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In Vitro and In Vivo Models of Colorectal Cancer for...
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In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 46728

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Marta Baiocchi

E-Mail Website
Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 199, Roma 00161, Italy
Interests: colorectal cancer; cancer stem cells; stem cells biobanks; high-throughput analysis; target-oriented therapies
Dr. Ann Zeuner

E-Mail Website
Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 199, Roma 00161, Italy
Interests: cancer stem cells; colorectal cancer; breast cancer; quiescence; chemotherapy resistance

Special Issue Information

Dear Colleagues,

Recent years have witnessed an unprecedented expansion of therapeutic options for colorectal cancer (CRC), with several molecularly targeted agents now established in clinical practice. Moreover, many new approaches are currently under evaluation, aimed at targeting different aspects of tumor biology including proliferating and quiescent cancer stem cells, antitumor immunity, tumor–microenvironment interactions, cancer metabolism, and cancer-associated epigenetic modifications. Advancements of high-throughput molecular analyses keep unveiling new details of the CRC molecular landscape contributing to identifying novel targets, to define improved methods for patients’ classification and to achieve a better tuning of personalized therapies. Despite increasing knowledge of the molecular mechanisms underlying CRC, the percentage of new drugs that are obtaining clinical approval has been constantly decreasing in the last decades. The reason for this disconnection between basic/translational research and the related clinical outcomes resides, at least in part, in the limitations of preclinical models currently available for CRC. In fact, increasingly sophisticated experimental systems recapitulating CRC in vitro and in vivo, such as organoids and patient-derived xenografts are characterized by both intriguing complexities and intrinsic limitations, some of which are yet beginning to be understood. In this scenario, it is equally necessary to fully understand the potential of existing preclinical CRC models and to develop and validate novel tools for anticancer therapies. In this Special Issue, we will collect original research papers and reviews depicting the current state and the perspectives of CRC models for preclinical and translational research, examining and discussing their usefulness for patient diagnosis and therapy.

Dr. Marta Baiocchi
Dr. Ann Zeuner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (12 papers)

