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Colorectal Cancers: From Present Problems to Future Solutions

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 41521

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Prof. Dr. Heike Allgayer

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Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany
Interests: cancer metastasis; translational research; tumor-associated proteases; microRNAs; molecular staging; gastrointestinal cancers
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Colorectal cancer is still one of the most frequent cancer entities in humankind. The scientific community has made significant progress in our molecular understanding of colorectal carcinogenesis, of hereditary as well as sporadic colorectal cancer types, this pertaining to the discovery of, e.g., (mutated) oncogenes and tumor suppressor genes, microsatellite instabilities, modifications in DNA repair, cellular aging, signaling cascades, genomic, epigenetic, transcriptional, translational, and protein modifications, as well as microbiotic factors and further parameters. Progression and metastasis have been more intensively studied especially during recent years, this leading to an intensified knowledge on molecular protagonists and microenvironmental interactions contributing to invasion, dissemination, and metastasis; still, more concerted efforts need to be made to better understand issues such as metastasis to different sites, or the metastatic heterogeneity of single cells. Nevertheless, based on actual discoveries, personalized medicine, together with highly interdisciplinary therapeutic strategies combining advanced levels of surgical techniques, oncology, and radiation in neoadjuvant, adjuvant, or palliative settings, has started to improve the clinical prognosis of individual patients with colorectal cancer. However, too many patients with this disease will still be diagnosed in too advanced stages, develop relapse and metastasis despite of modern interdisciplinary and personalized therapy advances, and finally die of this disease which still belongs to the top killer cancer entities in the World.

The present Special Issue will feature articles of different international experts with the latest data in the fields mentioned above. It will include novel hypotheses on molecular drivers of the disease, advanced ideas on cancer cell heterogeneity and its diagnosis, and discuss the latest model systems and advances in the translation of molecular knowledge into clinical studies. With this Special Issue, we aim to deepen discussions and ideas amongst colleagues in all kinds of disciplines working on this disease, and to intensify translational and interdisciplinary collaborations aimed at an ultimate understanding of strategies to defeat, and prevent, colorectal cancer and its progression

Prof. Heike Allgayer, MD, PhD
Guest Editor

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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.

Keywords

colorectal cancer
(molecular) carcinogenesis
progression
metastasis
(single) cancer cell heterogeneity
models
(targeted) therapy
personalized medicine

Related Special Issue

Colorectal Cancers: From Present Problems to Future Solutions Volume II in Cancers (13 articles)

Published Papers (14 papers)

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Editorial

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4 pages, 171 KiB

Open AccessEditorial

An Editorial View on the Special Issue “Colorectal Cancers: From Present Problems to Future Solutions”

by Heike Allgayer

Cancers 2022, 14(4), 975; https://doi.org/10.3390/cancers14040975 - 15 Feb 2022

Viewed by 1103

Abstract

Colorectal cancer (CRC) represents one of the most frequent human cancer entities and is still amongst the “top killers” in human cancer, although fundamental progress has been made in recent years in CRC prevention, early diagnosis, basic and translational research, and (targeted) therapy [...] Read more.

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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18 pages, 4750 KiB

Open AccessArticle

Influence of Gender on Radiosensitivity during Radiochemotherapy of Advanced Rectal Cancer

by Barbara Schuster, Markus Hecht, Manfred Schmidt, Marlen Haderlein, Tina Jost, Maike Büttner-Herold, Klaus Weber, Axel Denz, Robert Grützmann, Arndt Hartmann, Hans Geinitz, Rainer Fietkau and Luitpold V. Distel

