Cancers

Editorial

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3 pages, 183 KiB

Open AccessEditorial

Metastatic Colorectal Cancer

by Alessandro Passardi, Giorgia Marisi and Paola Ulivi

Cancers 2021, 13(24), 6346; https://doi.org/10.3390/cancers13246346 - 17 Dec 2021

Cited by 1 | Viewed by 1997

Abstract

International experts in the study of metastatic colorectal cancer (mCRC) present this series of 14 articles (eleven original articles and three literature reviews) [...] Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

Research

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20 pages, 1835 KiB

Open AccessArticle

Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis

by Carmen Ili, Kurt Buchegger, Hannah Demond, Juan Castillo-Fernandez, Gavin Kelsey, Louise Zanella, Michel Abanto, Ismael Riquelme, Jaime López, Tamara Viscarra, Patricia García, Enrique Bellolio, David Saavedra and Priscilla Brebi

Cancers 2020, 12(9), 2710; https://doi.org/10.3390/cancers12092710 - 22 Sep 2020

Cited by 19 | Viewed by 5547

Abstract

Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples [...] Read more.

Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, FIGN, HTRA3, BDNF, HCN4 and STAC2 genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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35 pages, 31412 KiB

Open AccessArticle

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

by Jan Schulte am Esch, Beatrice Ariane Windmöller, Johannes Hanewinkel, Jonathan Storm, Christine Förster, Ludwig Wilkens, Martin Krüger, Barbara Kaltschmidt and Christian Kaltschmidt

Cancers 2020, 12(9), 2582; https://doi.org/10.3390/cancers12092582 - 10 Sep 2020

Cited by 10 | Viewed by 4453

Abstract

Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers [...] Read more.

Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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18 pages, 1631 KiB

Open AccessArticle

The Level of Preoperative Plasma KRAS Mutations and CEA Predict Survival of Patients Undergoing Surgery for Colorectal Cancer Liver Metastases

by Jiri Polivka, Jindra Windrichova, Martin Pesta, Katerina Houfkova, Hana Rezackova, Tereza Macanova, Ondrej Vycital, Radek Kucera, David Slouka and Ondrej Topolcan

Cancers 2020, 12(9), 2434; https://doi.org/10.3390/cancers12092434 - 27 Aug 2020

Cited by 19 | Viewed by 2874

Abstract

Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA [...] Read more.

Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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24 pages, 87099 KiB

Open AccessArticle

An Integrative Omics Approach Reveals Involvement of BRCA1 in Hepatic Metastatic Progression of Colorectal Cancer

by Daniela Gerovska, Gorka Larrinaga, Jon Danel Solano-Iturri, Joana Márquez, Patricia García Gallastegi, Abdel-Majid Khatib, Gereon Poschmann, Kai Stühler, María Armesto, Charles H. Lawrie, Iker Badiola and Marcos J. Araúzo-Bravo

Cancers 2020, 12(9), 2380; https://doi.org/10.3390/cancers12092380 - 22 Aug 2020

Cited by 10 | Viewed by 3521

Abstract

(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). [...] Read more.

(1) Background & Aims: The roles of different cells in the tumor microenvironment (TME) are critical to the metastatic process. The phenotypic transformation of the liver cells is one of the most important stages of the hepatic metastasis progression of colorectal cancer (CRC). Our aim was to identify the major molecules (i.e., genes, miRNAs and proteins) involved in this process. (2) Methods: We isolated and performed whole-genome analysis of gene, miRNA, and protein expression in three types of liver cells (Ito cells, Kupffer cells, and liver sinusoidal endothelial cells) from the TME of a murine model of CRC liver metastasis. We selected the statistically significant differentially expressed molecules using the Student’s t-test with Benjamini-Hochberg correction and performed functional statistically-significant enrichment analysis of differentially expressed molecules with hypergeometric distribution using the curated collection of molecular signatures, MSigDB. To build a gene-miRNA-protein network centered in Brca1, we developed a software package (miRDiana) that collects miRNA targets from the union of the TargetScan, MicroCosm, mirTarBase, and miRWalk databases. This was used to search for miRNAs targeting Brca1. We validated the most relevant miRNAs with real-time quantitative PCR. To investigate BRCA1 protein expression, we built tissue microarrays (TMAs) from hepatic metastases of 34 CRC patients. (3) Results: Using integrated omics analyses, we observed that the Brca1 gene is among the twenty transcripts simultaneously up-regulated in all three types of TME liver cells during metastasis. Further analysis revealed that Brca1 is the last BRCA1-associated genome surveillance complex (BASC) gene activated in the TME. We confirmed this finding in human reanalyzing transcriptomics datasets from 184 patients from non-tumor colorectal tissue, primary colorectal tumor and colorectal liver metastasis of the GEO database. We found that the most probable sequence of cell activation during metastasis is Endothelial→Ito→Kupffer. Immunohistochemical analysis of human liver metastases showed the BRCA1 protein was co-localized in Ito, Kupffer, and endothelial cells in 81.8% of early or synchronous metastases. However, in the greater part of the metachronous liver metastases, this protein was not expressed in any of these TME cells. (4) Conclusions: These results suggest a possible role of the co-expression of BRCA1 in Ito, Kupffer, and sinusoidal endothelial cells in the early occurrence of CRC liver metastases, and point to BRCA1 as a potential TME biomarker. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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12 pages, 1276 KiB

