Biomarker in Metastatic Colorectal Cancer

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 27221

Special Issue Editors


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Guest Editor
1. Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - University Medicine Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Str. 10, 13125 Berlin, Germany
2. German Cancer Consortium (DKTK), Heidelberg, im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Interests: translational oncology; metastasis research, biomarker identification and analysis; cancer signaling; cancer therapy

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Guest Editor
Experimental and Clinical Research Center, Charitè Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany
Interests: translational oncology; metastasis research; in vitro and in vivo cancer models; pre-clinical drug development and testing

Special Issue Information

Dear Colleagues,

Colorectal cancer is a cancer entity with high incidence. Metastasis represents the most lethal attribute of CRC, limiting successful therapy. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in efficient metastasis intervention and patient-tailored therapy. The fact that 40–50% of all patients newly diagnosed with CRC without distant metastases (stages I–III) will develop distant metastasis metachronously defines the clinical need for improved diagnosis and novel therapeutic options for metastasis intervention.

We are pleased to invite you to contribute original research articles and reviews to this Special Issue, which aims to highlight the research as well as clinical activities for discovery and consolidation of biomarkers of metastatic CRC, which may also serve as targets for specific therapies in metastatic CRC. Aspects of early diagnosis for metastasis detection, the identification of gene signatures and their use for the design of novel, individualized therapies, and translation into pre-clinical as well as clinical applications will be covered in this Special Issue.

We very much look forward to receiving your contribution.

Prof. Dr. Ulrike Stein
Prof. Dr. Wolfgang Walther
Guest Editors

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Keywords

  • colorectal cancer
  • metastasis
  • biomarker
  • diagnosis
  • prognosis
  • prediction
  • therapy

Published Papers (12 papers)