Cancers 2022, 14(1), 148; https://doi.org/10.3390/cancers14010148 - 29 Dec 2021

Cited by 10 | Viewed by 1441

Abstract

Gender is increasingly recognized as an important factor in medicine, although it has long been neglected in medical research in many areas. We have studied the influence of gender in advanced rectal cancer with a special focus on radiosensitivity. For this purpose, we studied a cohort of 495 men (84.1% ≥ T3, 63.6% N1, 17.6%, M1) and 215 women (84.2% ≥ T3, 56.7% N1, 22.8%, M1) who all suffered from advanced rectal cancer and were treated with radiochemotherapy. The energy deposited, DNA double-strand break (dsb) repair, occurrence of chromosomal aberrations, duration of therapy, tumor regression and tumor-infiltrating lymphocytes, laboratory parameters, quality of life and survival were assessed. The residual DNA dsb damage 24 h after irradiation in lymphocytes was identical in both sexes. Furthermore, chromosomal aberrations accurately reflecting radiosensitivity, were similar in both sexes. There were no gender-dependent differences in tumor regression, tumor-infiltrating lymphocytes and outcome indicating no differences in the radiosensitivity of cancer cells. The irradiated tumor volume in women was slightly lower than in men, related to body weight, no difference was observed. However, when the total energy deposited was calculated and related to the body weight, women were exposed to higher amounts of ionizing radiation. During radiochemotherapy, decreases in blood lymphocyte counts and albumin and several quality-of-life parameters such as nausea and vomiting, loss of appetite, and diarrhea were significantly worse in women. There is no difference in radiation sensitivity between men and women in both normal tissue and tumors. During radiochemotherapy, the quality of life deteriorates more in women than in men. However, women also recover quickly and there are no long-term differences in quality of life. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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24 pages, 2726 KiB

Open AccessArticle

Combination of Wnt/β-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer

by Mathias Dahlmann, Anne Monks, Erik D. Harris, Dennis Kobelt, Marc Osterland, Fadi Khaireddine, Pia Herrmann, Wolfgang Kemmner, Susen Burock, Wolfgang Walther, Robert H. Shoemaker and Ulrike Stein

Cancers 2022, 14(1), 37; https://doi.org/10.3390/cancers14010037 - 22 Dec 2021

Cited by 7 | Viewed by 3726

Abstract

Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metastasis for improved patient survival. S100A4-induced transcriptome arrays, confirmatory studies in isogenic CRC cell lines with defined β-catenin genotypes, and functional metastasis studies were performed. S100A4-regulated transcriptome examination revealed the transcriptional cross-regulation of metastasis-inducing S100A4 with Wnt pathway antagonist Dickkopf-1 (DKK1). S100A4 overexpression down-regulated DKK1, S100A4 knock-down increased DKK1. Recombinant DKK1 reduced S100A4 expression and S100A4-mediated cell migration. In xenografted mice, systemic S100A4-shRNA application increased intratumoral DKK1. The inverse correlation of S100A4 and DKK1 was confirmed in five independent publicly available CRC expression datasets. Combinatorial analysis of S100A4 and DKK1 in two additional independent CRC patient cohorts improved prognosis of overall and metastasis-free survival. The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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13 pages, 3256 KiB

Open AccessArticle

Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data

by Marlen Keil, Theresia Conrad, Michael Becker, Ulrich Keilholz, Marie-Laure Yaspo, Hans Lehrach, Moritz Schütte, Johannes Haybaeck and Jens Hoffmann

Cancers 2021, 13(23), 6018; https://doi.org/10.3390/cancers13236018 - 30 Nov 2021

Cited by 3 | Viewed by 2239

Abstract

The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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20 pages, 2205 KiB

Open AccessArticle

Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

by Nitin Patil, Mohammed L. Abba, Chan Zhou, Shujian Chang, Timo Gaiser, Jörg H. Leupold and Heike Allgayer

Cancers 2021, 13(23), 5951; https://doi.org/10.3390/cancers13235951 - 26 Nov 2021

Cited by 7 | Viewed by 2042

Abstract

MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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17 pages, 5358 KiB

Open AccessArticle

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

by Tanja Groll, Franziska Schopf, Daniela Denk, Carolin Mogler, Ulrike Schwittlick, Heike Aupperle-Lellbach, Sabrina Rim Jahan Sarker, Nicole Pfarr, Wilko Weichert, Kaspar Matiasek, Moritz Jesinghaus and Katja Steiger

