Journal of Clinical Medicine

Editorial

3 pages, 187 KiB

Open AccessEditorial

Insights into the Multi-Dimensional Dynamic Landscape of Epithelial–Mesenchymal Plasticity through Inter-Disciplinary Approaches

by Mohit Kumar Jolly and Toni Celia-Terrassa

J. Clin. Med. 2020, 9(6), 1624; https://doi.org/10.3390/jcm9061624 - 27 May 2020

Cited by 1 | Viewed by 1669

Abstract

Epithelial–mesenchymal transition (EMT), first described by Dr [...] Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

Research

Jump to: Editorial, Review

21 pages, 3882 KiB

Open AccessArticle

Epithelial-Mesenchymal Transition-Related MicroRNAs and Their Target Genes in Colorectal Cancerogenesis

by Branislava Ranković, Nina Zidar, Margareta Žlajpah and Emanuela Boštjančič

J. Clin. Med. 2019, 8(10), 1603; https://doi.org/10.3390/jcm8101603 - 3 Oct 2019

Cited by 24 | Viewed by 3107

Abstract

MicroRNAs of the miR-200 family have been shown experimentally to regulate epithelial-mesenchymal transition (EMT). Although EMT is the postulated mechanism of development and progression of colorectal cancer (CRC), there are still limited and controversial data on expression of miR-200 family and their target [...] Read more.

MicroRNAs of the miR-200 family have been shown experimentally to regulate epithelial-mesenchymal transition (EMT). Although EMT is the postulated mechanism of development and progression of colorectal cancer (CRC), there are still limited and controversial data on expression of miR-200 family and their target genes during CRC cancerogenesis. Our study included formalin-fixed paraffin-embedded biopsy samples of 40 patients (10 adenomas and 30 cases of CRC with corresponding normal mucosa). Expression of miR-141, miR-200a/b/c and miR-429 and their target genes (CDKN1B, ONECUT2, PTPN13, RND3, SOX2, TGFB2 and ZEB2) was analysed using quantitative real-time PCR. Expression of E-cadherin was analysed using immunohistochemistry. All miRNAs were down-regulated and their target genes showed the opposite expression in CRC compared to adenoma. Down-regulation of the miR-200 family at the invasive front in comparison to the central part of tumour was observed as well as a correlation of expression of miR-200b, CDKN1B, ONECUT2 and ZEB2 expression to nodal metastases. Expression of the miR-200 family and SOX2 also correlated with E-cadherin staining. These results suggest that the miR-200 family and their target genes contribute to progression of adenoma to CRC, invasive properties and development of metastases. Our results strongly support the postulated hypotheses of partial EMT and intra-tumour heterogeneity during CRC cancerogenesis. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

16 pages, 2253 KiB

Open AccessArticle

Iduronate-2-Sulfatase-Regulated Dermatan Sulfate Levels Potentiate the Invasion of Breast Cancer Epithelia through Collagen Matrix

by Vishal Singh, Keshav Kumar Jha, Jyothsna K. M, Rekha V. Kumar, Varun Raghunathan and Ramray Bhat

J. Clin. Med. 2019, 8(10), 1562; https://doi.org/10.3390/jcm8101562 - 30 Sep 2019

Cited by 8 | Viewed by 3590

Abstract

Cancer epithelia show elevation in levels of sulfated proteoglycans including dermatan sulfates (DS). The effect of increased DS on cancer cell behavior is still unclear. We hypothesized that decreased expression of the enzyme Iduronate-2-sulfatase (IDS) can lead to increased DS levels, which would [...] Read more.

Cancer epithelia show elevation in levels of sulfated proteoglycans including dermatan sulfates (DS). The effect of increased DS on cancer cell behavior is still unclear. We hypothesized that decreased expression of the enzyme Iduronate-2-sulfatase (IDS) can lead to increased DS levels, which would enhance the invasion of cancer cells. Breast cancer sections shows depleted IDS levels in tumor epithelia, when compared with adjacent untransformed breast tissues. IDS signals showed a progressive decrease in the non-transformed HMLE, transformed but non-invasive MCF-7 and transformed and invasive MDA-MB-231 cells, respectively, when cultured on Type 1 collagen scaffolds. DS levels measured by ELISA increased in an inverse-association with IDS levels. Knockdown of IDS in MCF-7 epithelia also increased the levels of DS. MCF-7 cells with depleted IDS expression, when imaged using two photon-excited fluorescence and second harmonic generation microscopy, exhibited a mesenchymal morphology with multiple cytoplasmic projections compared with epithelioid control cells, interacted with their surrounding matrix, and showed increased invasion through Type 1 collagen matrices. Both these traits were phenocopied when control MCF-7 cells were cultivated on Type 1 collagen gels polymerized in the presence of DS. In monolayer cultures, DS had no effect on MCF-7 migration. In the context of our demonstration that DS enhances the elastic modulus of Type 1 collagen gels, we propose that a decrease of IDS expression leads to accumulation within cancer epithelia of DS: the latter remodels the collagen around cancer cells leading to changes in cell shape and invasiveness through fibrillar matrix milieu. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