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Research

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13 pages, 2894 KiB  
Article
Thioredoxin Reductase-1 as a Potential Biomarker in Fibroblast-Associated HCT116 Cancer Cell Progression and Dissemination in a Zebrafish Model
by Tharathip Muangthong, Pornnapat Chusangnin, Artchaya Hassametto, Rataya Tanomrat and Prasit Suwannalert
Cancers 2023, 15(1), 56; https://doi.org/10.3390/cancers15010056 - 22 Dec 2022
Cited by 1 | Viewed by 1346
Abstract
The tumor microenvironment, especially that of fibroblasts, strongly promotes colorectal cancer (CRC) progression. Progressive cancers usually accumulate high reactive oxygen species (ROS), leading to oxidative stress. The stress relates to the expression of thioredoxin reductase-1 (TrxR-1), which is an oxidative stress sensitivity molecule. [...] Read more.
The tumor microenvironment, especially that of fibroblasts, strongly promotes colorectal cancer (CRC) progression. Progressive cancers usually accumulate high reactive oxygen species (ROS), leading to oxidative stress. The stress relates to the expression of thioredoxin reductase-1 (TrxR-1), which is an oxidative stress sensitivity molecule. This study aimed to investigate TrxR-1 expression as an indication of colon-fibroblast-inducing colorectal cancer progression and metastasis. We found that the high proliferative fibroblast-cultured media (FCM) contained pro-inflammatory cytokines that have a high ability to influence HCT116 and CRC cell progression, when compared with complete media (CM) as a control in terms of growth (CM = 100.00%, FCM = 165.96%), migration (CM = 32.22%, FCM = 83.07%), invasion (CM = 130 cells/field, FCM = 449 cells/field), and EMT transformation while decreasing E-cadherin expression (CM = 1.00, FCM = 0.69) and shape factor (CM = 0.94, FCM = 0.61). In addition, the overexpression of TrxR-1 is associated with cellular oxidant enchantment in FCM-treated cells. A dot plot analysis showed a strong relation between the EMT process and the overexpression of TrxR-1 in FCM-treated cells (CM = 13/100 cells, FCM = 45/100 cells). The cancer transplantation of the adult zebrafish model illustrated a significantly higher number of microtumors in FCM-treated cells (CM = 4.33 ± 1.51/HPF, FCM = 25.00 ± 13.18/HPF) disseminated in the intraperitoneal cavity with TrxR-1 positive cells. The overexpression of TrxR-1 indicated fibroblast-associated CRC progression in HCT116 cells and the zebrafish model. Therefore, TrxR-1 could be applied as a novel biomarker for colorectal cancer progression and prognostic evaluation. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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19 pages, 2268 KiB  
Article
Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53–Mutated Metastatic Colorectal Cancer
by Sara Lahoz, Adela Rodríguez, Laia Fernández, Teresa Gorría, Reinaldo Moreno, Francis Esposito, Helena Oliveres, Santiago Albiol, Tamara Saurí, David Pesantez, Gisela Riu, Miriam Cuatrecasas, Pedro Jares, Leire Pedrosa, Estela Pineda, Antonio Postigo, Antoni Castells, Aleix Prat, Joan Maurel and Jordi Camps
Cancers 2022, 14(23), 5921; https://doi.org/10.3390/cancers14235921 - 30 Nov 2022
Cited by 1 | Viewed by 2153
Abstract
Next–generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors [...] Read more.
Next–generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first–line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time–dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double–mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK–IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time–dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53–defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53–altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first–line regimens. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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34 pages, 4145 KiB  
Article
Involvement of HHV-4 (Epstein–Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis
by Luigi Marongiu, Sascha Venturelli and Heike Allgayer
Cancers 2022, 14(20), 5085; https://doi.org/10.3390/cancers14205085 - 17 Oct 2022
Cited by 4 | Viewed by 2269
Abstract
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk [...] Read more.
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein–Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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14 pages, 2673 KiB  
Article
Inflammation- and Metastasis-Related Proteins Expression Changes in Early Stages in Tumor and Non-Tumor Adjacent Tissues of Colorectal Cancer Samples
by Marina Alorda-Clara, Margalida Torrens-Mas, Reyniel Hernández-López, Javier M. Ibarra de la Rosa, Esther Falcó, Teresa Fernández, Maria Margarita Company, Jorge Sastre-Serra, Jordi Oliver, Daniel Gabriel Pons and Pilar Roca
Cancers 2022, 14(18), 4487; https://doi.org/10.3390/cancers14184487 - 16 Sep 2022
Cited by 1 | Viewed by 1319
Abstract
Chronic inflammation can induce malignant cell transformation, having an important role in all colorectal cancer (CRC) phases. Non-tumor adjacent tissue plays an important role in tumor progression, but its implication in CRC has not yet been fully elucidated. The aim was to analyze [...] Read more.
Chronic inflammation can induce malignant cell transformation, having an important role in all colorectal cancer (CRC) phases. Non-tumor adjacent tissue plays an important role in tumor progression, but its implication in CRC has not yet been fully elucidated. The aim was to analyze the expression of inflammatory, epithelial-mesenchymal transition (EMT), and metastasis-related proteins in both tumor and non-tumor adjacent tissues from CRC patients by western blot. Tumor tissue presented an increase in metastasis and EMT-related proteins compared to non-tumor adjacent tissue, especially in stage II. Tumor tissue stage II also presented an increase in inflammatory-related proteins compared to other stages, which was also seen in non-tumor adjacent tissue stage II. Additionally, the relapse-free survival study of Vimentin and VEGF-B expression levels in stage II patients showed that the higher the expression levels of each protein, the lower 10-year relapse-free survival. These could suggest that some metastasis-related signalling pathways may be activated in stage II in tumor tissue, accompanied by an increase in inflammation. Furthermore, non-tumor adjacent tissue presented an increase of the inflammatory status that could be the basis for future tumor progression. In conclusion, these proteins could be useful as biomarkers of diagnosis for CRC at early stages. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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22 pages, 4524 KiB  
Article
Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL
by Jörg Kumbrink, Lisa Bohlmann, Soulafa Mamlouk, Torben Redmer, Daniela Peilstöcker, Pan Li, Sylvie Lorenzen, Hana Algül, Stefan Kasper, Dirk Hempel, Florian Kaiser, Marlies Michl, Harald Bartsch, Jens Neumann, Frederick Klauschen, Michael von Bergwelt-Baildon, Dominik Paul Modest, Arndt Stahler, Sebastian Stintzing, Andreas Jung, Thomas Kirchner, Reinhold Schäfer, Volker Heinemann and Julian W. Holchadd Show full author list remove Hide full author list