Open AccessArticle

Correlation of RECIST, Computed Tomography Morphological Response, and Pathological Regression in Hepatic Metastasis Secondary to Colorectal Cancer: The AVAMET Study

by Ruth Vera, María Luisa Gómez, Juan Ramón Ayuso, Joan Figueras, Pilar García-Alfonso, Virginia Martínez, Adelaida Lacasta, Ana Ruiz-Casado, María José Safont, Jorge Aparicio, Juan Manuel Campos, Juan Carlos Cámara, Marta Martín-Richard, Clara Montagut, Carles Pericay, Jose María Vieitez, Esther Falcó, Mónica Jorge, Miguel Marín, Mercedes Salgado and Antonio Viúdez Show full author list Hide full author list

Cancers 2020, 12(8), 2259; https://doi.org/10.3390/cancers12082259 - 12 Aug 2020

Cited by 11 | Viewed by 2711

Abstract

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged [...] Read more.

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m², capecitabine 1000 mg/m² bid on days 1–14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3–5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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13 pages, 889 KiB

Open AccessArticle

Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial

by Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Chiara Cremolini, Sabina Murgioni, Sara Lonardi, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Afsaneh Barzi, Fotios Loupakis, Alfredo Falcone and Heinz-Josef Lenz

Cancers 2020, 12(7), 1742; https://doi.org/10.3390/cancers12071742 - 30 Jun 2020

Cited by 5 | Viewed by 2445

Abstract

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 [...] Read more.

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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9 pages, 752 KiB

Open AccessArticle

The Role of Anti-Angiogenics in Pre-Treated Metastatic BRAF-Mutant Colorectal Cancer: A Pooled Analysis

by Fabio Gelsomino, Andrea Casadei-Gardini, Daniele Rossini, Alessandra Boccaccino, Gianluca Masi, Chiara Cremolini, Andrea Spallanzani, Massimo Giuseppe Viola, Ingrid Garajovà, Massimiliano Salati, Maria Teresa Elia, Francesco Caputo, Chiara Santini, Alfredo Falcone, Stefano Cascinu and Emiliano Tamburini

Cancers 2020, 12(4), 1022; https://doi.org/10.3390/cancers12041022 - 21 Apr 2020

Cited by 16 | Viewed by 3399

Abstract

Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated [...] Read more.

Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29–0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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11 pages, 1190 KiB

Open AccessArticle

Effectiveness and Costs Associated to Adding Cetuximab or Bevacizumab to Chemotherapy as Initial Treatment in Metastatic Colorectal Cancer: Results from the Observational FABIO Project

by Matteo Franchi, Donatella Garau, Ursula Kirchmayer, Mirko Di Martino, Marilena Romero, Ilenia De Carlo, Salvatore Scondotto and Giovanni Corrao

Cancers 2020, 12(4), 839; https://doi.org/10.3390/cancers12040839 - 31 Mar 2020

Cited by 11 | Viewed by 2819

Abstract

Evidence available on the effectiveness and costs of biological therapies for the initial treatment of metastatic colorectal cancer (mCRC) is scarce and contrasting. We conducted a population-based cohort investigation for assessing overall survival and costs associated with their use in a real-world setting. [...] Read more.