14 pages, 2062 KiB

Open AccessArticle

A Novel Ex Vivo System Using 3D Polymer Scaffold to Culture Circulating Tumor Cells from Breast Cancer Patients Exhibits Dynamic E-M Phenotypes

by Tamasa De, Shina Goyal, Gowri Balachander, Kaushik Chatterjee, Prashant Kumar, Govind Babu K. and Annapoorni Rangarajan

J. Clin. Med. 2019, 8(9), 1473; https://doi.org/10.3390/jcm8091473 - 16 Sep 2019

Cited by 22 | Viewed by 6845

Abstract

The majority of the cancer-associated deaths is due to metastasis—the spread of tumors to other organs. Circulating tumor cells (CTCs), which are shed from the primary tumor into the circulation, serve as precursors of metastasis. CTCs have now gained much attention as a [...] Read more.

The majority of the cancer-associated deaths is due to metastasis—the spread of tumors to other organs. Circulating tumor cells (CTCs), which are shed from the primary tumor into the circulation, serve as precursors of metastasis. CTCs have now gained much attention as a new prognostic and diagnostic marker, as well as a screening tool for patients with metastatic disease. However, very little is known about the biology of CTCs in cancer metastasis. An increased understanding of CTC biology, their heterogeneity, and interaction with other cells can help towards a better understanding of the metastatic process, as well as identify novel drug targets. Here we present a novel ex vivo 3D system for culturing CTCs from breast cancer patient blood samples using porous poly(ε-caprolactone) (PCL) scaffolds. As a proof of principle study, we show that ex vivo culture of 12/16 (75%) advanced stage breast cancer patient blood samples were enriched for CTCs identified as CK+ (cytokeratin positive) and CD45− (CD45 negative) cells. The deposition of extracellular matrix proteins on the PCL scaffolds permitted cellular attachment to these scaffolds. Detection of Ki-67 and bromodeoxyuridine (BrdU) positive cells revealed proliferating cell population in the 3D scaffolds. The CTCs cultured without prior enrichment exhibited dynamic differences in epithelial (E) and mesenchymal (M) composition. Thus, our 3D PCL scaffold system offers a physiologically relevant model to be used for studying CTC biology as well as for individualized testing of drug susceptibility. Further studies are warranted for longitudinal monitoring of epithelial–mesenchymal transition (EMT) in CTCs for clinical association. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

31 pages, 6139 KiB

Open AccessArticle

Multi-Omics Characterization of the Spontaneous Mesenchymal–Epithelial Transition in the PMC42 Breast Cancer Cell Lines

by Sugandha Bhatia, James Monkman, Tony Blick, Pascal HG Duijf, Shivashankar H. Nagaraj and Erik W. Thompson

J. Clin. Med. 2019, 8(8), 1253; https://doi.org/10.3390/jcm8081253 - 19 Aug 2019

Cited by 20 | Viewed by 5961

Abstract

Epithelial–mesenchymal plasticity (EMP), encompassing epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), are considered critical events for cancer metastasis. We investigated chromosomal heterogeneity and chromosomal instability (CIN) profiles of two sister PMC42 breast cancer (BC) cell lines to assess the relationship between their karyotypes [...] Read more.

Epithelial–mesenchymal plasticity (EMP), encompassing epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), are considered critical events for cancer metastasis. We investigated chromosomal heterogeneity and chromosomal instability (CIN) profiles of two sister PMC42 breast cancer (BC) cell lines to assess the relationship between their karyotypes and EMP phenotypic plasticity. Karyotyping by GTG banding and exome sequencing were aligned with SWATH quantitative proteomics and existing RNA-sequencing data from the two PMC42 cell lines; the mesenchymal, parental PMC42-ET cell line and the spontaneously epithelially shifted PMC42-LA daughter cell line. These morphologically distinct PMC42 cell lines were also compared with five other BC cell lines (MDA-MB-231, SUM-159, T47D, MCF-7 and MDA-MB-468) for their expression of EMP and cell surface markers, and stemness and metabolic profiles. The findings suggest that the epithelially shifted cell line has a significantly altered ploidy of chromosomes 3 and 13, which is reflected in their transcriptomic and proteomic expression profiles. Loss of the TGFβR2 gene from chromosome 3 in the epithelial daughter cell line inhibits its EMT induction by TGF-β stimulus. Thus, integrative ‘omics’ characterization established that the PMC42 system is a relevant MET model and provides insights into the regulation of phenotypic plasticity in breast cancer. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

15 pages, 4325 KiB

Open AccessArticle

Deciphering Hydrodynamic and Drug-Resistant Behaviors of Metastatic EMT Breast Cancer Cells Moving in a Constricted Microcapillary

by Binita Nath, Anil P. Bidkar, Vikash Kumar, Amaresh Dalal, Mohit Kumar Jolly, Siddhartha S. Ghosh and Gautam Biswas

J. Clin. Med. 2019, 8(8), 1194; https://doi.org/10.3390/jcm8081194 - 9 Aug 2019

Cited by 13 | Viewed by 4960

Abstract

Epithelial to mesenchymal transition (EMT) induces cell migration, invasion, and drug resistance, and consequently, contributes to cancer metastasis and disease aggressiveness. This study attempted to address crucial biological parameters to correlate EMT and drug-treated cancer cells traversing through microcapillaries, reminiscent of metastatic conditions. [...] Read more.