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12 pages, 3233 KiB  
Article
Preclinical PET Imaging of Tumor Cell Death following Therapy Using Gallium-68-Labeled C2Am
by Flaviu Bulat, Friederike Hesse, Bala Attili, Chandra Solanki, Iosif A. Mendichovszky, Franklin Aigbirhio, Finian J. Leeper, Kevin M. Brindle and André A. Neves
Cancers 2023, 15(5), 1564; https://doi.org/10.3390/cancers15051564 - 2 Mar 2023
Viewed by 1723
Abstract
There is an unmet clinical need for imaging agents capable of detecting early evidence of tumor cell death, since the timing, extent, and distribution of cell death in tumors following treatment can give an indication of treatment outcome. We describe here 68Ga-labeled [...] Read more.
There is an unmet clinical need for imaging agents capable of detecting early evidence of tumor cell death, since the timing, extent, and distribution of cell death in tumors following treatment can give an indication of treatment outcome. We describe here 68Ga-labeled C2Am, which is a phosphatidylserine-binding protein, for imaging tumor cell death in vivo using positron emission tomography (PET). A one-pot synthesis of 68Ga-C2Am (20 min, 25 °C, >95% radiochemical purity) has been developed, using a NODAGA-maleimide chelator. The binding of 68Ga-C2Am to apoptotic and necrotic tumor cells was assessed in vitro using human breast and colorectal cancer cell lines, and in vivo, using dynamic PET measurements in mice implanted subcutaneously with the colorectal tumor cells and treated with a TRAIL-R2 agonist. 68Ga-C2Am showed predominantly renal clearance and low retention in the liver, spleen, small intestine, and bone and generated a tumor-to-muscle (T/m) ratio of 2.3 ± 0.4, at 2 h post probe administration and at 24 h following treatment. 68Ga-C2Am has the potential to be used in the clinic as a PET tracer for assessing early treatment response in tumors. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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8 pages, 1365 KiB  
Article
Sequential Isolation and Characterization of Single CTCs and Large CTC Clusters in Metastatic Colorectal Cancer Patients
by Federica Francescangeli, Valentina Magri, Maria Laura De Angelis, Gianluigi De Renzi, Orietta Gandini, Ann Zeuner, Paola Gazzaniga and Chiara Nicolazzo
Cancers 2021, 13(24), 6362; https://doi.org/10.3390/cancers13246362 - 18 Dec 2021
Cited by 16 | Viewed by 2576
Abstract
Circulating tumor cells (CTCs) detach from a primary tumor or its metastases and circulate in the bloodstream. The vast majority of CTCs are deemed to die into the bloodstream, with only few cells representing viable metastatic precursors. Particularly, single epithelial CTCs do not [...] Read more.
Circulating tumor cells (CTCs) detach from a primary tumor or its metastases and circulate in the bloodstream. The vast majority of CTCs are deemed to die into the bloodstream, with only few cells representing viable metastatic precursors. Particularly, single epithelial CTCs do not survive long in the circulation due to the loss of adhesion-dependent survival signals. In metastatic colorectal cancer, the generation of large CTC clusters is a very frequent occurrence, able to increase the aptitude of CTCs to survive in the bloodstream. Although a deepened analysis of large-sized CTC clusters might certainly offer new insights into the complexity of the metastatic cascade, most CTC isolation techniques are unfortunately not compatible with large-sized CTC clusters isolation. The inappropriateness of standard CTC isolation devices for large clusters isolation and the scarce availability of detection methods able to specifically isolate and characterize both single CTCs and CTC clusters finally prevented in-depth studies on the prognostic and predictive value of clusters in clinical practice, unlike that which has been described for single CTCs. In the present study, we validated a new sequential filtration method for the simultaneous isolation of large CTC clusters and single CTCs in patients with metastatic colorectal cancer at failure of first-line treatments. The new method might allow differential downstream analyses for single and clustered CTCs starting from a single blood draw, opening new scenarios for an ever more precise characterization of colorectal cancer metastatic cascade. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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15 pages, 1354 KiB  
Article
Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups
by Maxime Schmitt, Miguel Silva, Björn Konukiewitz, Corinna Lang, Katja Steiger, Kathrin Halfter, Jutta Engel, Paul Jank, Nicole Pfarr, Dirk Wilhelm, Sebastian Foersch, Carsten Denkert, Markus Tschurtschenthaler, Wilko Weichert and Moritz Jesinghaus
Cancers 2021, 13(24), 6177; https://doi.org/10.3390/cancers13246177 - 7 Dec 2021
Cited by 7 | Viewed by 2546
Abstract
Background: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. Methods: SATB2 expression was analysed in [...] Read more.
Background: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. Methods: SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. Results: SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p < 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p < 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. Conclusions: SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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16 pages, 34847 KiB  
Article
The HROC-Xenobank—A High Quality Assured PDX Biobank of >100 Individual Colorectal Cancer Models
by Stephanie Matschos, Florian Bürtin, Said Kdimati, Mandy Radefeldt, Susann Krake, Friedrich Prall, Nadja Engel, Mathias Krohn, Bianca Micheel, Michael Kreutzer, Christina Susanne Mullins and Michael Linnebacher
Cancers 2021, 13(23), 5882; https://doi.org/10.3390/cancers13235882 - 23 Nov 2021
Cited by 5 | Viewed by 2172
Abstract
Based on our research group’s large biobank of colorectal cancers (CRC), we here describe the ongoing activity of establishing a high quality assured PDX biobank for more than 100 individual CRC cases. This includes sufficient numbers of vitally frozen (n > 30 [...] Read more.