Evidence available on the effectiveness and costs of biological therapies for the initial treatment of metastatic colorectal cancer (mCRC) is scarce and contrasting. We conducted a population-based cohort investigation for assessing overall survival and costs associated with their use in a real-world setting. Healthcare utilization databases were used to select patients newly diagnosed with mCRC between 2010 and 2016. Those initially treated with biological therapy (bevacizumab or cetuximab) added to chemotherapy were propensity-score-matched to those treated with standard chemotherapy alone, and were followed up to June 30th, 2018. Kaplan–Meier survival estimates, restricted mean survival time (RMST) and cumulative costs were compared between the two treatment arms. The study cohort included 1896 mCRC patients treated with biological therapy matched to 5678 patients treated with chemotherapy alone. Median overall survival was 21.8 and 20.2 months, respectively. After 84 months of follow-up, RMSTs were 30.9 and 31.9 months (p = 0.193), indicating no differences between the average survival time between treatment arms. Patients treated with biological therapy were associated with higher costs. Cumulative per capita costs were €59,663 and €44,399, respectively. In our study, first-line biological therapy did not improve long-term overall survival and was associated with higher costs as compared to standard chemotherapy. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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10 pages, 534 KiB

Open AccessArticle

An Easy-To-Use Survival Score Compared to Existing Tools for Older Patients with Cerebral Metastases from Colorectal Cancer

by Dirk Rades, Trang Nguyen, Stefan Janssen and Steven E. Schild

Cancers 2020, 12(4), 833; https://doi.org/10.3390/cancers12040833 - 30 Mar 2020

Cited by 5 | Viewed by 2226

Abstract

An easy-to-use survival score was developed specifically for older patients with cerebral metastases from colorectal cancer, and was compared to existing tools regarding the accuracy of identifying patients who die in ≤6 months and those who survive for ≥6 months. The new score [...] Read more.

An easy-to-use survival score was developed specifically for older patients with cerebral metastases from colorectal cancer, and was compared to existing tools regarding the accuracy of identifying patients who die in ≤6 months and those who survive for ≥6 months. The new score was built from 57 patients receiving whole-brain irradiation. It included three groups identified from 6-month survival rates based on two independent predictors (performance status and absence/presence of non-cerebral metastases), with 6-month survival rates of 0% (0 points), 26% (1 point), and 75% (2 points), respectively. This score was compared to diagnosis-specific scores, namely the diagnosis-specific graded prognostic assessment (DS-GPA), the Dziggel-Score and the WBRT-30-CRC (whole-brain radiotherapy with 30 Gy in 10 fractions for cerebral metastases from colorectal cancer) score and to a non-diagnosis-specific score for older persons (Evers-Score). Positive predictive values were 100% (new score), 87% (DS-GPA), 86% (Dziggel-Score), 91% (WBRT-30-CRC), and 100% (Evers-Score), respectively, for patients dying ≤6 months, and 75%, 33%, 75%, 60%, and 45%, respectively, for survivors ≥6 months. Of the five tools, the new score and the Evers-Score were most precise in identifying patients dying ≤6 months. The new score and the Dziggel-Scores were best at identifying patients surviving ≥6 months. When combining the results, the new score appeared preferable to the existing tools. The score appears not necessary for patients with additional liver metastases, since their 6-month survival rate was 0%. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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13 pages, 2727 KiB

Open AccessArticle

Autocatalytic Tissue Polymerization Reaction Mechanism in Colorectal Cancer Development and Growth

by Bruce M. Boman, Arthur Guetter, Ryan M. Boman and Olaf A. Runquist

Cancers 2020, 12(2), 460; https://doi.org/10.3390/cancers12020460 - 17 Feb 2020

Cited by 3 | Viewed by 3111

Abstract

The goal of our study was to measure the kinetics of human colorectal cancer (CRC) development in order to identify aberrant mechanisms in tissue dynamics and processes that contribute to colon tumorigenesis. The kinetics of tumor development were investigated using age-at-tumor diagnosis (adenomas [...] Read more.