Epithelial to mesenchymal transition (EMT) induces cell migration, invasion, and drug resistance, and consequently, contributes to cancer metastasis and disease aggressiveness. This study attempted to address crucial biological parameters to correlate EMT and drug-treated cancer cells traversing through microcapillaries, reminiscent of metastatic conditions. MDA-MB-468 breast cancer cells induced to undergo EMT by treatment with 20 ng/mL of epidermal growth factor (EGF) were initially passed through several blockages and then through a constricted microchannel, mimicking the flow of invasive metastatic cells through constricted blood microcapillaries. EMT cells acquired enhanced migratory properties and retained 50% viability, even after migration through wells 10–15 μm in size and a constricted passage of 7 μm and 150 μm in length at a constant flow rate of 50 μL/h. The hydrodynamic properties revealed cellular deformation with a deformation index, average transit velocity, and entry time of 2.45, 12.3 mm/s, and 31,000 μs, respectively for a cell of average diameter 19 μm passing through one of the 7 μm constricted sections. Interestingly, cells collected at the channel outlet regained epithelial character, undergoing reverse transition (mesenchymal to epithelial transition, MET) in the absence of EGF. Remarkably, real-time polymerase chain reaction (PCR) analysis confirmed increases of 2- and 2.7-fold in the vimentin and fibronectin expression in EMT cells, respectively; however, their expression reduced to basal level in the MET cells. A scratch assay revealed the pronounced migratory nature of EMT cells compared with MET cells. Furthermore, the number of colonies formed from EMT cells and paclitaxel-treated EMT cells after passing through a constriction were found to be 95 ± 10 and 79 ± 4, respectively, confirming that the EMT cells were more drug resistant with a concomitant two-fold higher expression of the multi-drug resistance (MDR1) gene. Our results highlight the hydrodynamic and drug-evading properties of cells that have undergone an EMT, when passed through a constricted microcapillary that mimics their journey in blood circulation. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

13 pages, 3823 KiB

Open AccessArticle

ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

by Yan-Jiun Huang, Yi-Hua Jan, Yu-Chan Chang, Hsing-Fang Tsai, Alexander TH Wu, Chi-Long Chen and Michael Hsiao

J. Clin. Med. 2019, 8(7), 1070; https://doi.org/10.3390/jcm8071070 - 21 Jul 2019

Cited by 17 | Viewed by 4689

Abstract

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial [...] Read more.

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F₀F₁ ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

18 pages, 3089 KiB

Open AccessArticle

Morphological State Transition Dynamics in EGF-Induced Epithelial to Mesenchymal Transition

by Vimalathithan Devaraj and Biplab Bose

J. Clin. Med. 2019, 8(7), 911; https://doi.org/10.3390/jcm8070911 - 26 Jun 2019

Cited by 35 | Viewed by 5885

Abstract

Epithelial to Mesenchymal Transition (EMT) is a multi-state process. Here, we investigated phenotypic state transition dynamics of Epidermal Growth Factor (EGF)-induced EMT in a breast cancer cell line MDA-MB-468. We have defined phenotypic states of these cells in terms of their morphologies and [...] Read more.

Epithelial to Mesenchymal Transition (EMT) is a multi-state process. Here, we investigated phenotypic state transition dynamics of Epidermal Growth Factor (EGF)-induced EMT in a breast cancer cell line MDA-MB-468. We have defined phenotypic states of these cells in terms of their morphologies and have shown that these cells have three distinct morphological states—cobble, spindle, and circular. The spindle and circular states are the migratory phenotypes. Using quantitative image analysis and mathematical modeling, we have deciphered state transition trajectories in different experimental conditions. This analysis shows that the phenotypic state transition during EGF-induced EMT in these cells is reversible, and depends upon the dose of EGF and level of phosphorylation of the EGF receptor (EGFR). The dominant reversible state transition trajectory in this system was cobble to circular to spindle to cobble. We have observed that there exists an ultrasensitive on/off switch involving phospho-EGFR that decides the transition of cells in and out of the circular state. In general, our observations can be explained by the conventional quasi-potential landscape model for phenotypic state transition. As an alternative to this model, we have proposed a simpler discretized energy-level model to explain the observed state transition dynamics. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

24 pages, 6291 KiB

Open AccessArticle

Interrogation of Phenotypic Plasticity between Epithelial and Mesenchymal States in Breast Cancer

by Sugandha Bhatia, James Monkman, Tony Blick, Cletus Pinto, Mark Waltham, Shivashankar H Nagaraj and Erik W Thompson

J. Clin. Med. 2019, 8(6), 893; https://doi.org/10.3390/jcm8060893 - 21 Jun 2019

Cited by 36 | Viewed by 7000

Abstract

Dynamic interconversions between transitional epithelial and mesenchymal states underpin the epithelial mesenchymal plasticity (EMP) seen in some carcinoma cell systems. We have delineated epithelial and mesenchymal subpopulations existing within the PMC42-LA breast cancer cell line by their EpCAM expression. These purified but phenotypically [...] Read more.