Cancers 2021, 13(23), 5941; https://doi.org/10.3390/cancers13235941 - 25 Nov 2021

Cited by 5 | Viewed by 2982

Abstract

Limited availability of in vivo experimental models for invasive colorectal cancer (CRC) including metastasis and high tumor budding activity is a major problem in colorectal cancer research. In order to compare feline and human intestinal carcinomas, tumors of 49 cats were histologically subtyped, graded and further characterized according to the human WHO classification. Subsequently, feline tumors were compared to a cohort of 1004 human CRC cases. Feline intestinal tumors closely resembled the human phenotype on a histomorphological level. In both species, adenocarcinoma not otherwise specified (ANOS) was the most common WHO subtype. In cats, the second most common subtype of the colon (36.4%), serrated adenocarcinoma (SAC), was overrepresented compared to human CRC (8.7%). Mucinous adenocarcinoma (MAC) was the second most common subtype of the small intestine (12.5%). Intriguingly, feline carcinomas, particularly small intestinal, were generally of high tumor budding (Bd) status (Bd3), which is designated an independent prognostic key factor in human CRC. We also investigated the relevance of feline CTNNB1 exon 2 alterations by Sanger sequencing. In four cases of feline colonic malignancies (3 ANOS, 1 SAC), somatic missense mutations of feline CTNNB1 (p.D32G, p.D32N, p.G34R, and p.S37F) were detected, indicating that mutational alterations of the WNT/β-catenin signaling pathway potentially play an essential role in feline intestinal tumorigenesis comparable to humans and dogs. These results indicate that spontaneous intestinal tumors of cats constitute a useful but so far underutilized model for human CRC. Our study provides a solid foundation for advanced comparative oncology studies and emphasizes the need for further (molecular) characterization of feline intestinal carcinomas. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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13 pages, 13155 KiB

Open AccessArticle

The Immune Landscape of Colorectal Cancer

by Artur Mezheyeuski, Patrick Micke, Alfonso Martín-Bernabé, Max Backman, Ina Hrynchyk, Klara Hammarström, Simon Ström, Joakim Ekström, Per-Henrik Edqvist, Magnus Sundström, Fredrik Ponten, Karin Leandersson, Bengt Glimelius and Tobias Sjöblom

Cancers 2021, 13(21), 5545; https://doi.org/10.3390/cancers13215545 - 04 Nov 2021

Cited by 13 | Viewed by 3035

Abstract

While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naïve CRC patients clustered into an ‘inflamed’ and a ‘desert’ group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046–0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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13 pages, 276 KiB

Open AccessArticle

Clinical Characteristics and Outcomes of Colorectal Cancer in the ColoCare Study: Differences by Age of Onset

by Caroline Himbert, Jane C. Figueiredo, David Shibata, Jennifer Ose, Tengda Lin, Lyen C. Huang, Anita R. Peoples, Courtney L. Scaife, Bartley Pickron, Laura Lambert, Jessica N. Cohan, Mary Bronner, Seth Felder, Julian Sanchez, Sophie Dessureault, Domenico Coppola, David M. Hoffman, Yosef F. Nasseri, Robert W. Decker, Karen Zaghiyan, Zuri A. Murrell, Andrew Hendifar, Jun Gong, Eiman Firoozmand, Alexandra Gangi, Beth A. Moore, Kyle G. Cologne, Maryliza S. El-Masry, Nathan Hinkle, Justin Monroe, Matthew Mutch, Cory Bernadt, Deyali Chatterjee, Mika Sinanan, Stacey A. Cohen, Ulrike Wallin, William M. Grady, Paul D. Lampe, Deepti Reddi, Mukta Krane, Alessandro Fichera, Ravi Moonka, Esther Herpel, Peter Schirmacher, Matthias Kloor, Magnus von Knebel-Doeberitz, Johanna Nattenmueller, Hans-Ulrich Kauczor, Eric Swanson, Jolanta Jedrzkiewicz, Stephanie L. Schmit, Biljana Gigic, Alexis B. Ulrich, Adetunji T. Toriola, Erin M. Siegel, Christopher I. Li, Cornelia M. Ulrich and Sheetal Hardikar Show full author list Hide full author list

