, 109–119. [Google Scholar] [CrossRef] [PubMed]
  230. Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.Y.; Dieras, V.; Guardino, E.; et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012, 367, 1783–1791. [Google Scholar] [CrossRef] [PubMed]
  231. Kubota, T.; Kuroda, S.; Kanaya, N.; Morihiro, T.; Aoyama, K.; Kakiuchi, Y.; Kikuchi, S.; Nishizaki, M.; Kagawa, S.; Tazawa, H.; et al. HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer. Nanomedicine 2018, 14, 1919–1929. [Google Scholar] [CrossRef]
  232. Nunes, T.; Pons, T.; Hou, X.; Caron, B.; Rigal, M.; Di Benedetto, M.; Palpant, B.; Leboeuf, C.; Janin, A.; Bousquet, G. Pulsed Laser Irradiation of Multifunctional Gold Nanoshells to Overcome Trastuzumab Resistance in HER2-Overexpressing Breast Cancer. (submitted).
  233. Sargazi, A.; Shiri, F.; Keikha, S.; Majd, M.H. Hyaluronan magnetic nanoparticle for mitoxantrone delivery toward CD44-positive cancer cells. Colloids Surf. B Biointerfaces 2018, 171, 150–158. [Google Scholar] [CrossRef]
  234. Patskovsky, S.; Bergeron, E.; Meunier, M. Hyperspectral darkfield microscopy of PEGylated gold nanoparticles targeting CD44-expressing cancer cells. J. Biophotonics 2015, 8, 162–167. [Google Scholar] [CrossRef]
  235. Cho, J.H.; Kim, A.R.; Kim, S.H.; Lee, S.J.; Chung, H.; Yoon, M.Y. Development of a novel imaging agent using peptide-coated gold nanoparticles toward brain glioma stem cell marker CD133. Acta Biomater. 2017, 47, 182–192. [Google Scholar] [CrossRef] [PubMed]
  236. Liang, S.; Li, C.; Zhang, C.; Chen, Y.; Xu, L.; Bao, C.; Wang, X.; Liu, G.; Zhang, F.; Cui, D. CD44v6 Monoclonal Antibody-Conjugated Gold Nanostars for Targeted Photoacoustic Imaging and Plasmonic Photothermal Therapy of Gastric Cancer Stem-like Cells. Theranostics 2015, 5, 970–984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  237. Sehedic, D.; Chourpa, I.; Tetaud, C.; Griveau, A.; Loussouarn, C.; Avril, S.; Legendre, C.; Lepareur, N.; Wion, D.; Hindre, F.; et al. Locoregional Confinement and Major Clinical Benefit of (188)Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma. Theranostics 2017, 7, 4517–4536. [Google Scholar] [CrossRef]
  238. Liu, Y.; Yang, M.; Zhang, J.; Zhi, X.; Li, C.; Zhang, C.; Pan, F.; Wang, K.; Yang, Y.; Martinez de la Fuentea, J.; et al. Human Induced Pluripotent Stem Cells for Tumor Targeted Delivery of Gold Nanorods and Enhanced Photothermal Therapy. ACS Nano 2016, 10, 2375–2385. [Google Scholar] [CrossRef]
  239. Platt, V.M.; Szoka, F.C., Jr. Anticancer therapeutics: Targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. Mol. Pharm. 2008, 5, 474–486. [Google Scholar] [CrossRef]
  240. Mero, A.; Campisi, M. Hyaluronic Acid Bioconjugates for the Delivery of Bioactive Molecules. Polymers 2014, 6, 346–369. [Google Scholar] [CrossRef] [Green Version]
  241. Yan, Y.; Zuo, X.; Wei, D. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target. Stem Cells Transl. Med. 2015, 4, 1033–1043. [Google Scholar] [CrossRef] [Green Version]
  242. Cirimbei, C.; Rotaru, V.; Chitoran, E.; Pavaleanu, O.; Cirimbei, S.E. Immediate and Long-term Results of Radiofrequency Ablation for Colorectal Liver Metastases. Anticancer Res. 2017, 37, 6489–6494. [Google Scholar]
  243. Jamil, M.; Ng, E.Y. Quantification of the effect of electrical and thermal parameters on radiofrequency ablation for concentric tumour model of different sizes. J. Therm. Biol. 2015, 51, 23–32. [Google Scholar] [CrossRef]
  244. Rylander, M.N.; Stafford, R.J.; Hazle, J.; Whitney, J.; Diller, K.R. Heat shock protein expression and temperature distribution in prostate tumours treated with laser irradiation and nanoshells. Int. J. Hyperth. 2011, 27, 791–801. [Google Scholar] [CrossRef] [PubMed]
  245. Zaimy, M.A.; Jebali, A.; Bazrafshan, B.; Mehrtashfar, S.; Shabani, S.; Tavakoli, A.; Hekmatimoghaddam, S.H.; Sarli, A.; Azizi, H.; Izadi, P.; et al. Coinhibition of overexpressed genes in acute myeloid leukemia subtype M2 by gold nanoparticles functionalized with five antisense oligonucleotides and one anti-CD33(+)/CD34(+) aptamer. Cancer Gene Ther. 2016, 23, 315–320. [Google Scholar] [CrossRef] [PubMed]
Ijms 19 04036 g001 550
Figure 1. (a) Tumor response to conventional treatment is hampered by resistant cancer stem cells that can regenerate the tumor bulk. (b) Hybrid iron-gold nanoparticle conjugated with an anti-HER2 antibody and targeted against cancer stem cell marker CXCR4 for theranostic purposes; Photothermal irradiation destroys cancer stem cells and, thus, prevents tumor relapse following chemotherapy.
Figure 1. (a) Tumor response to conventional treatment is hampered by resistant cancer stem cells that can regenerate the tumor bulk. (b) Hybrid iron-gold nanoparticle conjugated with an anti-HER2 antibody and targeted against cancer stem cell marker CXCR4 for theranostic purposes; Photothermal irradiation destroys cancer stem cells and, thus, prevents tumor relapse following chemotherapy.
Ijms 19 04036 g001
Table
Table 1. ABC transporters involved in cancer drug resistance.
Table 1. ABC transporters involved in cancer drug resistance.
GeneChemotherapeutic Drugs Effluxed by TransporterReferences
ABCA1Cisplatin[22]
ABCA2Estramustine[15]
ABCB1Anthracyclines, actinomycin D, methotrexate, etoposide, mitomycin C, mitoxantrone, vincristine, vinblastine, taxanes, imatinib, nilotinib, EGFR TKI[15,22,23]