Dynamic interconversions between transitional epithelial and mesenchymal states underpin the epithelial mesenchymal plasticity (EMP) seen in some carcinoma cell systems. We have delineated epithelial and mesenchymal subpopulations existing within the PMC42-LA breast cancer cell line by their EpCAM expression. These purified but phenotypically plastic states, EpCAM^High (epithelial) and EpCAM^Low (mesenchymal), have the ability to regain the phenotypic equilibrium of the parental population (i.e., 80% epithelial and 20% mesenchymal) over time, although the rate of reversion in the mesenchymal direction (epithelial-mesenchymal transition; EMT) is higher than that in the epithelial direction (mesenchymal-epithelial transition; MET). Single-cell clonal propagation was implemented to delineate the molecular and cellular features of this intrinsic heterogeneity with respect to EMP flux. The dynamics of the phenotypic proportions of epithelial and mesenchymal states in single-cell generated clones revealed clonal diversity and intrinsic plasticity. Single cell-derived clonal progenies displayed differences in their functional attributes of proliferation, stemness marker (CD44/CD24), migration, invasion and chemo-sensitivity. Interrogation of genomic copy number variations (CNV) with whole exome sequencing (WES) in the context of chromosome count from metaphase spread indicated that chromosomal instability was not influential in driving intrinsic phenotypic plasticity. Overall, these findings reveal the stochastic nature of both the epithelial and mesenchymal subpopulations, and the single cell-derived clones for differential functional attributes. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

18 pages, 2596 KiB

Open AccessArticle

Snail-Overexpression Induces Epithelial-mesenchymal Transition and Metabolic Reprogramming in Human Pancreatic Ductal Adenocarcinoma and Non-tumorigenic Ductal Cells

by Menghan Liu, Sarah E. Hancock, Ghazal Sultani, Brendan P. Wilkins, Eileen Ding, Brenna Osborne, Lake-Ee Quek and Nigel Turner

J. Clin. Med. 2019, 8(6), 822; https://doi.org/10.3390/jcm8060822 - 8 Jun 2019

Cited by 28 | Viewed by 5402

Abstract

The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic [...] Read more.

The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of ¹³C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

21 pages, 14434 KiB

Open AccessArticle

Phosphoproteomic Profiling Identifies Aberrant Activation of Integrin Signaling in Aggressive Non-Type Bladder Carcinoma

by Barnali Deb, Vinuth N. Puttamallesh, Kirti Gondkar, Jean P. Thiery, Harsha Gowda and Prashant Kumar

J. Clin. Med. 2019, 8(5), 703; https://doi.org/10.3390/jcm8050703 - 17 May 2019

Cited by 17 | Viewed by 5244

Abstract

Bladder carcinoma is highly heterogeneous and its complex molecular landscape; thus, poses a significant challenge for resolving an effective treatment in metastatic tumors. We computed the epithelial-mesenchymal transition (EMT) scores of three bladder carcinoma subtypes—luminal, basal, and non-type. The EMT score of the [...] Read more.

Bladder carcinoma is highly heterogeneous and its complex molecular landscape; thus, poses a significant challenge for resolving an effective treatment in metastatic tumors. We computed the epithelial-mesenchymal transition (EMT) scores of three bladder carcinoma subtypes—luminal, basal, and non-type. The EMT score of the non-type indicated a “mesenchymal-like” phenotype, which correlates with a relatively more aggressive form of carcinoma, typified by an increased migration and invasion. To identify the altered signaling pathways potentially regulating this EMT phenotype in bladder cancer cell lines, we utilized liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach. Bioinformatics analyses were carried out to determine the activated pathways, networks, and functions in bladder carcinoma cell lines. A total of 3125 proteins were identified, with 289 signature proteins noted to be differentially phosphorylated (p ≤ 0.05) in the non-type cell lines. The integrin pathway was significantly enriched and five major proteins (TLN1, CTTN, CRKL, ZYX and BCAR3) regulating cell motility and invasion were hyperphosphorylated. Our study reveals GSK3A/B and CDK1 as promising druggable targets for the non-type molecular subtype, which could improve the treatment outcomes for aggressive bladder carcinoma. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

17 pages, 3901 KiB

Open AccessArticle

Clinical Stratification of High-Grade Ovarian Serous Carcinoma Using a Panel of Six Biomarkers

by Swapnil C. Kamble, Arijit Sen, Rahul D. Dhake, Aparna N. Joshi, Divya Midha and Sharmila A. Bapat

J. Clin. Med. 2019, 8(3), 330; https://doi.org/10.3390/jcm8030330 - 8 Mar 2019

Cited by 5 | Viewed by 4092

Abstract

Molecular stratification of high-grade serous ovarian carcinoma (HGSC) for targeted therapy is a pertinent approach in improving prognosis of this highly heterogeneous disease. Enabling the same necessitates identification of class-specific biomarkers and their robust detection in the clinic. We have earlier resolved three [...] Read more.