Cancers 2021, 13(15), 3817; https://doi.org/10.3390/cancers13153817 - 29 Jul 2021

Cited by 14 | Viewed by 3524

Abstract

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m², 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

22 pages, 4874 KiB

Open AccessFeature PaperArticle

Tackling Tumour Cell Heterogeneity at the Super-Resolution Level in Human Colorectal Cancer Tissue

by Fabian Lang, María F. Contreras-Gerenas, Márton Gelléri, Jan Neumann, Ole Kröger, Filip Sadlo, Krzysztof Berniak, Alexander Marx, Christoph Cremer, Hans-Achim Wagenknecht and Heike Allgayer

Cancers 2021, 13(15), 3692; https://doi.org/10.3390/cancers13153692 - 22 Jul 2021

Cited by 4 | Viewed by 2784

Abstract

Tumour cell heterogeneity, and its early individual diagnosis, is one of the most fundamental problems in cancer diagnosis and therapy. Single molecule localisation microscopy (SMLM) resolves subcellular features but has been limited to cultured cell lines only. Since nuclear chromatin architecture and microRNAs are critical in metastasis, we introduce a first-in-field approach for quantitative SMLM-analysis of chromatin nanostructure in individual cells in resected, routine-pathology colorectal carcinoma (CRC) patient tissue sections. Chromatin density profiles proved to differ for cells in normal and carcinoma colorectal tissues. In tumour sections, nuclear size and chromatin compaction percentages were significantly different in carcinoma versus normal epithelial and other cells of colorectal tissue. SMLM analysis in nuclei from normal colorectal tissue revealed abrupt changes in chromatin density profiles at the nanoscale, features not detected by conventional widefield microscopy. SMLM for microRNAs relevant for metastasis was achieved in colorectal cancer tissue at the nuclear level. Super-resolution microscopy with quantitative image evaluation algorithms provide powerful tools to analyse chromatin nanostructure and microRNAs of individual cells from normal and tumour tissue at the nanoscale. Our new perspectives improve the differential diagnosis of normal and (metastatically relevant) tumour cells at the single-cell level within the heterogeneity of primary tumours of patients. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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12 pages, 1085 KiB

Open AccessArticle

Clinical Relevance of Viable Circulating Tumor Cells in Patients with Metastatic Colorectal Cancer: The COLOSPOT Prospective Study

by Thibault Mazard, Laure Cayrefourcq, Françoise Perriard, Hélène Senellart, Benjamin Linot, Christelle de la Fouchardière, Eric Terrebonne, Eric François, Stéphane Obled, Rosine Guimbaud, Laurent Mineur, Marianne Fonck, Jean-Pierre Daurès, Marc Ychou, Eric Assenat and Catherine Alix-Panabières

Cancers 2021, 13(12), 2966; https://doi.org/10.3390/cancers13122966 - 13 Jun 2021

Cited by 13 | Viewed by 2195

Abstract

Background: Circulating tumor cells (CTCs) allow the real-time monitoring of tumor course and treatment response. This prospective multicenter study evaluates and compares the early predictive value of CTC enumeration with EPISPOT, a functional assay that detects only viable CTCs, and with the CellSearch^® system in patients with metastatic colorectal cancer (mCRC). Methods: Treatment-naive patients with mCRC and measurable disease (RECIST criteria 1.1) received FOLFIRI–bevacizumab until progression or unacceptable toxicity. CTCs in peripheral blood were enumerated at D₀, D₁₄, D₂₈, D₄₂, and D₅₆ (EPISPOT assay) and at D₀ and D₂₈ (CellSearch^® system). Progression-free survival (PFS) and overall survival (OS) were assessed with the Kaplan–Meier method and log-rank test. Results: With the EPISPOT assay, at least 1 viable CTC was detected in 21% (D₀), 15% (D₁₄), 12% (D₂₈), 10% (D₄₂), and 12% (D₅₆) of 155 patients. PFS and OS were shorter in patients who remained positive, with viable CTCs between D₀ and D₂₈ compared with the other patients (PFS = 7.36 vs. 9.43 months, p = 0.0161 and OS = 25.99 vs. 13.83 months, p = 0.0178). The prognostic and predictive values of ≥3 CTCs (CellSearch^® system) were confirmed. Conclusions: CTC detection at D₂₈ and the D₀–D₂₈ CTC dynamics evaluated with the EPISPOT assay were associated with outcomes and may predict response to treatment. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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Review

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20 pages, 1165 KiB

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Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer

by Zahra Pezeshkian, Stefania Nobili, Noshad Peyravian, Bahador Shojaee, Haniye Nazari, Hiva Soleimani, Hamid Asadzadeh-Aghdaei, Maziar Ashrafian Bonab, Ehsan Nazemalhosseini-Mojarad and Enrico Mini

Cancers 2021, 13(24), 6226; https://doi.org/10.3390/cancers13246226 - 10 Dec 2021

Cited by 26 | Viewed by 4571

Abstract

Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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14 pages, 5438 KiB

Open AccessFeature PaperReview

Bovine Meat and Milk Factors (BMMFs): Their Proposed Role in Common Human Cancers and Type 2 Diabetes Mellitus

by Ethel-Michele de Villiers and Harald zur Hausen

Cancers 2021, 13(21), 5407; https://doi.org/10.3390/cancers13215407 - 28 Oct 2021

Cited by 9 | Viewed by 3963

Abstract

Exemplified by infections with bovine meat and milk factors (BMMFs), this manuscript emphasizes the different mechanistic aspects of infectious agents contributing to human cancers by “direct” or “indirect” interactions. The epidemiology of cancers linked to direct carcinogens (e.g., response to immunosuppression) differs from those cancers linked with indirect infectious interactions. Cancers induced by direct infectious carcinogens commonly increase under immunosuppression, whereas the cancer risk by indirect carcinogens is reduced. This influences their responses to preventive and therapeutic interferences. In addition, we discuss their role in colon, breast and prostate cancers and type II diabetes mellitus. A brief discussion covers the potential role of BMMF infections in acute myeloid leukemia. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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15 pages, 582 KiB

Open AccessReview

Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as a Liquid Biopsy Marker in Colorectal Cancer

by Isabel Heidrich, Thaer S. A. Abdalla, Matthias Reeh and Klaus Pantel

Cancers 2021, 13(18), 4500; https://doi.org/10.3390/cancers13184500 - 07 Sep 2021

Cited by 11 | Viewed by 3136

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. It is a heterogeneous tumor with a wide genomic instability, leading to tumor recurrence, distant metastasis, and therapy resistance. Therefore, adjunct non-invasive tools are urgently needed to help the current classical staging systems for more accurate prognostication and guiding personalized therapy. In recent decades, there has been an increasing interest in the diagnostic, prognostic, and predictive value of circulating cancer-derived material in CRC. Liquid biopsies provide direct non-invasive access to tumor material, which is shed into the circulation; this enables the analysis of circulating tumor cells (CTC) and genomic components such as circulating free DNA (cfDNA), which could provide the key for personalized therapy. Liquid biopsy (LB) allows for the identification of patients with a high risk for disease progression after curative surgery, as well as longitudinal monitoring for disease progression and therapy response. Here, we will review the most recent studies on CRC, demonstrating the clinical potential and utility of CTCs and ctDNA. We will discuss some of the advantages and limitations of LBs and the future perspectives in the field of CRC management. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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21 pages, 3040 KiB

Open AccessReview

Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer

by Luigi Marongiu, Markus Burkard, Sascha Venturelli and Heike Allgayer

Cancers 2021, 13(9), 2036; https://doi.org/10.3390/cancers13092036 - 23 Apr 2021

Cited by 6 | Viewed by 3253

Abstract

Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer. Full article

(This article belongs to the Special Issue Colorectal Cancers: From Present Problems to Future Solutions)

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