ABCB5Doxorubicin, 5-fluorouracil, camptothecin, mitoxantrone,[22]
ABCC1Anthracyclines, etoposide, camptothecins, methotrexate, mitoxantrone, vincristine, vinblastine, irinotecan, TKI as imatinib[15,22,23]
ABCC2Vinblastine, cisplatin, doxorubicin, methotrexate, paclitaxel[15]
ABCC3Cisplatin, doxorubicin Methotrexate, etoposide, vincristine[15,22]
ABCC46-mercaptopurine, 6-thioguanine, methotrexate, topotecan[15,22]
ABCC56-mercaptopurine, 6-thioguanine, and metabolites[15]
ABCC6Etoposide[15]
ABCC10Taxanes, vincristine, vinblastine, vinorelbine, cytarabine, gemcitabine[23]
ABCC115-fluorouracil[15]
ABCG2Mitoxantrone, topotecan, anthracyclines, irinotecan, methotrexate, paclitaxel, TKI[15,22,23]
ABC: ATP-binding cassette; EGFR: epidermal growth factor inhibitor; TKI: tyrosine kinase inhibitors.
Table
Table 2. Cancer stem cells pathways.
Table 2. Cancer stem cells pathways.
PathwayFunctionsCancersReferences
HEDGEHOGRegulates adult stem cells, tissue maintenance, and repair, EMT phenotypeBasal cell carcinoma, glioblastoma, medulloblastoma, rhabdomyosarcoma, colon cancer[69,70,71,72]
JAK/STATSelf-renewal properties in hematopoiesis and neurogenesisBreast, glioblastoma, AML[73,74]
NOTCHDifferentiation of stem cells and organ developmentBreast, colon, pancreatic, prostate, skin cancers, CNS tumors[75,76,77,78]
WNT/β-cateninSelf-renewal signal of stem cell and EMT phenotypeMelanoma, breast, gastric, colorectal, pancreatic, ovarian, skin cancers[15,67,79,80,81,82]
PI3K/PTENSelf-renewal and regulation of embryonic, hematopoietic, intestinal and neuronal stem cells, EMT phenotypeGlioblastoma, myeloproliferative disease, leukemia, breast cancer[21,83,84,85,86,87]
NF-κBInflammatory and immune responses, proliferation, survival and differentiation, inhibit the activity of embryonic stem cell regulators SOX2 and NANOGHematologic, GI, Breast, GU, gynecologic, thoracic, head and neck cancers, fibrosarcoma, melanoma, squamous cell carcinoma[88,89,90,91,92,93]
EMT: epithelial-to-mesenchymal transformation; AML: acute myeloid leukemia; CNS: central nervous system; GI: gastrointestinal; GU: genito-urinary.
Table
Table 3. Markers preferentially used for the characterization of cancer stem cells.
Table 3. Markers preferentially used for the characterization of cancer stem cells.
MarkerCancerPhenotypeReferences
CD44Ovary, stomach, breast, liver, head and neck, colon, prostate, pancreasTumorigenicity, spheroid formation, chemoresistance, hierarchical organization[27,103,104,105,106,107,108,109,110,111,112]
CD117GIST, ovary, skin, colon, blood, head and neck, sarcoma, germ cells tumors, prostate, lung, mesothelioma, breast, renal, CNSTumorigenicity, spheroid formation, self-renewal, chemoresistance, hierarchical organization, undifferentiated state[27,111,113,114,115,116]
CD133Blood, ovary, brain, pancreas, liver, skin, prostate, colon, lung, stomach, head and neckPoorly differentiated gastric cancer, independent prognostic factor[109,110,117,118,119,120,121,122,123,124,125]
CD24Ovary, stomach, head and neck, pancreasTumorigenicity, self-renewal, hierarchical organization, chemoresistance[104,110,111,123,126]
ALDHStomach, prostate, ovary, cervixTumorigenicity, phenotypical heterogeneity, chemoresistance[35,123,127,128,129]
CD44/CD166/ALDHStomach, lung, colon, rectumTumorigenicity, chemoresistance, self-renewal[110,123,128,130,131]
CXCR4Stomach, blood, breast, ovary, melanoma, prostate, brain, lung, pancreas, colon, rectum, head and neckTumorigenicity, chemoresistance, angiogenesis, invasion[132,133,134,135]
EpCAMStomach, ovary, pancreasTumorigenicity, phenotypical heterogeneity, self-renewal, metastasis, chemoresistance[109,122,136,137]
CD105Kidney, CNSProliferation, differentiation, migration, and angiogenesis, tumorigenicity[138,139,140,141]
CD90Stomach, kidney, CNSTumorigenicity, trastuzumab-reduced CD90-positive population[120,123,138,139]
CD54Liver, stomach, rectumMetastases, tumorigenicity, spheroid formation, self-renewal[122,142,143]
CD71-negativeStomachQuiescence, tumorigenicity, chemoresistance, tumor cell invasion[144]
LGR5Colon, liver, pancreas, stomach, brain, breastTumorigenicity, self-renewal, spheroid formation, self-renewal, invasion[110,122,145,146]
Oct4Stomach, head and neck, prostate, ovary, kidney, colonTumorigenicity, self-renewal, chemoresistance, hierarchical organization, invasion[111,122,124,126,138,147,148]
Sox2Stomach, head and neck, glioblastoma, kidney, brain, breast, pancreasWell or moderately differentiated gastric cancer, tumorigenicity, self-renewal, chemoresistance, hierarchical organization[35,111,122,125,138]
SP (efflux Vybrant® DyeCycleTM Violet)OvaryClonogenicity, asymmetric division and high tumorigenicity[30]
SP (efflux Hoechst 33342)OvaryChemoresistance, asymmetric division[31]
SP (efflux Hoechst 33342)OvaryChemoresistance[149]
SP/ALDHBrOvaryTumorigenicity, spheroid formation, pluripotency, chemoresistance[35]
GIST: gastro-intestinal tumors; CNS: central nervous system; ALDH: aldehyde dehydrogenase; CSC: cancer stem cells; CXCR4: C-X-C chemokine receptor type 4; EpCAM: epithelial cell adhesion molecule; HCC: hepatocellular carcinoma; LGR5: Leucine-rich repeat-containing G-protein coupled receptor 5; Oct4: octamer-binding transcription factor 4; Sox2: sex determining region Y-box 2; SP: side population; Br: bright.