Molecular stratification of high-grade serous ovarian carcinoma (HGSC) for targeted therapy is a pertinent approach in improving prognosis of this highly heterogeneous disease. Enabling the same necessitates identification of class-specific biomarkers and their robust detection in the clinic. We have earlier resolved three discrete molecular HGSC classes associated with distinct functional behavior based on their gene expression patterns, biological networks, and pathways. An important difference revealed was that Class 1 is likely to exhibit cooperative cell migration (CCM), Class 2 undergoes epithelial to mesenchymal transition (EMT), while Class 3 is possibly capable of both modes of migration. In the present study, we define clinical stratification of HGSC tumors through the establishment of standard operating procedures for immunohistochemistry and histochemistry based detection of a panel of biomarkers including TCF21, E-cadherin, PARP1, Slug, AnnexinA2, and hyaluronan. Further development and application of scoring guidelines based on expression of this panel in cell line-derived xenografts, commercial tissue microarrays, and patient tumors led to definitive stratification of samples. Biomarker expression was observed to vary significantly between primary and metastatic tumors suggesting class switching during disease progression. Another interesting feature in the study was of enhanced CCM-marker expression in tumors following disease progression and chemotherapy. These stratification principles and the new information thus generated is the first step towards class-specific personalized therapies in the disease. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

15 pages, 3318 KiB

Open AccessArticle

An Integrative Systems Biology and Experimental Approach Identifies Convergence of Epithelial Plasticity, Metabolism, and Autophagy to Promote Chemoresistance

by Shengnan Xu, Kathryn E. Ware, Yuantong Ding, So Young Kim, Maya U. Sheth, Sneha Rao, Wesley Chan, Andrew J. Armstrong, William C. Eward, Mohit Kumar Jolly and Jason A. Somarelli

J. Clin. Med. 2019, 8(2), 205; https://doi.org/10.3390/jcm8020205 - 7 Feb 2019

Cited by 14 | Viewed by 4904

Abstract

The evolution of therapeutic resistance is a major cause of death for cancer patients. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure of the host immune system. These selective forces often lead [...] Read more.

The evolution of therapeutic resistance is a major cause of death for cancer patients. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure of the host immune system. These selective forces often lead to evolutionary convergence on pathways or hallmarks that drive progression. Thus, a deeper understanding of the evolutionary convergences that occur could reveal vulnerabilities to treat therapy-resistant cancer. To this end, we combined phylogenetic clustering, systems biology analyses, and molecular experimentation to identify convergences in gene expression data onto common signaling pathways. We applied these methods to derive new insights about the networks at play during transforming growth factor-β (TGF-β)-mediated epithelial–mesenchymal transition in lung cancer. Phylogenetic analyses of gene expression data from TGF-β-treated cells revealed convergence of cells toward amine metabolic pathways and autophagy during TGF-β treatment. Knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to cancer therapies following TGF-β-induced resistance, implicating autophagy as a TGF-β-mediated chemoresistance mechanism. In addition, high ATG16L expression was found to be a poor prognostic marker in multiple cancer types. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities for cancer. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

19 pages, 996 KiB

Open AccessReview

Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

by Mohit Kumar Jolly and Toni Celià-Terrassa

J. Clin. Med. 2019, 8(10), 1542; https://doi.org/10.3390/jcm8101542 - 25 Sep 2019

Cited by 91 | Viewed by 6134

Abstract

Genetic and phenotypic heterogeneity contribute to the generation of diverse tumor cell populations, thus enhancing cancer aggressiveness and therapy resistance. Compared to genetic heterogeneity, a consequence of mutational events, phenotypic heterogeneity arises from dynamic, reversible cell state transitions in response to varying intracellular/extracellular [...] Read more.

Genetic and phenotypic heterogeneity contribute to the generation of diverse tumor cell populations, thus enhancing cancer aggressiveness and therapy resistance. Compared to genetic heterogeneity, a consequence of mutational events, phenotypic heterogeneity arises from dynamic, reversible cell state transitions in response to varying intracellular/extracellular signals. Such phenotypic plasticity enables rapid adaptive responses to various stressful conditions and can have a strong impact on cancer progression. Herein, we have reviewed relevant literature on mechanisms associated with dynamic phenotypic changes and cellular plasticity, such as epithelial–mesenchymal transition (EMT) and cancer stemness, which have been reported to facilitate cancer metastasis. We also discuss how non-cell-autonomous mechanisms such as cell–cell communication can lead to an emergent population-level response in tumors. The molecular mechanisms underlying the complexity of tumor systems are crucial for comprehending cancer progression, and may provide new avenues for designing therapeutic strategies. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

18 pages, 1805 KiB

Open AccessReview

Markers of Cancer Cell Invasion: Are They Good Enough?

by Tatiana S. Gerashchenko, Nikita M. Novikov, Nadezhda V. Krakhmal, Sofia Y. Zolotaryova, Marina V. Zavyalova, Nadezhda V. Cherdyntseva, Evgeny V. Denisov and Vladimir M. Perelmuter

J. Clin. Med. 2019, 8(8), 1092; https://doi.org/10.3390/jcm8081092 - 24 Jul 2019

Cited by 49 | Viewed by 8953

Abstract

Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic [...] Read more.

Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial–mesenchymal, collective–amoeboid, mesenchymal–amoeboid, and vice versa) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial–mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

24 pages, 1697 KiB

Open AccessReview

Metabolic Plasticity and Epithelial-Mesenchymal Transition

by Timothy M. Thomson, Cristina Balcells and Marta Cascante

J. Clin. Med. 2019, 8(7), 967; https://doi.org/10.3390/jcm8070967 - 3 Jul 2019

Cited by 25 | Viewed by 5007

Abstract

A major transcriptional and phenotypic reprogramming event during development is the establishment of the mesodermal layer from the ectoderm through epithelial-mesenchymal transition (EMT). EMT is employed in subsequent developmental events, and also in many physiological and pathological processes, such as the dissemination of [...] Read more.

A major transcriptional and phenotypic reprogramming event during development is the establishment of the mesodermal layer from the ectoderm through epithelial-mesenchymal transition (EMT). EMT is employed in subsequent developmental events, and also in many physiological and pathological processes, such as the dissemination of cancer cells through metastasis, as a reversible transition between epithelial and mesenchymal states. The remarkable phenotypic remodeling accompanying these transitions is driven by characteristic transcription factors whose activities and/or activation depend upon signaling cues and co-factors, including intermediary metabolites. In this review, we summarize salient metabolic features that enable or instigate these transitions, as well as adaptations undergone by cells to meet the metabolic requirements of their new states, with an emphasis on the roles played by the metabolic regulation of epigenetic modifications, notably methylation and acetylation. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

22 pages, 1843 KiB

Open AccessReview

Uncoupling Traditional Functionalities of Metastasis: The Parting of Ways with Real-Time Assays

by Sagar S. Varankar and Sharmila A. Bapat

J. Clin. Med. 2019, 8(7), 941; https://doi.org/10.3390/jcm8070941 - 28 Jun 2019

Cited by 2 | Viewed by 4707

Abstract

The experimental evaluation of metastasis overly focuses on the gain of migratory and invasive properties, while disregarding the contributions of cellular plasticity, extra-cellular matrix heterogeneity, niche interactions, and tissue architecture. Traditional cell-based assays often restrict the inclusion of these processes and warrant the [...] Read more.

The experimental evaluation of metastasis overly focuses on the gain of migratory and invasive properties, while disregarding the contributions of cellular plasticity, extra-cellular matrix heterogeneity, niche interactions, and tissue architecture. Traditional cell-based assays often restrict the inclusion of these processes and warrant the implementation of approaches that provide an enhanced spatiotemporal resolution of the metastatic cascade. Time lapse imaging represents such an underutilized approach in cancer biology, especially in the context of disease progression. The inclusion of time lapse microscopy and microfluidic devices in routine assays has recently discerned several nuances of the metastatic cascade. Our review emphasizes that a complete comprehension of metastasis in view of evolving ideologies necessitates (i) the use of appropriate, context-specific assays and understanding their inherent limitations; (ii) cautious derivation of inferences to avoid erroneous/overestimated clinical extrapolations; (iii) corroboration between multiple assay outputs to gauge metastatic potential; and (iv) the development of protocols with improved in situ implications. We further believe that the adoption of improved quantitative approaches in these assays can generate predictive algorithms that may expedite therapeutic strategies targeting metastasis via the development of disease relevant model systems. Such approaches could potentiate the restructuring of the cancer metastasis paradigm through an emphasis on the development of next-generation real-time assays. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

21 pages, 1282 KiB

Open AccessReview

Snail1: A Transcriptional Factor Controlled at Multiple Levels

by Josep Baulida, Víctor M. Díaz and Antonio García de Herreros

J. Clin. Med. 2019, 8(6), 757; https://doi.org/10.3390/jcm8060757 - 28 May 2019

Cited by 52 | Viewed by 9870

Abstract

Snail1 transcriptional factor plays a key role in the control of epithelial to mesenchymal transition and fibroblast activation. As a consequence, Snail1 expression and function is regulated at multiple levels from gene transcription to protein modifications, affecting its interaction with specific cofactors. In [...] Read more.

Snail1 transcriptional factor plays a key role in the control of epithelial to mesenchymal transition and fibroblast activation. As a consequence, Snail1 expression and function is regulated at multiple levels from gene transcription to protein modifications, affecting its interaction with specific cofactors. In this review, we describe the different elements that control Snail1 expression and its activity both as transcriptional repressor or activator. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

16 pages, 2558 KiB

Open AccessReview

Epithelial-Mesenchymal Plasticity in Organotropism Metastasis and Tumor Immune Escape

by Xiang Nan, Jiang Wang, Haowen Nikola Liu, Stephen T.C. Wong and Hong Zhao

J. Clin. Med. 2019, 8(5), 747; https://doi.org/10.3390/jcm8050747 - 25 May 2019

Cited by 18 | Viewed by 6055

Abstract

Most cancer deaths are due to metastasis, and almost all cancers have their preferential metastatic organs, known as “organotropism metastasis”. Epithelial-mesenchymal plasticity has been described as heterogeneous and dynamic cellular differentiation states, supported by emerging experimental evidence from both molecular and morphological levels. [...] Read more.

