Cancers

Research

20 pages, 22396 KiB

Open AccessArticle

Microsatellite Status and IκBα Expression Levels Predict Sensitivity to Pharmaceutical Curcumin in Colorectal Cancer Cells

by Lili Lu, Randy Przybylla, Yuru Shang, Meng Dai, Mathias Krohn, Oliver Holger Krämer, Christina Susanne Mullins and Michael Linnebacher

Cancers 2022, 14(4), 1032; https://doi.org/10.3390/cancers14041032 - 17 Feb 2022

Cited by 6 | Viewed by 2188

Abstract

Clinical utilization of curcumin in colorectal cancer (CRC) was revived as a result of the development of novel curcumin formulations with improved bioavailability. Additionally, identification of biomarkers for curcumin sensitivity would also promote successful clinical applications. Here, we wanted to identify such biomarkers [...] Read more.

Clinical utilization of curcumin in colorectal cancer (CRC) was revived as a result of the development of novel curcumin formulations with improved bioavailability. Additionally, identification of biomarkers for curcumin sensitivity would also promote successful clinical applications. Here, we wanted to identify such biomarkers in order to establish a predictive model for curcumin sensitivity. Thirty-two low-passage CRC cell lines with specified tumor characteristics were included. Curcumin suppressed cell proliferation, yet sensitivity levels were distinct. Most curcumin-sensitive CRC cell lines were microsatellite stable and expressed high levels of IκBα. The predictive capacity of this biomarker combination possessed a statistical significance of 72% probability to distinguish correctly between curcumin-sensitive and -resistant CRC cell lines. Detailed functional analyses were performed with three sensitive and three resistant CRC cell lines. As curcumin’s mode of action, inhibition of NF-κB p65 activation via IκBα was identified. In consequence, we hypothesize that novel curcumin formulations—either alone or, more likely, in combination with standard therapeutics—can be expected to prove clinically beneficial for CRC patients with high IκBα expression levels. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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20 pages, 41610 KiB

Open AccessArticle

The Interaction between Reactive Peritoneal Mesothelial Cells and Tumor Cells via Extracellular Vesicles Facilitates Colorectal Cancer Dissemination

by Simona Serratì, Letizia Porcelli, Francesco Fragassi, Marianna Garofoli, Roberta Di Fonte, Livia Fucci, Rosa Maria Iacobazzi, Antonio Palazzo, Francesca Margheri, Grazia Cristiani, Anna Albano, Raffaele De Luca, Donato Francesco Altomare, Michele Simone and Amalia Azzariti

Cancers 2021, 13(10), 2505; https://doi.org/10.3390/cancers13102505 - 20 May 2021

Cited by 10 | Viewed by 3120

Abstract

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and [...] Read more.

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and CRC cells in generating a pro-metastatic environment in the peritoneal cavity. Peritoneal MCs isolated from peritoneal lavage fluids displayed high CD44 expression, substantial mesothelial-to-mesenchymal transition (MMT) and released EVs that both directed tumor invasion and caused reprogramming of secretory profiles by increasing TGF-β1 and uPA/uPAR expression and MMP-2/9 activation in tumor cells. Notably, the EVs released by tumor cells induced apoptosis by activating caspase-3, peritoneal MC senescence, and MMT, thereby augmenting the tumor-promoting potential of these cells in the peritoneal cavity. By using pantoprazole, we reduced the biogenesis of EVs and their pro-tumor functions. In conclusion, our findings provided evidence of underlying mechanisms of CRC dissemination driven by the interaction of peritoneal MCs and tumor cells via the EVs released in the peritoneal cavity, which may have important implications for the clinical management of patients. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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16 pages, 1925 KiB

Open AccessArticle

Zona Pellucida Protein 2 (ZP2) Is Expressed in Colon Cancer and Promotes Cell Proliferation

by Dominik Kraus, Alexander Glassmann, Carsten Golletz, Glen Kristiansen, Jochen Winter and Rainer Probstmeier

Cancers 2021, 13(8), 1759; https://doi.org/10.3390/cancers13081759 - 7 Apr 2021

Cited by 6 | Viewed by 2444

Abstract

Background: Zona pellucida protein ZP2 has been identified as a new colon tumor biomarker. Its transcripts were specifically expressed in four out of four human colon cancer cell lines and enhanced in about 60% of primary colon cancer tissues when compared to matched [...] Read more.

Background: Zona pellucida protein ZP2 has been identified as a new colon tumor biomarker. Its transcripts were specifically expressed in four out of four human colon cancer cell lines and enhanced in about 60% of primary colon cancer tissues when compared to matched healthy ones. ZP2 down-regulation by siRNA led to a decreased proliferation rate, EXOSC5 transcript, cyclin D1 protein level, and ERK1/2 phosphorylation state. Methods: Sensitivity and quantitative expression analysis of ZP2 transcripts in tumor and matched normal colon tissue was performed with respective cDNA preparations. Silencing RNA effects on colon cancer cells were examined by q-PCR, western blot, and proliferation rate experiments. Results: In a significant portion of 69 primary colon tumor samples, the molecule showed a low but specific expression, which revealed a sensitivity value of around 90% and a specificity value of 30% when matched to the respective normal counterparts. Down-regulation of ZP2 protein by siRNA led to a decreased proliferation rate, EXOSC5 and cyclin D1 level, and phosphorylation state of ERK1/2. ZP2 has also been found to be a cell membrane-bound protein. Conclusion: ZP2 shows an enhanced expression level in colon cancer tissue and, thus, can be used as a diagnostic tool, albeit in combination with other biomarkers. Its character as a membrane protein makes ZP2 even a potential target molecule for tumor therapy, especially as it positively affects colon cancer cell proliferation. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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19 pages, 3027 KiB

Open AccessArticle

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

by Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo

Cancers 2021, 13(6), 1433; https://doi.org/10.3390/cancers13061433 - 21 Mar 2021

Cited by 8 | Viewed by 2918

Abstract

The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full [...] Read more.

The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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22 pages, 9853 KiB

Open AccessArticle

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

by Tiago De Oliveira, Tina Goldhardt, Marcus Edelmann, Torben Rogge, Karsten Rauch, Nikola Dobrinov Kyuchukov, Kerstin Menck, Annalen Bleckmann, Joanna Kalucka, Shawez Khan, Jochen Gaedcke, Martin Haubrock, Tim Beissbarth, Hanibal Bohnenberger, Mélanie Planque, Sarah-Maria Fendt, Lutz Ackermann, Michael Ghadimi and Lena-Christin Conradi

Cancers 2021, 13(5), 1011; https://doi.org/10.3390/cancers13051011 - 28 Feb 2021

Cited by 26 | Viewed by 7062

Abstract

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- [...] Read more.

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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19 pages, 6721 KiB

Open AccessFeature PaperArticle

Chemosensitivity of Patient-Derived Cancer Stem Cells Identifies Colorectal Cancer Patients with Potential Benefit from FGFR Inhibitor Therapy

by Takehito Yamamoto, Hiroyuki Miyoshi, Fumihiko Kakizaki, Hisatsugu Maekawa, Tadayoshi Yamaura, Tomonori Morimoto, Toshiro Katayama, Kenji Kawada, Yoshiharu Sakai and M. Mark Taketo

Cancers 2020, 12(8), 2010; https://doi.org/10.3390/cancers12082010 - 22 Jul 2020

Cited by 13 | Viewed by 4879

Abstract

Some colorectal cancer patients harboring FGFR (fibroblast growth factor receptor) genetic alterations, such as copy number gain, mutation, and/or mRNA overexpression, were selected for enrollment in several recent clinical trials of FGFR inhibitor, because these genetic alterations were preclinically reported to be associated [...] Read more.

Some colorectal cancer patients harboring FGFR (fibroblast growth factor receptor) genetic alterations, such as copy number gain, mutation, and/or mRNA overexpression, were selected for enrollment in several recent clinical trials of FGFR inhibitor, because these genetic alterations were preclinically reported to be associated with FGFR inhibitor sensitivity as well as poor prognosis, invasiveness, and/or metastatic potential. However, few enrolled patients were responsive to FGFR inhibitors. Thus, practical strategies are eagerly awaited that can stratify patients for the subset that potentially responds to FGFR inhibitor chemotherapy. In the present study, we evaluated the sensitivity to FGFR inhibitor erdafitinib on 25 patient-derived tumor-initiating cell (TIC) spheroid lines carrying wild-type RAS and RAF genes, both in vitro and in vivo. Then, we assessed possible correlations between the sensitivity and the genetic/genomic data of the spheroid lines tested. Upon their exposure to erdafitinib, seven lines (7/25, 28%) responded significantly. Normal colonic epithelial stem cells were unaffected by the inhibitors. Moreover, the combination of erdafitinib with EGFR inhibitor erlotinib showed stronger growth inhibition than either drug alone, as efficacy was observed in 21 lines (84%) including 14 (56%) that were insensitive to erdafitinib alone. The in vitro erdafitinib response was accurately reflected on mouse xenografts of TIC spheroid lines. However, we found little correlation between their genetic/genomic alterations of TIC spheroids and the sensitivity to the FGFR inhibitor. Accordingly, we propose that direct testing of the patient-derived spheroids in vitro is one of the most reliable personalized methods in FGFR-inhibitor therapy of colorectal cancer patients. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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25 pages, 13542 KiB

Open AccessArticle

Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway

by Thetchinamoorthy Kannathasan, Wei-Wen Kuo, Ming-Cheng Chen, Vijaya Padma Viswanadha, Chia-Yao Shen, Chuan-Chou Tu, Yu-Lan Yeh, Mahalakshmi Bharath, Marthandam Asokan Shibu and Chih-Yang Huang

Cancers 2020, 12(5), 1231; https://doi.org/10.3390/cancers12051231 - 14 May 2020

Cited by 21 | Viewed by 3746

Abstract

Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is [...] Read more.

Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of GNL3L in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence GNL3L may remarkably reduce oncogenic cell survival that depends on GNL3L/NF-κB signaling, making miR-4454 a candidate for treating metastatic human CRC. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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22 pages, 3618 KiB

Open AccessArticle

Vitamin C Restricts the Emergence of Acquired Resistance to EGFR-Targeted Therapies in Colorectal Cancer

by Annalisa Lorenzato, Alessandro Magrì, Vittoria Matafora, Valentina Audrito, Pamela Arcella, Luca Lazzari, Monica Montone, Simona Lamba, Silvia Deaglio, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Angela Bachi, Federica Di Nicolantonio, Alberto Bardelli and Sabrina Arena

Cancers 2020, 12(3), 685; https://doi.org/10.3390/cancers12030685 - 14 Mar 2020

Cited by 53 | Viewed by 6427

Abstract

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents [...] Read more.

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRC RAS/BRAF wild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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20 pages, 4266 KiB

Open AccessArticle

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

by Andrea Díaz-Díaz, Daniel Roca-Lema, Alba Casas-Pais, Gabriela Romay, Giovanni Colombo, Ángel Concha, Begoña Graña and Angélica Figueroa

Cancers 2020, 12(1), 215; https://doi.org/10.3390/cancers12010215 - 15 Jan 2020

Cited by 13 | Viewed by 4662

Abstract

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug [...] Read more.

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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22 pages, 4622 KiB

Open AccessArticle

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

by Alaa A. A. Aljabali, Hamid A. Bakshi, Faruck L. Hakkim, Yusuf A. Haggag, Khalid M. Al-Batanyeh, Mazhar S. Al Zoubi, Bahaa Al-Trad, Mohamed M. Nasef, Saurabh Satija, Meenu Mehta, Kavita Pabreja, Vijay Mishra, Mohammed Khan, Salem Abobaker, Ibrahim M. Azzouz, Harish Dureja, Ritesh M. Pabari, Ashref Ali K. Dardouri, Prashant Kesharwani, Gaurav Gupta, Shakti Dhar Shukla, Parteek Prasher, Nitin B. Charbe, Poonam Negi, Deepak N. Kapoor, Dinesh Kumar Chellappan, Mateus Webba da Silva, Paul Thompson, Kamal Dua, Paul McCarron and Murtaza M. Tambuwala Show full author list Hide full author list

Cancers 2020, 12(1), 113; https://doi.org/10.3390/cancers12010113 - 1 Jan 2020

Cited by 79 | Viewed by 8828 | Correction

Abstract

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In [...] Read more.

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC–BSA nanoparticles (NPs). These PIC–BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC–BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC–BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC–BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC–BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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19 pages, 6340 KiB

Open AccessArticle

Repurposing Antibacterial AM404 As a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells

by Mehreen Ahmed, Nicholas Jinks, Roya Babaei-Jadidi, Hossein Kashfi, Marcos Castellanos-Uribe, Sean T. May, Abhik Mukherjee and Abdolrahman S. Nateri

Cancers 2020, 12(1), 106; https://doi.org/10.3390/cancers12010106 - 31 Dec 2019

Cited by 15 | Viewed by 5130

Abstract

Tumour-promoting inflammation is involved in colorectal cancer (CRC) development and therapeutic resistance. However, the antibiotics and antibacterial drugs and signalling that regulate the potency of anticancer treatment upon forced differentiation of cancer stem-like cell (CSC) are not fully defined yet. We screened an [...] Read more.

Tumour-promoting inflammation is involved in colorectal cancer (CRC) development and therapeutic resistance. However, the antibiotics and antibacterial drugs and signalling that regulate the potency of anticancer treatment upon forced differentiation of cancer stem-like cell (CSC) are not fully defined yet. We screened an NIH-clinical collection of the small-molecule compound library of antibacterial/anti-inflammatory agents that identified potential candidate drugs targeting CRC-SC for differentiation. Selected compounds were validated in both in vitro organoids and ex vivo colon explant models for their differentiation induction, impediment on neoplastic cell growth, and to elucidate the mechanism of their anticancer activity. We initially focused on AM404, an anandamide uptake inhibitor. AM404 is a metabolite of acetaminophen with antibacterial activity, which showed high potential in preventing CRC-SC features, such as stemness/de-differentiation, migration and drug-resistance. Furthermore, AM404 suppressed the expression of FBXL5 E3-ligase, where AM404 sensitivity was mimicked by FBXL5-knockout. This study uncovers a new molecular mechanism for AM404-altering FBXL5 oncogene which mediates chemo-resistance and CRC invasion, thereby proposes to repurpose antibacterial AM404 as an anticancer agent. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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27 pages, 7443 KiB

Open AccessArticle

Connecting Cancer Pathways to Tumor Engines: A Stratification Tool for Colorectal Cancer Combining Human In Vitro Tissue Models with Boolean In Silico Models

by Florentin Baur, Sarah L. Nietzer, Meik Kunz, Fabian Saal, Julian Jeromin, Stephanie Matschos, Michael Linnebacher, Heike Walles, Thomas Dandekar and Gudrun Dandekar

Cancers 2020, 12(1), 28; https://doi.org/10.3390/cancers12010028 - 20 Dec 2019

Cited by 10 | Viewed by 5736

Abstract

To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells [...] Read more.

To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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15 pages, 2598 KiB

Open AccessArticle

TREM2 Acts as a Tumor Suppressor in Colorectal Carcinoma through Wnt1/β-catenin and Erk Signaling

by Su-Man Kim, Eun-Mi Kim, Kon-Young Ji, Hwa-Youn Lee, Su-Min Yee, Su-Min Woo, Ja-Woon Yi, Chul-Ho Yun, Harim Choi and Hyung-Sik Kang

Cancers 2019, 11(9), 1315; https://doi.org/10.3390/cancers11091315 - 6 Sep 2019

Cited by 28 | Viewed by 5929

Abstract

TREM2 (triggering receptor expressed on myeloid cells) is involved in the development of malignancies. However, the function of TREM2 in colorectal cancer has not been clearly elucidated. Here, we investigated TREM2 function for the first time in colorectal epithelial cancer cells and demonstrated [...] Read more.

TREM2 (triggering receptor expressed on myeloid cells) is involved in the development of malignancies. However, the function of TREM2 in colorectal cancer has not been clearly elucidated. Here, we investigated TREM2 function for the first time in colorectal epithelial cancer cells and demonstrated that TREM2 is a novel tumor suppressor in colorectal carcinoma. Blockade of TREM2 significantly promoted the proliferation of HT29 colorectal carcinoma cells by regulating cell cycle-related factors, such as p53 phosphorylation and p21 and cyclin D1 protein levels. HT29 cell migration was also increased by TREM2 inhibition via MMP9 (matrix metalloproteinase 9) expression upregulation. Furthermore, we found that the tumor suppressor effects of TREM2 were associated with Wnt/β-catenin and extracellular signal-regulated kinase (ERK) signaling. Importantly, the effect of TREM2 in the suppression of tumor development was demonstrated by in vivo and in vitro assays, as well as in human colon cancer patient tissue arrays. Overall, our results identify TREM2 as a potential prognostic biomarker and therapeutic target for colorectal cancer. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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Review

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19 pages, 4034 KiB

Open AccessReview

Relevance of Regulatory T Cells during Colorectal Cancer Development

by Jonadab E. Olguín, Itzel Medina-Andrade, Tonathiu Rodríguez, Miriam Rodríguez-Sosa and Luis I. Terrazas

Cancers 2020, 12(7), 1888; https://doi.org/10.3390/cancers12071888 - 14 Jul 2020

Cited by 40 | Viewed by 5326

Abstract

In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in [...] Read more.

In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called “phenotypic plasticity”, where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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25 pages, 2202 KiB

Open AccessReview

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

by Hao Wang, Liye Wang, Zuoxu Xie, Shuang Zhou, Yan Li, Yue Zhou and Meiyan Sun

Cancers 2020, 12(7), 1881; https://doi.org/10.3390/cancers12071881 - 13 Jul 2020

Cited by 50 | Viewed by 6591

Abstract

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. [...] Read more.

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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29 pages, 2781 KiB

Open AccessReview

Combinatorial Immunotherapies for Metastatic Colorectal Cancer

by Eline Janssen, Beatriz Subtil, Fàtima de la Jara Ortiz, Henk M. W. Verheul and Daniele V. F. Tauriello

Cancers 2020, 12(7), 1875; https://doi.org/10.3390/cancers12071875 - 12 Jul 2020

Cited by 24 | Viewed by 5381

Abstract

Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady [...] Read more.

Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady advances in treatment options. Immunotherapies are currently not widely applicable for this disease, yet show potential in preclinical models and clinical translation. The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion—forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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32 pages, 1496 KiB

Open AccessReview

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

by Carina Neitzel, Philipp Demuth, Simon Wittmann and Jörg Fahrer

Cancers 2020, 12(7), 1731; https://doi.org/10.3390/cancers12071731 - 29 Jun 2020

Cited by 37 | Viewed by 7451

Abstract

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order [...] Read more.

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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25 pages, 899 KiB

Open AccessReview

Targeting Protein Synthesis in Colorectal Cancer

by Stefanie Schmidt, Sarah Denk and Armin Wiegering

Cancers 2020, 12(5), 1298; https://doi.org/10.3390/cancers12051298 - 21 May 2020

Cited by 26 | Viewed by 7713

Abstract

Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation [...] Read more.

Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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19 pages, 1036 KiB

Open AccessFeature PaperReview

Targeting Programmed Fusobacterium nucleatum Fap2 for Colorectal Cancer Therapy

by Kumar Ganesan, Songhe Guo, Sundaz Fayyaz, Ge Zhang and Baojun Xu

Cancers 2019, 11(10), 1592; https://doi.org/10.3390/cancers11101592 - 18 Oct 2019

Cited by 36 | Viewed by 7700

Abstract

Colorectal patients generally have the maximum counts of Fusobacterium nucleatum (F. nucleatum) in tumors and elevate colorectal adenomas and carcinomas, which show the lowest rate of human survival. Hence, F. nucleatum is a diagnostic marker of colorectal cancer (CRC). Studies demonstrated that targeting [...] Read more.

Colorectal patients generally have the maximum counts of Fusobacterium nucleatum (F. nucleatum) in tumors and elevate colorectal adenomas and carcinomas, which show the lowest rate of human survival. Hence, F. nucleatum is a diagnostic marker of colorectal cancer (CRC). Studies demonstrated that targeting fusobacterial Fap2 or polysaccharide of the host epithelium may decrease fusobacteria count in the CRC. Attenuated F. nucleatum-Fap2 prevents transmembrane signals and inhibits tumorigenesis inducing mechanisms. Hence, in this review, we hypothesized that application of genetically programmed fusobacterium can be skillful and thus reduce fusobacterium in the CRC. Genetically programmed F. nucleatum is a promising antitumor strategy. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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4 pages, 1632 KiB

Open AccessCorrection

Correction: Aljabali, A.A.A.; et al. Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer via down Regulation of Nuclear p65 and HIF-1α. Cancers 2020, 12, 113

by Alaa A. A. Aljabali, Hamid A. Bakshi, Faruck L. Hakkim, Yusuf A. Haggag, Khalid M. Al-Batanyeh, Mazhar S. Al Zoubi, Bahaa Al-Trad, Mohamed M. Nasef, Saurabh Satija, Meenu Mehta, Kavita Pabreja, Vijay Mishra, Mohammed Khan, Salem Abobaker, Ibrahim M. Azzouz, Harish Dureja, Ritesh M. Pabari, Ashref Ali K. Dardouri, Prashant Kesharwani, Gaurav Gupta, Shakti Dhar Shukla, Parteek Prasher, Nitin B. Charbe, Poonam Negi, Deepak N. Kapoor, Dinesh Kumar Chellappan, Mateus Webba da Silva, Paul Thompson, Kamal Dua, Paul McCarron and Murtaza M. Tambuwala Show full author list Hide full author list

Cancers 2020, 12(12), 3587; https://doi.org/10.3390/cancers12123587 - 30 Nov 2020

Cited by 6 | Viewed by 2099

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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