Cancers 2022, 14(15), 3631; https://doi.org/10.3390/cancers14153631 - 26 Jul 2022
Cited by 3 | Viewed by 2451
Abstract
Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected [...] Read more.
Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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20 pages, 4847 KiB  
Article
2D-DIGE-MS Proteomics Approaches for Identification of Gelsolin and Peroxiredoxin 4 with Lymph Node Metastasis in Colorectal Cancer
by Cheng-Yi Huang, Ko-Chao Lee, Shui-Yi Tung, Wen-Shin Huang, Chih-Chuan Teng, Kam-Fai Lee, Meng-Chiao Hsieh and Hsing-Chun Kuo
Cancers 2022, 14(13), 3189; https://doi.org/10.3390/cancers14133189 - 29 Jun 2022
Cited by 12 | Viewed by 2171
Abstract
Background/Aims: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). [...] Read more.
Background/Aims: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). This quantitative proteomic survey aimed to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC from stage I to stage IV. Methods: Sixteen CRC cases were categorized into paired non-LNM and LNM groups, and two-dimensional difference gel electrophoresis and MS proteome analysis were performed. Differential protein expression between non-LNM and LNM CRC was further validated in a tissue microarray, including 40 paraffin-embedded samples by immunohistochemistry staining. Moreover, a Boyden chamber assay, flow cytometry, and shRNA were used to examine the epithelial–mesenchymal transition and mechanism invasiveness of the differentially expressed proteins in DLD-1 cells and in vivo xenograft mouse model. Results: Eighteen differentially expressed proteins were found between non-LNM and LNM CRC tissues. Among them, protein levels of Gelsolin (GSN) and peroxiredoxin 4 (PRDX4) were abundant in node-positive CRC. Downregulation of GSN and PRDX4 markedly suppressed migration and invasiveness and also induced cell cycle G1/S arrest in DLD-1. Mechanistically, the EGFR/RhoA/PKCα/ERK pathways are critical for transcriptional activation of histone modification of H3 lysine 4 trimethylation (H3K4me3) of GSN and PRDX4 promoters, resulting in upregulation of GSN, PRDX4, Twist-1/2, cyclinD1, proliferating cell-nuclear antigen, β-catenin, N-cadherin, and matrix metalloprotein-9. Conclusions: GSN and PRDX4 are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as a biomarker for CRC diagnosis at the metastatic stage. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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21 pages, 55597 KiB  
Article
MACC1-Induced Collective Migration Is Promoted by Proliferation Rather Than Single Cell Biomechanics
by Tim Hohmann, Urszula Hohmann, Mathias Dahlmann, Dennis Kobelt, Ulrike Stein and Faramarz Dehghani
Cancers 2022, 14(12), 2857; https://doi.org/10.3390/cancers14122857 - 09 Jun 2022
Cited by 7 | Viewed by 1756
Abstract
Metastasis-associated in colon cancer 1 (MACC1) is a marker for metastasis, tumor cell migration, and increased proliferation in colorectal cancer (CRC). Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. Yet, many facets of the pro-migratory effects [...] Read more.
Metastasis-associated in colon cancer 1 (MACC1) is a marker for metastasis, tumor cell migration, and increased proliferation in colorectal cancer (CRC). Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. Yet, many facets of the pro-migratory effects are not fully understood. Atomic force microscopy and single cell live imaging were used to quantify biomechanical and migratory properties in low- and high-MACC1-expressing CRC cells. Furthermore, collective migration and expansion of small, cohesive cell colonies were analyzed using live cell imaging and particle image velocimetry. Lastly, the impact of proliferation on collective migration was determined by inhibition of proliferation using mitomycin. MACC1 did not affect elasticity, cortex tension, and single cell migration of CRC cells but promoted collective migration and colony expansion in vitro. Measurements of the local velocities in the dense cell layers revealed proliferation events as regions of high local speeds. Inhibition of proliferation via mitomycin abrogated the MACC1-associated effects on the collective migration speeds. A simple simulation revealed that the expansion of cell clusters without proliferation appeared to be determined mostly by single cell properties. MACC1 overexpression does not influence single cell biomechanics and migration but only collective migration in a proliferation-dependent manner. Thus, targeting proliferation in high-MACC1-expressing tumors may offer additional effects on cell migration. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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17 pages, 4279 KiB  
Article
Elevated MACC1 Expression in Colorectal Cancer Is Driven by Chromosomal Instability and Is Associated with Molecular Subtype and Worse Patient Survival
by Vincent Vuaroqueaux, Alexandra Musch, Dennis Kobelt, Thomas Risch, Pia Herrmann, Susen Burock, Anne-Lise Peille, Marie-Laure Yaspo, Heinz-Herbert Fiebig and Ulrike Stein
Cancers 2022, 14(7), 1749; https://doi.org/10.3390/cancers14071749 - 29 Mar 2022
Cited by 4 | Viewed by 2931
Abstract
Metastasis-Associated in Colon Cancer 1 (MACC1) is a strong prognostic biomarker inducing proliferation, migration, invasiveness, and metastasis of cancer cells. The context of MACC1 dysregulation in cancers is, however, still poorly understood. Here, we investigated whether chromosomal instability and somatic copy [...] Read more.
Metastasis-Associated in Colon Cancer 1 (MACC1) is a strong prognostic biomarker inducing proliferation, migration, invasiveness, and metastasis of cancer cells. The context of MACC1 dysregulation in cancers is, however, still poorly understood. Here, we investigated whether chromosomal instability and somatic copy number alterations (SCNA) frequently occurring in CRC contribute to MACC1 dysregulation, with prognostic and predictive impacts. Using the Oncotrack and Charité CRC cohorts of CRC patients, we showed that elevated MACC1 mRNA expression was tightly dependent on increased MACC1 gene SCNA and was associated with metastasis and shorter metastasis free survival. Deep analysis of the COAD-READ TCGA cohort revealed elevated MACC1 expression due to SCNA for advanced tumors exhibiting high chromosomal instability (CIN), and predominantly classified as CMS2 and CMS4 transcriptomic subtypes. For that cohort, we validated that elevated MACC1 mRNA expression correlated with reduced disease-free and overall survival. In conclusion, this study gives insights into the context of MACC1 expression in CRC. Increased MACC1 expression is largely driven by CIN, SCNA gains, and molecular subtypes, potentially determining the molecular risk for metastasis that might serve as a basis for patient-tailored treatment decisions. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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Review

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18 pages, 1067 KiB  
Review
Aberrant HMGA2 Expression Sustains Genome Instability That Promotes Metastasis and Therapeutic Resistance in Colorectal Cancer
by Rubi Campos Gudiño, Kirk J. McManus and Sabine Hombach-Klonisch
Cancers 2023, 15(6), 1735; https://doi.org/10.3390/cancers15061735 - 13 Mar 2023
Cited by 1 | Viewed by 1940
Abstract
Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, [...] Read more.
Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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21 pages, 1473 KiB  
Review
CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer
by Kevin Domanegg, Jonathan P. Sleeman and Anja Schmaus
Cancers 2022, 14(20), 5093; https://doi.org/10.3390/cancers14205093 - 18 Oct 2022
Cited by 7 | Viewed by 2977
Abstract
Originally discovered as a hypothetical protein with unknown function, CEMIP (cell migration-inducing and hyaluronan-binding protein) has been implicated in the pathogenesis of numerous diseases, including deafness, arthritis, atherosclerosis, idiopathic pulmonary fibrosis, and cancer. Although a comprehensive definition of its molecular functions is still [...] Read more.
Originally discovered as a hypothetical protein with unknown function, CEMIP (cell migration-inducing and hyaluronan-binding protein) has been implicated in the pathogenesis of numerous diseases, including deafness, arthritis, atherosclerosis, idiopathic pulmonary fibrosis, and cancer. Although a comprehensive definition of its molecular functions is still in progress, major functions ascribed to CEMIP include the depolymerization of the extracellular matrix component hyaluronic acid (HA) and the regulation of a number of signaling pathways. CEMIP is a promising biomarker for colorectal cancer. Its expression is associated with poor prognosis for patients suffering from colorectal and other types of cancer and functionally contributes to tumor progression and metastasis. Here, we review our current understanding of how CEMIP is able to foster the process of tumor growth and metastasis, focusing particularly on colorectal cancer. Studies in cancer cells suggest that CEMIP exerts its pro-tumorigenic and pro-metastatic activities through stimulating migration and invasion, suppressing cell death and promoting survival, degrading HA, regulating pro-metastatic signaling pathways, inducing the epithelial–mesenchymal transition (EMT) program, and contributing to the metabolic reprogramming and pre-metastatic conditioning of future metastatic microenvironments. There is also increasing evidence indicating that CEMIP may be expressed in cells within the tumor microenvironment that promote tumorigenesis and metastasis formation, although this remains in an early stage of investigation. CEMIP expression and activity can be therapeutically targeted at a number of levels, and preliminary findings in animal models show encouraging results in terms of reduced tumor growth and metastasis, as well as combating therapy resistance. Taken together, CEMIP represents an exciting new player in the progression of colorectal and other types of cancer that holds promise as a therapeutic target and biomarker. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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25 pages, 458 KiB  
Review
Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective
by Alberto Puccini, Andreas Seeber and Martin D. Berger
Cancers 2022, 14(19), 4828; https://doi.org/10.3390/cancers14194828 - 03 Oct 2022
Cited by 9 | Viewed by 2802
Abstract
Colorectal cancer (CRC) is the third most frequent cancer worldwide, and its incidence is steadily increasing. During the last two decades, a tremendous improvement in outcome has been achieved, mainly due to the introduction of novel drugs, targeted treatment, immune checkpoint inhibitors (CPIs) [...] Read more.
Colorectal cancer (CRC) is the third most frequent cancer worldwide, and its incidence is steadily increasing. During the last two decades, a tremendous improvement in outcome has been achieved, mainly due to the introduction of novel drugs, targeted treatment, immune checkpoint inhibitors (CPIs) and biomarker-driven patient selection. Moreover, progress in molecular diagnostics but also improvement in surgical techniques and local ablative treatments significantly contributed to this success. However, novel therapeutic approaches are needed to further improve outcome in patients diagnosed with metastatic CRC. Besides the established biomarkers for mCRC, such as microsatellite instability (MSI) or mismatch repair deficiency (dMMR), RAS/BRAF, sidedness and HER2 amplification, new biomarkers have to be identified to better select patients who derive the most benefit from a specific treatment. In this review, we provide an overview about therapeutic relevant and established biomarkers but also shed light on potential promising markers that may help us to better tailor therapy to the individual mCRC patient in the near future. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)

Other

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15 pages, 1372 KiB  
Systematic Review
A GNAS Gene Mutation’s Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis
by Hafeez Abiola Afolabi, Salzihan Md Salleh, Zaidi Zakaria, Ewe Seng Ch’ng, Siti Norasikin Mohd Nafi, Ahmad Aizat Bin Abdul Aziz, Ahmad Adebayo Irekeola, Yusuf Wada and Sameer Badri Al-Mhanna
Cancers 2022, 14(22), 5480; https://doi.org/10.3390/cancers14225480 - 08 Nov 2022
Cited by 4 | Viewed by 1825
Abstract
Globally, colorectal carcinoma CRC is the third most common cancer and the third most common reason for cancer-associated mortality in both genders. The GNAS mutations are significantly linked with poor prognosis and failed treatment outcomes in CRC. A systematic review and meta-analysis of [...] Read more.
Globally, colorectal carcinoma CRC is the third most common cancer and the third most common reason for cancer-associated mortality in both genders. The GNAS mutations are significantly linked with poor prognosis and failed treatment outcomes in CRC. A systematic review and meta-analysis of multiple studies executed following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria and registered with PROSPERO (registration number: CRD42021256452). The initial search includes a total of 271 publications; however, only 30 studies that merit the eligibility criteria were eventually chosen. Data analysis via OpenMeta Analyst and comprehensive meta-analysis 3.0 (CMA 3.0) software were used to investigate the prevalence of GNAS gene mutation among CRC patients. The meta-analysis consisted of 10,689 participants with most being males 6068/10,689 (56.8%). Overall, prevalence of GNAS mutations was 4.8% (95% CI: 3.1–7.3) with I2 = 94.39% and (p < 0.001). In 11/30 studies, the frequency of GNAS gene mutations was majorly in codons R201C [40.7% (95% CI: 29.2–53.2%)] and in codon R201H [39.7% (95% CI = 27.1–53.8)]. Overall prevalence of GNAS mutations was highest among the male gender: 53.9% (95% CI: 48.2–59.5%: I2 = 94.00%, (p < 0.001), tumour location (colon): 50.5% (95% CI: 33.2–67.6%: I2 = 97.93%, (p < 0.001), tumour grade (Well): 57.5% (95% CI: 32.4–79.2%: I2 = 98.10%, (p < 0.001) and tumour late stage: 67.9% (95% CI: 49.7–84.3%: I2 = 98.%, (p < 0.001). When stratified according to study location, a higher prevalence was observed in Japan (26.8%) while Italy has the lowest (0.4%). Overall prevalence of GNAS gene mutations was 4.8% with codons R201C and R201H being the most mutated, and the results conformed with numerous published studies on GNAS mutation. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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