Most cancer deaths are due to metastasis, and almost all cancers have their preferential metastatic organs, known as “organotropism metastasis”. Epithelial-mesenchymal plasticity has been described as heterogeneous and dynamic cellular differentiation states, supported by emerging experimental evidence from both molecular and morphological levels. Many molecular factors regulating epithelial-mesenchymal plasticity have tissue-specific and non-redundant properties. Reciprocally, cellular epithelial-mesenchymal plasticity contributes to shaping organ-specific pre-metastatic niche (PMN) including distinct local immune landscapes, mainly through secreted bioactive molecular factors. Here, we summarize recent progress on the involvement of tumor epithelial-mesenchymal plasticity in driving organotropic metastasis and regulating the function of different immune cells in organ-specific metastasis. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

32 pages, 2966 KiB

Open AccessReview

Quantifying Cancer Epithelial-Mesenchymal Plasticity and its Association with Stemness and Immune Response

by Dongya Jia, Xuefei Li, Federico Bocci, Shubham Tripathi, Youyuan Deng, Mohit Kumar Jolly, José N. Onuchic and Herbert Levine

J. Clin. Med. 2019, 8(5), 725; https://doi.org/10.3390/jcm8050725 - 22 May 2019

Cited by 58 | Viewed by 8774

Abstract

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial–mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play [...] Read more.

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial–mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e., the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

23 pages, 503 KiB

Open AccessReview

Contribution of Epithelial Plasticity to Therapy Resistance

by Patricia G. Santamaría, Gema Moreno-Bueno and Amparo Cano

J. Clin. Med. 2019, 8(5), 676; https://doi.org/10.3390/jcm8050676 - 14 May 2019

Cited by 44 | Viewed by 4191

Abstract

Therapy resistance is responsible for tumour recurrence and represents one of the major challenges in present oncology. Significant advances have been made in the understanding of the mechanisms underlying resistance to conventional and targeted therapies improving the clinical management of relapsed patients. Unfortunately, [...] Read more.

Therapy resistance is responsible for tumour recurrence and represents one of the major challenges in present oncology. Significant advances have been made in the understanding of the mechanisms underlying resistance to conventional and targeted therapies improving the clinical management of relapsed patients. Unfortunately, in too many cases, resistance reappears leading to a fatal outcome. The recent introduction of immunotherapy regimes has provided an unprecedented success in the treatment of specific cancer types; however, a good percentage of patients do not respond to immune-based treatments or ultimately become resistant. Cellular plasticity, cancer cell stemness and tumour heterogeneity have emerged as important determinants of treatment resistance. Epithelial-to-mesenchymal transition (EMT) is associated with resistance in many different cellular and preclinical models, although little evidence derives directly from clinical samples. The recognition of the presence in tumours of intermediate hybrid epithelial/mesenchymal states as the most likely manifestation of epithelial plasticity and their potential link to stemness and tumour heterogeneity, provide new clues to understanding resistance and could be exploited in the search for anti-resistance strategies. Here, recent evidence linking EMT/epithelial plasticity to resistance against conventional, targeted and immune therapy are summarized. In addition, future perspectives for related clinical approaches are also discussed. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

14 pages, 1014 KiB

Open AccessReview

Control of Invasion by Epithelial-to-Mesenchymal Transition Programs during Metastasis

by Gray W. Pearson

J. Clin. Med. 2019, 8(5), 646; https://doi.org/10.3390/jcm8050646 - 10 May 2019

Cited by 112 | Viewed by 6732

Abstract

Epithelial-to-mesenchymal transition (EMT) programs contribute to the acquisition of invasive properties that are essential for metastasis. It is well established that EMT programs alter cell state and promote invasive behavior. This review discusses how rather than following one specific program, EMT states are [...] Read more.

Epithelial-to-mesenchymal transition (EMT) programs contribute to the acquisition of invasive properties that are essential for metastasis. It is well established that EMT programs alter cell state and promote invasive behavior. This review discusses how rather than following one specific program, EMT states are diverse in their regulation and invasive properties. Analysis across a spectrum of models using a combination of approaches has revealed how unique features of distinct EMT programs dictate whether tumor cells invade as single cells or collectively as cohesive groups of cells. It has also been shown that the mode of collective invasion is determined by the nature of the EMT, with cells in a trailblazer-type EMT state being capable of initiating collective invasion, whereas cells that have undergone an opportunist-type EMT are dependent on extrinsic factors to invade. In addition to altering cell intrinsic properties, EMT programs can influence invasion through non-cell autonomous mechanisms. Analysis of tumor subpopulations has demonstrated how EMT-induced cells can drive the invasion of sibling epithelial populations through paracrine signaling and remodeling of the microenvironment. Importantly, the variation in invasive properties controlled by EMT programs influences the kinetics and location of metastasis. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

20 pages, 660 KiB

Open AccessReview

Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells

by Snahlata Singh and Rumela Chakrabarti

J. Clin. Med. 2019, 8(5), 642; https://doi.org/10.3390/jcm8050642 - 9 May 2019

Cited by 49 | Viewed by 8183

Abstract

Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression [...] Read more.

Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression and metastatic invasion. In breast cancer, EMT both increases the migratory capacity and invasive potential of tumor cells, and initiates protumorigenic alterations in the tumor microenvironment (TME). In particular, recent evidence has linked increased expression of EMT markers such as TWIST1 and MMPs in breast tumors with increased immune infiltration in the TME. These immune cells then provide cues that promote immune evasion by tumor cells, which is associated with enhanced tumor progression and metastasis. In the current review, we will summarize the current knowledge of the role of EMT in the biology of different subtypes of breast cancer. We will further explore the correlation between genetic switches leading to EMT and EMT-induced alterations within the TME that drive tumor growth and metastasis, as well as their possible effect on therapeutic response in breast cancer. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

18 pages, 901 KiB

Open AccessFeature PaperReview

UPR: An Upstream Signal to EMT Induction in Cancer

by Patricia G. Santamaría, María J. Mazón, Pilar Eraso and Francisco Portillo

J. Clin. Med. 2019, 8(5), 624; https://doi.org/10.3390/jcm8050624 - 8 May 2019

Cited by 29 | Viewed by 5624

Abstract

The endoplasmic reticulum (ER) is the organelle where newly synthesized proteins enter the secretory pathway. Different physiological and pathological conditions may perturb the secretory capacity of cells and lead to the accumulation of misfolded and unfolded proteins. To relieve the produced stress, cells [...] Read more.

The endoplasmic reticulum (ER) is the organelle where newly synthesized proteins enter the secretory pathway. Different physiological and pathological conditions may perturb the secretory capacity of cells and lead to the accumulation of misfolded and unfolded proteins. To relieve the produced stress, cells evoke an adaptive signalling network, the unfolded protein response (UPR), aimed at recovering protein homeostasis. Tumour cells must confront intrinsic and extrinsic pressures during cancer progression that produce a proteostasis imbalance and ER stress. To overcome this situation, tumour cells activate the UPR as a pro-survival mechanism. UPR activation has been documented in most types of human tumours and accumulating evidence supports a crucial role for UPR in the establishment, progression, metastasis and chemoresistance of tumours as well as its involvement in the acquisition of other hallmarks of cancer. In this review, we will analyse the role of UPR in cancer development highlighting the ability of tumours to exploit UPR signalling to promote epithelial-mesenchymal transition (EMT). Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Graphical abstract

17 pages, 1031 KiB

Open AccessReview

Epithelial to Mesenchymal Transition and Cell Biology of Molecular Regulation in Endometrial Carcinogenesis

by Hsiao-Chen Chiu, Chia-Jung Li, Giou-Teng Yiang, Andy Po-Yi Tsai and Meng-Yu Wu

J. Clin. Med. 2019, 8(4), 439; https://doi.org/10.3390/jcm8040439 - 30 Mar 2019

Cited by 50 | Viewed by 6054

Abstract

Endometrial carcinogenesis is involved in several signaling pathways and it comprises multiple steps. The four major signaling pathways—PI3K/AKT, Ras/Raf/MEK/ERK, WNT/β-catenin, and vascular endothelial growth factor (VEGF)—are involved in tumor cell metabolism, growth, proliferation, survival, and angiogenesis. The genetic mutation and germline mitochondrial DNA [...] Read more.

Endometrial carcinogenesis is involved in several signaling pathways and it comprises multiple steps. The four major signaling pathways—PI3K/AKT, Ras/Raf/MEK/ERK, WNT/β-catenin, and vascular endothelial growth factor (VEGF)—are involved in tumor cell metabolism, growth, proliferation, survival, and angiogenesis. The genetic mutation and germline mitochondrial DNA mutations also impair cell proliferation, anti-apoptosis signaling, and epithelial–mesenchymal transition by several transcription factors, leading to endometrial carcinogenesis and distant metastasis. The PI3K/AKT pathway activates the ransforming growth factor beta (TGF-β)-mediated endothelial-to-mesenchymal transition (EMT) and it interacts with downstream signals to upregulate EMT-associated factors. Estrogen and progesterone signaling in EMT also play key roles in the prognosis of endometrial carcinogenesis. In this review article, we summarize the current clinical and basic research efforts regarding the detailed molecular regulation in endometrial carcinogenesis, especially in EMT, to provide novel targets for further anti-carcinogenesis treatment. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

17 pages, 633 KiB

Open AccessReview

Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression

by Alice Conigliaro and Carla Cicchini

J. Clin. Med. 2019, 8(1), 26; https://doi.org/10.3390/jcm8010026 - 27 Dec 2018

Cited by 57 | Viewed by 5636

Abstract

Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes [...] Read more.

Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes in gene expression of recipient cells in addition to microenvironment alterations. Notably, exosomes may deliver signals able to induce the transdifferentiation process known as Epithelial-to-Mesenchymal Transition (EMT). In this review, we summarize recent findings on the role of exosomes in tumor progression and EMT, highlighting current knowledge on exosome-mediated intercellular communication in tumor-niche establishment, migration, invasion, and metastasis processes. This body of evidence suggests the relevance of taking into account exosome-mediated signaling and its multifaceted aspects to develop innovative anti-tumoral therapeutic approaches. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (26 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI