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Special Issue "Molecular Biology of Colorectal Cancers"

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

Deadline for manuscript submissions: closed (30 October 2023) | Viewed by 13306

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Special Issue Editors

Dr. María Jesús Fernández-Aceñero

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Guest Editor

Departments of Medical Oncology and Surgical Pathology, Universidad Complutense de Madrid, 28040 Madrid, Spain
Interests: gastrointestinal cancer; prognosis; prediction

Dr. Rodrigo Barderas-Manchado

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Guest Editor

Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain
Interests: protein microarrays and mass-spectrometry-based proteomics; spatial proteomics; quantitative proteomics; integrated omics; systems biology; chronic diseases; colorectal cancer

Dr. Javier Martinez Useros

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OncoHealth Institute, Health Research Institute - Fundacion Jimenez Diaz University Hospital, Autonomous University, 28040 Madrid, Spain
Interests: gastric cancer; pancreatic cancer; colorectal cancer and metastatic melanoma
Special Issues, Collections and Topics in MDPI journals

Dr. Cristina Díaz del Arco

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Department of Surgical Pathology, Hospital Clínico Universitario San Carlos, Madrid, Spain
Interests: tumors; histopathology; immunohistochemistry; histology; cancer diagnostics; surgical pathology; prognostic markers; cancer biomarker; cancer biology; tumor markers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As a pathologist for more than 30 years now, I have had the exciting chance to live in the front line the amazing advances in the comprehension of colorectal cancer (CRC). As known, CRC was one of the first tumors in which molecular mechanisms were investigated and confirmed. We now accept that tumors that look identical on microscopic grounds are different at the molecular level, and this explains the varying patient outcomes that we usually face in clinical practice. Tumors look alike but are not the same! However, and having said so, even in the era of molecular medicine and targeted therapies, most of the patients that develop metastatic CRC eventually die of disease with a poor quality of life and significant years of potential life lost , specially when ever younger people are getting affected by this disease. Much remains to be known about the mechanisms that contribute to the aggressive behaviour of CRC and factors predicting therapy response. This special issue is devoted to recent research involving molecular mechanisms underlying colorectal carcinoma, including epigenetic changes, interaction with the environment, and analysis by omics technologies. A fascinating world is open to research, and we would like to invite you to join us in this issue in which we hope to shed some more light into the biology of this common and still lethal tumor.

I am happy to share this journey with my colleagues. Today’s science can only progress through the collaboration between clinicians and basic scientists and I deeply thank my coeditors for their continuing efforts and help in the last decade.

I hope you enjoy this special issue.

Dr. María Jesús Fernández-Aceñero
Chief of the Molecular Pathology section at the Pathology Department
Hospital Clínico San Carlos, Madrid, Spain

Dr. María Jesús Fernández-Aceñero
Dr. Rodrigo Barderas-Manchado
Dr. Javier Martinez Useros
Dr. Cristina Díaz del Arco
Guest Editors

Manuscript Submission Information

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

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

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

Keywords

colorectal carcinoma
metastatic behaviour
predictive factors
prognostic factors
signaling pathways
tumor microenvironment
epithelial-mesenchymal transition
omics technologies
targeted therapies

Published Papers (10 papers)

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22 pages, 8754 KiB

Open AccessArticle

Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC—A New Opportunity to Predict Therapy Response

Jakub Kryczka

and

Joanna Boncela

Cancers 2023, 15(23), 5623; https://doi.org/10.3390/cancers15235623 - 28 Nov 2023

Viewed by 304

Abstract

Background: Our previous findings proved that ABCC4 and ABCG2 proteins present much more complex roles in colorectal cancer (CRC) than typically cancer-associated functions as drug exporters. Our objective was to evaluate their predictive/diagnostic potential. Methods: CRC patients’ transcriptomic data from the Gene Expression Omnibus database (GSE18105, GSE21510 and GSE41568) were discriminated into two subpopulations presenting either high expression levels of ABCC4 (ABCC4 High) or ABCG2 (ABCG2 High). Subpopulations were analysed using various bioinformatical tools and platforms (KEEG, Gene Ontology, FunRich v3.1.3, TIMER2.0 and STRING 12.0). Results: The analysed subpopulations present different gene expression patterns. The protein–protein interaction network of subpopulation-specific genes revealed the top hub proteins in ABCC4 High: RPS27A, SRSF1, DDX3X, BPTF, RBBP7, POLR1B, HNRNPA2B1, PSMD14, NOP58 and EIF2S3 and in ABCG2 High: MAPK3, HIST2H2BE, LMNA, HIST1H2BD, HIST1H2BK, HIST1H2AC, FYN, TLR4, FLNA and HIST1H2AJ. Additionally, our multi-omics analysis proved that the ABCC4 expression correlates with substantially increased tumour-associated macrophage infiltration and sensitivity to FOLFOX treatment. Conclusions: ABCC4 and ABCG2 may be used to distinguish CRC subpopulations that present different molecular and physiological functions. The ABCC4 High subpopulation demonstrates significant EMT reprogramming, RNA metabolism and high response to DNA damage stimuli. The ABCG2 High subpopulation may resist the anti-EGFR therapy, presenting higher proteolytical activity. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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21 pages, 6800 KiB

Open AccessArticle

Luciferase Expressing Preclinical Model Systems Representing the Different Molecular Subtypes of Colorectal Cancer

and

Cancers 2023, 15(16), 4122; https://doi.org/10.3390/cancers15164122 - 16 Aug 2023

Viewed by 692

Abstract

Colorectal cancer (CRC) is a heterogeneous disease. More insight into the biological diversity of CRC is needed to improve therapeutic outcomes. Established CRC cell lines are frequently used and were shown to be representative models of the main subtypes of CRC at the genomic and transcriptomic level. In the present work, we established stable, luciferase expressing derivatives from 10 well-established CRC cell lines, generated spheroids and subcutaneous xenograft tumors in nude mice, and performed comparative characterization of these model systems. Transcriptomic analyses revealed the close relation of cell lines with their derived spheroids and xenograft tumors. The preclinical model systems clustered with patient tumor samples when compared to normal tissue thereby confirming that cell-line-based tumor models retain specific characteristics of primary tumors. Xenografts showed different differentiation patterns and bioluminescence imaging revealed metastatic spread to the lungs. In addition, the models were classified according to the CMS classification system, with further sub-classification according to the recently identified two intrinsic epithelial tumor cell states of CRC, iCMS2 and iCMS3. The combined data showed that regarding primary tumor characteristics, 3D-spheroid cultures resemble xenografts more closely than 2D-cultured cells do. Furthermore, we set up a bioluminescence-based spheroid cytotoxicity assay in order to be able to perform dose–response relationship studies in analogy to typical monolayer assays. Applying the established assay, we studied the efficacy of oxaliplatin. Seven of the ten used cell lines showed a significant reduction in the response to oxaliplatin in the 3D-spheroid model compared to the 2D-monolayer model. Therapy studies in selected xenograft models confirmed the response or lack of response to oxaliplatin treatment. Analyses of differentially expressed genes in these models identified CAV1 as a possible marker of oxaliplatin resistance. In conclusion, we established a combined 2D/3D, in vitro/in vivo model system representing the heterogeneity of CRC, which can be used in preclinical research applications. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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11 pages, 1182 KiB

Open AccessArticle

High OCT4 Expression Might Be Associated with an Aggressive Phenotype in Rectal Cancer

Lina Lambis-Anaya

Mashiel Fernández-Ruiz

Yamil Liscano

and

Amileth Suarez-Causado

Cancers 2023, 15(14), 3740; https://doi.org/10.3390/cancers15143740 - 23 Jul 2023

Cited by 1 | Viewed by 813

Abstract

Rectal cancer (RC) is one of the most common malignant neoplasms, and cancer stem cells (CSCs) of the intestinal tract have been implicated in its origin. The oncofetal protein OCT4 has been linked to neoplastic processes, but its role and clinical significance in RC are unknown. This study investigates the expression of the stem cell marker OCT4 related to clinical-pathological characteristics and its clinical significance in RC patients. The expression level of stem cell marker OCT4 was analyzed in 22 primary rectal tumors by western blot. The association between OCT4 protein expression and the clinical-pathological features of tumors was evaluated by χ² test and Fisher’s exact test. We demonstrated that the expression of the stem cell marker OCT4 was observed in tumor tissue but not adjacent non-tumor tissue. High expression of the stem cell marker OCT4 was significantly associated with histological differentiation grade (p = 0.039), tumor invasion level (p = 0.004), lymph node involvement (p = 0.044), tumor-node-metastasis (TNM) stage (p = 0.002), and clinical stage (p = 0.021). These findings suggest that high OCT4 expression is associated with a more aggressive RC phenotype, with a greater likelihood of progression and metastasis. These results shed light on the importance of targeting this CSC marker to attenuate RC progression. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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13 pages, 1936 KiB

Open AccessArticle

Identification of a Twelve-microRNA Signature with Prognostic Value in Stage II Microsatellite Stable Colon Cancer

Ferran Moratalla-Navarro

Anna Díez-Villanueva

Ainhoa Garcia-Serrano

and

Cancers 2023, 15(13), 3301; https://doi.org/10.3390/cancers15133301 - 23 Jun 2023

Cited by 1 | Viewed by 1068

Abstract

We aimed to identify and validate a set of miRNAs that could serve as a prognostic signature useful to determine the recurrence risk for patients with COAD. Small RNAs from tumors of 100 stage II, untreated, MSS colon cancer patients were sequenced for the discovery step. For this purpose, we built an miRNA score using an elastic net Cox regression model based on the disease-free survival status. Patients were grouped into high or low recurrence risk categories based on the median value of the score. We then validated these results in an independent sample of stage II microsatellite stable tumor tissues, with a hazard ratio of 3.24, (CI_95% = 1.05–10.0) and a 10-year area under the receiver operating characteristic curve of 0.67. Functional analysis of the miRNAs present in the signature identified key pathways in cancer progression. In conclusion, the proposed signature of 12 miRNAs can contribute to improving the prediction of disease relapse in patients with stage II MSS colorectal cancer, and might be useful in deciding which patients may benefit from adjuvant chemotherapy. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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12 pages, 3047 KiB

Open AccessArticle

Knockdown of UBQLN1 Functions as a Strategy to Inhibit CRC Progression through the ERK-c-Myc Pathway

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Cancers 2023, 15(12), 3088; https://doi.org/10.3390/cancers15123088 - 07 Jun 2023

Viewed by 726

Abstract

Purpose: Colorectal cancer (CRC) is characterized by the absence of obvious symptoms in the early stage. Due to the high rate of late diagnosis of CRC patients, the mortality rate of CRC is higher than that of other malignant tumors. Accumulating evidence has demonstrated that UBQLN1 plays an important role in many biological processes. However, the role of UBQLN1 in CRC progression is still elusive. Methods and results: we found that UBQLN1 was significantly highly expressed in CRC tissues compared with normal tissues. Enhanced/reduced UBQLN1 promoted/inhibited CRC cell proliferation, colony formation, epithelial–mesenchymal transition (EMT) in vitro, and knockdown of UBQLN1 inhibited CRC cells’ tumorigenesis and metastasis in nude mice in vivo. Moreover, the knockdown of UBQLN1 reduced the expression of c-Myc by downregulating the ERK-MAPK pathway. Furthermore, the elevation of c-Myc in UBQLN1-deficient cells rescued proliferation caused by UBQLN1 silencing. Conclusions: Knockdown of UBQLN1 inhibits the progression of CRC through the ERK-c-Myc pathway, which provides new insights into the mechanism of CRC progression. UBQLN1 may be a potential prognostic biomarker and therapeutic target of CRC. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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16 pages, 4987 KiB

Open AccessArticle

Hedgehog-GLI and Notch Pathways Sustain Chemoresistance and Invasiveness in Colorectal Cancer and Their Inhibition Restores Chemotherapy Efficacy

Anna Citarella

Giuseppina Catanzaro

Zein Mersini Besharat

and

Cancers 2023, 15(5), 1471; https://doi.org/10.3390/cancers15051471 - 25 Feb 2023

Cited by 3 | Viewed by 1795

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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22 pages, 3404 KiB

Open AccessArticle

Microbiome Profiling from Fecal Immunochemical Test Reveals Microbial Signatures with Potential for Colorectal Cancer Screening

Olfat Khannous-Lleiffe

and

on behalf of the CRIPREV Consortium

Cancers 2023, 15(1), 120; https://doi.org/10.3390/cancers15010120 - 25 Dec 2022

Cited by 2 | Viewed by 1959

Abstract

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Early diagnosis of CRC, which saves lives and enables better outcomes, is generally implemented through a two-step population screening approach based on the use of Fecal Immunochemical Test (FIT) followed by colonoscopy if the test is positive. However, the FIT step has a high false positive rate, and there is a need for new predictive biomarkers to better prioritize cases for colonoscopy. Here we used 16S rRNA metabarcoding from FIT positive samples to uncover microbial taxa, taxon co-occurrence and metabolic features significantly associated with different colonoscopy outcomes, underscoring a predictive potential and revealing changes along the path from healthy tissue to carcinoma. Finally, we used machine learning to develop a two-phase classifier which reduces the current false positive rate while maximizing the inclusion of CRC and clinically relevant samples. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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18 pages, 3181 KiB

Open AccessArticle

Analysis of Circulating Immune Subsets in Primary Colorectal Cancer

Can Lu

Josefine Schardey

Ulrich Wirth

Viktor von Ehrlich-Treuenstätt

and

Cancers 2022, 14(24), 6105; https://doi.org/10.3390/cancers14246105 - 12 Dec 2022

Viewed by 1106

Abstract

The development and progression of colorectal cancer (CRC) are known to be affected by the interplay between tumor and immune cells. However, the impact of CRC cells on the systemic immunity has yet to be elucidated. We aimed to comprehensively evaluate the circulating immune subsets and transcriptional profiles of CRC patients. In contrast to healthy controls (HCs), CRC patients had a lower percentage of B and T lymphocytes, T helper (Th) cells, non-classical monocytes, dendritic cells, and a higher proportion of polymorphonuclear myeloid-derived suppressor cells, as well as a reduced expression of CD69 on NK cells. Therefore, CRC patients exhibit a more evident systemic immune suppression than HCs. A diagnostic model integrating seven immune subsets was constructed to distinguish CRC patients from HCs with an AUC of 1.000. Moreover, NR3C2, CAMK4, and TRAT1 were identified as candidate genes regulating the number of Th cells in CRC patients. The altered composition of circulating immune cells in CRC could complement the regional immune status of the tumor microenvironment and contribute to the discovery of immune-related biomarkers for the diagnosis of CRC. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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13 pages, 2067 KiB

Open AccessArticle

Molecular Classification of Colorectal Cancer by microRNA Profiling: Correlation with the Consensus Molecular Subtypes (CMS) and Validation of miR-30b Targets

Mateo Paz-Cabezas

Tania Calvo-López

Alejandro Romera-Lopez

Daniel Tabas-Madrid

Jesus Ogando

María-Jesús Fernández-Aceñero

Javier Sastre

Alberto Pascual-Montano

Santos Mañes

Eduardo Díaz-Rubio

and

Beatriz Perez-Villamil

Cancers 2022, 14(21), 5175; https://doi.org/10.3390/cancers14215175 - 22 Oct 2022

Cited by 3 | Viewed by 1374

Abstract

Colorectal cancer consensus molecular subtypes (CMSs) are widely accepted and constitutes the basis for patient stratification to improve clinical practice. We aimed to find whether miRNAs could reproduce molecular subtypes, and to identify miRNA targets associated to the High-stroma/CMS4 subtype. The expression of 939 miRNAs was analyzed in tumors classified in CMS. TALASSO was used to find gene-miRNA interactions. A miR-mRNA regulatory network was constructed using Cytoscape. Candidate gene-miR interactions were validated in 293T cells. Hierarchical-Clustering identified three miRNA tumor subtypes (miR-LS; miR-MI; and miR-HS) which were significantly associated (p < 0.001) to the reported mRNA subtypes. miR-LS correlated with the low-stroma/CMS2; miR-MI with the mucinous-MSI/CMS1 and miR-HS with high-stroma/CMS4. MicroRNA tumor subtypes and association to CMSs were validated with TCGA datasets. TALASSO identified 1462 interactions (p < 0.05) out of 21,615 found between 176 miRs and 788 genes. Based on the regulatory network, 88 miR-mRNA interactions were selected as candidates. This network was functionally validated for the pair miR-30b/SLC6A6. We found that miR-30b overexpression silenced 3′-UTR-SLC6A6-driven luciferase expression in 293T-cells; mutation of the target sequence in the 3′-UTR-SLC6A6 prevented the miR-30b inhibitory effect. In conclusion CRC subtype classification using a miR-signature might facilitate a real-time analysis of the disease course and treatment response. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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49 pages, 1091 KiB

Open AccessReview

Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques

Aldona Kasprzak

Cancers 2023, 15(18), 4570; https://doi.org/10.3390/cancers15184570 - 15 Sep 2023

Viewed by 1314

Abstract

Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients’ overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC. Full article

(This article belongs to the Special Issue Molecular Biology of Colorectal Cancers)

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