Based on our research group’s large biobank of colorectal cancers (CRC), we here describe the ongoing activity of establishing a high quality assured PDX biobank for more than 100 individual CRC cases. This includes sufficient numbers of vitally frozen (n > 30 aliquots) and snap frozen (n > 5) backups, “ready to use”. Additionally, PDX tumor pieces were paraffin embedded. At the current time, we have completed 125 cases. This resource allows histopathological examinations, molecular characterizations, and gene expression analysis. Due to its size, different issues of interest can be addressed. Most importantly, the application of low-passage, cryopreserved, and well-characterized PDX for in vivo studies guarantees the reliability of results due to the largely preserved tumor microenvironment. All cases described were molecularly subtyped and genetic identity, in comparison to the original tumor tissue, was confirmed by fingerprint analysis. The latter excludes ambiguity errors between the PDX and the original patient tumor. A cancer hot spot mutation analysis was performed for n = 113 of the 125 cases entities. All relevant CRC molecular subtypes identified so far are represented in the Hansestadt Rostock CRC (HROC)-Xenobank. Notably, all models are available for cooperative research approaches. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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16 pages, 2807 KiB  
Article
A Patient-Derived Organoid-Based Radiosensitivity Model for the Prediction of Radiation Responses in Patients with Rectal Cancer
by Misun Park, Junhye Kwon, Joonseog Kong, Sun Mi Moon, Sangsik Cho, Ki Young Yang, Won Il Jang, Mi Sook Kim, Younjoo Kim and Ui Sup Shin
Cancers 2021, 13(15), 3760; https://doi.org/10.3390/cancers13153760 - 27 Jul 2021
Cited by 21 | Viewed by 2934
Abstract
Patient-derived tumor organoids closely resemble original patient tumors. We conducted this co-clinical trial with treatment-naive rectal cancer patients and matched patient-derived tumor organoids to determine whether a correlation exists between experimental results obtained after irradiation in patients and organoids. Between November 2017 and [...] Read more.
Patient-derived tumor organoids closely resemble original patient tumors. We conducted this co-clinical trial with treatment-naive rectal cancer patients and matched patient-derived tumor organoids to determine whether a correlation exists between experimental results obtained after irradiation in patients and organoids. Between November 2017 and March 2020, we prospectively enrolled 33 patients who were diagnosed with mid-to-lower rectal adenocarcinoma based on endoscopic biopsy findings. We constructed a prediction model through a machine learning algorithm using clinical and experimental radioresponse data. Our data confirmed that patient-derived tumor organoids closely recapitulated original tumors, both pathophysiologically and genetically. Radiation responses in patients were positively correlated with those in patient-derived tumor organoids. Our machine learning-based prediction model showed excellent performance. In the prediction model for good responders trained using the random forest algorithm, the area under the curve, accuracy, and kappa value were 0.918, 81.5%, and 0.51, respectively. In the prediction model for poor responders, the area under the curve, accuracy, and kappa value were 0.971, 92.1%, and 0.75, respectively. Our patient-derived tumor organoid-based radiosensitivity model could lead to more advanced precision medicine for treating patients with rectal cancer. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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15 pages, 1332 KiB  
Article
Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression
by Janneke F. Linnekamp, Raju Kandimalla, Evelyn Fessler, Joan H. de Jong, Hans M. Rodermond, Gregor G. W. van Bochove, Frans O. The, Cornelis J. A. Punt, Willem A. Bemelman, Anthony W. H. van de Ven, Pieter J. Tanis, Elles M. Kemper, Lianne Koens, Evelien Dekker, Louis Vermeulen, Hanneke W. M. van Laarhoven and Jan Paul Medema
Cancers 2021, 13(10), 2357; https://doi.org/10.3390/cancers13102357 - 13 May 2021
Cited by 2 | Viewed by 2560
Abstract
DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and [...] Read more.
DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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18 pages, 3269 KiB  
Article
The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition
by Luca Mattiello, Sara Soliman Abdel Rehim, Martina Musella, Antonella Sistigu, Andrea Guarracino, Sara Vitale, Francesca Corradi, Claudia Galassi, Francesca Sperati, Gwenola Manic, Ruggero De Maria and Ilio Vitale
Cancers 2021, 13(8), 1957; https://doi.org/10.3390/cancers13081957 - 19 Apr 2021
Cited by 9 | Viewed by 2936
Abstract
Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, [...] Read more.
Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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32 pages, 4436 KiB  
Article
Functional States in Tumor-Initiating Cell Differentiation in Human Colorectal Cancer
by Martina K. Zowada, Stephan M. Tirier, Sebastian M. Dieter, Teresa G. Krieger, Ava Oberlack, Robert Lorenz Chua, Mario Huerta, Foo Wei Ten, Karin Laaber, Jeongbin Park, Katharina Jechow, Torsten Müller, Mathias Kalxdorf, Mark Kriegsmann, Katharina Kriegsmann, Friederike Herbst, Jeroen Krijgsveld, Martin Schneider, Roland Eils, Hanno Glimm, Christian Conrad and Claudia R. Balladd Show full author list remove Hide full author list
Cancers 2021, 13(5), 1097; https://doi.org/10.3390/cancers13051097 - 4 Mar 2021
Cited by 9 | Viewed by 5361
Abstract
Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell RNA-sequencing of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and [...] Read more.
Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell RNA-sequencing of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Furthermore, identified expression signatures are linked to patient prognosis. Targeting transcriptional states associated to cancer cell differentiation might unravel novel vulnerabilities in human CRC. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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Review

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17 pages, 1852 KiB  
Review
Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts
by Maria Laura De Angelis, Federica Francescangeli, Ann Zeuner and Marta Baiocchi
Cancers 2021, 13(23), 5910; https://doi.org/10.3390/cancers13235910 - 24 Nov 2021
Cited by 11 | Viewed by 2769
Abstract
Colorectal cancer (CRC) represents one of the most deadly cancers worldwide. Colorectal cancer stem cells (cCSCs) are the driving units of CRC initiation and development. After the concept of cCSC was first formulated in 2007, a huge bulk of research has contributed to [...] Read more.
Colorectal cancer (CRC) represents one of the most deadly cancers worldwide. Colorectal cancer stem cells (cCSCs) are the driving units of CRC initiation and development. After the concept of cCSC was first formulated in 2007, a huge bulk of research has contributed to expanding its definition, from a cell subpopulation defined by a fixed phenotype in a plastic entity modulated by complex interactions with the tumor microenvironment, in which cell position and niche-driven signals hold a prominent role. The wide development of cellular and molecular technologies recent years has been a main driver of advancements in cCSCs research. Here, we will give an overview of the parallel role of technological progress and of theoretical evolution in shaping the concept of cCSCs. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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25 pages, 1328 KiB  
Review
Colorectal Cancer and Immunity: From the Wet Lab to Individuals
by Elodie Pramil, Clémentine Dillard and Alexandre E. Escargueil
Cancers 2021, 13(7), 1713; https://doi.org/10.3390/cancers13071713 - 4 Apr 2021
Cited by 1 | Viewed by 8598
Abstract
Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as [...] Read more.
Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies. Intrinsic resistance can be mediated by the development of an immuno-suppressive environment in CRC. The mutational status of cancer cells also plays a role in this process. CRC can indeed be distinguished in two main subtypes. Microsatellite instable (MSI) tumors show a hyper-mutable phenotype caused by the deficiency of the DNA mismatch repair machinery (MMR) while microsatellite stable (MSS) tumors show a comparatively more “stable” mutational phenotype. Several studies demonstrated that MSI CRC generally display good prognoses for patients and immunotherapy is considered as a therapeutic option for this type of tumors. On the contrary, MSS metastatic CRC usually presents a worse prognosis and is not responsive to immunotherapy. According to this, developing new and innovative models for studying CRC response towards immune targeted therapies has become essential in the last years. Herein, we review the in vitro and in vivo models used for research in the field of immunotherapy applied to colorectal cancer. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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24 pages, 14961 KiB  
Review
The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials
by Céline Hervieu, Niki Christou, Serge Battu and Muriel Mathonnet
Cancers 2021, 13(5), 1092; https://doi.org/10.3390/cancers13051092 - 4 Mar 2021
Cited by 41 | Viewed by 5107
Abstract
The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The [...] Read more.
The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient’s overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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22 pages, 1380 KiB  
Review
Patient-Derived In Vitro Models for Drug Discovery in Colorectal Carcinoma
by George M. Ramzy, Thibaud Koessler, Eloise Ducrey, Thomas McKee, Frédéric Ris, Nicolas Buchs, Laura Rubbia-Brandt, Pierre-Yves Dietrich and Patrycja Nowak-Sliwinska
Cancers 2020, 12(6), 1423; https://doi.org/10.3390/cancers12061423 - 31 May 2020
Cited by 26 | Viewed by 5631
Abstract
Lack of relevant preclinical models that reliably recapitulate the complexity and heterogeneity of human cancer has slowed down the development and approval of new anti-cancer therapies. Even though two-dimensional in vitro culture models remain widely used, they allow only partial cell-to-cell and cell-to-matrix [...] Read more.
Lack of relevant preclinical models that reliably recapitulate the complexity and heterogeneity of human cancer has slowed down the development and approval of new anti-cancer therapies. Even though two-dimensional in vitro culture models remain widely used, they allow only partial cell-to-cell and cell-to-matrix interactions and therefore do not represent the complex nature of the tumor microenvironment. Therefore, better models reflecting intra-tumor heterogeneity need to be incorporated in the drug screening process to more reliably predict the efficacy of drug candidates. Classic methods of modelling colorectal carcinoma (CRC), while useful for many applications, carry numerous limitations. In this review, we address the recent advances in in vitro CRC model systems, ranging from conventional CRC patient-derived models, such as conditional reprogramming-based cell cultures, to more experimental and state-of-the-art models, such as cancer-on-chip platforms or liquid biopsy. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application)
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