The goal of our study was to measure the kinetics of human colorectal cancer (CRC) development in order to identify aberrant mechanisms in tissue dynamics and processes that contribute to colon tumorigenesis. The kinetics of tumor development were investigated using age-at-tumor diagnosis (adenomas and CRCs) of familial adenomatous coli (FAP) patients and sporadic CRC patients. Plots of age-at-tumor diagnosis data as a function of age showed a distinct sigmoidal-shaped curve that is characteristic of an autocatalytic reaction. Consequently, we performed logistics function analysis and found an excellent fit (p < 0.05) of the logistic equation to the curves for age-at-tumor diagnoses. These findings indicate that the tissue mechanism that becomes altered in CRC development and growth involves an autocatalytic reaction. We conjecture that colonic epithelium normally functions as a polymer of cells which dynamically maintains itself in a steady state through an autocatalytic polymerization mechanism. Further, in FAP and sporadic CRC patients, mutation in the adenomatous polyposis coli (APC) gene increases autocatalytic tissue polymerization and induces tumor tissues to autocatalyze their own progressive growth, which drives tumor development in the colon. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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12 pages, 1093 KiB

Open AccessArticle

Small RNA Profiling of piRNAs in Colorectal Cancer Identifies Consistent Overexpression of piR-24000 That Correlates Clinically with an Aggressive Disease Phenotype

by Deepak Narayanan Iyer, Timothy Ming-Hun Wan, Johnny Hon-Wai Man, Ryan Wai-Yan Sin, Xue Li, Oswens Siu-Hung Lo, Dominic Chi-Chung Foo, Roberta Wen-Chi Pang, Wai-Lun Law and Lui Ng

Cancers 2020, 12(1), 188; https://doi.org/10.3390/cancers12010188 - 12 Jan 2020

Cited by 24 | Viewed by 3432

Abstract

Piwi-interacting RNAs (piRNAs) represent a novel class of small non-coding RNAs (ncRNAs) that have been shown to have a deregulated expression in several cancers, although their clinical significance in colorectal cancer (CRC) remains unclear. With an aim of delineating the piRNA distribution in [...] Read more.

Piwi-interacting RNAs (piRNAs) represent a novel class of small non-coding RNAs (ncRNAs) that have been shown to have a deregulated expression in several cancers, although their clinical significance in colorectal cancer (CRC) remains unclear. With an aim of delineating the piRNA distribution in CRC, we conducted a systematic discovery and validation of piRNAs within two clinical cohorts. In the discovery phase, we profiled tumor and adjacent normal tissues from 18 CRC patients by deep sequencing and identified a global piRNA downregulation in CRC. Moreover, we identified piR-24000 as an unexplored piRNA that was significantly overexpressed in CRC. Using qPCR, we validated the overexpression of piR-24000 in 87 CRC patients. Additionally, we identified a significant association between a high expression of piR-24000 and an aggressive CRC phenotype including poor differentiation, presence of distant metastases, and a higher stage. Lastly, ROC analysis demonstrated a strong diagnostic power of piR-24000 in discriminating CRC patients from normal subjects. Taken together, this study provides one of the earliest large-scale reports of the global distribution of piRNAs in CRC. In addition, piR-24000 was identified as a likely oncogene in CRC that can serve as a biomarker or a therapeutic target. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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Review

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27 pages, 654 KiB

Open AccessReview

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

by Federica Marmorino, Alessandra Boccaccino, Marco Maria Germani, Alfredo Falcone and Chiara Cremolini

Cancers 2020, 12(8), 2317; https://doi.org/10.3390/cancers12082317 - 17 Aug 2020

Cited by 39 | Viewed by 6064

Abstract

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in [...] Read more.

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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21 pages, 1155 KiB

Open AccessReview

Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer

by Erta Kalanxhi, Sebastian Meltzer and Anne Hansen Ree

Cancers 2020, 12(8), 2193; https://doi.org/10.3390/cancers12082193 - 6 Aug 2020

Cited by 6 | Viewed by 2607

Abstract

Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality [...] Read more.

Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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17 pages, 1425 KiB

Open AccessReview

Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer

by Manuela Porru, Pasquale Zizza, Nadia Panera, Anna Alisi, Annamaria Biroccio and Carlo Leonetti

Cancers 2020, 12(7), 1830; https://doi.org/10.3390/cancers12071830 - 8 Jul 2020

Cited by 2 | Viewed by 2859

Abstract

Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients’ outcome are needed. During the last decade, the application of a multi-omics approach has contributed [...] Read more.

Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients’ outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients. In particular, organoids and patient-derived-xenografts (PDXs), as well as genetically engineered mouse models (GEMMs) and patient-derived orthotopic xenografts (PDOXs), should be considered for translational purposes. Overall, omics and advanced mouse models of cancer represent a portfolio of sophisticated biological tools that, if optimized for use in concert with accurate data analysis, could accelerate the anticancer discovery process and provide new weapons against cancer. In this review, we highlight success reached following the integration of omics and experimental models; moreover, results produced by our group in the field of mCRC are also presented. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer)

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