Share and Cite

MDPI and ACS Style

Nunes, T.; Hamdan, D.; Leboeuf, C.; El Bouchtaoui, M.; Gapihan, G.; Nguyen, T.T.; Meles, S.; Angeli, E.; Ratajczak, P.; Lu, H.; et al. Targeting Cancer Stem Cells to Overcome Chemoresistance. Int. J. Mol. Sci. 2018, 19, 4036. https://doi.org/10.3390/ijms19124036

AMA Style

Nunes T, Hamdan D, Leboeuf C, El Bouchtaoui M, Gapihan G, Nguyen TT, Meles S, Angeli E, Ratajczak P, Lu H, et al. Targeting Cancer Stem Cells to Overcome Chemoresistance. International Journal of Molecular Sciences. 2018; 19(12):4036. https://doi.org/10.3390/ijms19124036

Chicago/Turabian Style

Nunes, Toni, Diaddin Hamdan, Christophe Leboeuf, Morad El Bouchtaoui, Guillaume Gapihan, Thi Thuy Nguyen, Solveig Meles, Eurydice Angeli, Philippe Ratajczak, He Lu, and et al. 2018. "Targeting Cancer Stem Cells to Overcome Chemoresistance" International Journal of Molecular Sciences 19, no. 12: 4036. https://doi.org/10.3390/ijms19124036

APA Style

Nunes, T., Hamdan, D., Leboeuf, C., El Bouchtaoui, M., Gapihan, G., Nguyen, T. T., Meles, S., Angeli, E., Ratajczak, P., Lu, H., Di Benedetto, M., Bousquet, G., & Janin, A. (2018). Targeting Cancer Stem Cells to Overcome Chemoresistance. International Journal of Molecular Sciences, 19(12), 4036. https://doi.org/10.3390/ijms19124036

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop