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Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 23337

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Special Issue Editors

Prof. Dr. Massimo Milione

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Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Interests: gastroenteropancreatic neuroendocrine tumors; lung neuroendocrine tumors; biliary tract and pancreas neoplasms
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Matteo Fassan

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Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy
Interests: gastrointestinal pathology; molecular pathology; preinvasive lesions; biomarkers
Special Issues, Collections and Topics in MDPI journals

Dr. Federica Morano

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Department of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy
Interests: gastrointestinal neoplasm; biliary tract and pancreas neoplasms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) covers at least 10% of human neoplasms detected each year, representing the third most common cancer. Several recent studies suggest that the CRC incidence rate could increase dramatically in near future. Pathological staging drives CRC prognosis; in more detail, the 5-year survival rate is 90% when it is detected early, usually localized only in the bowel, and dramatically decreases to 10% in metastatic CRC.

Colorectal cancer carcinogenesis plays a pivotal role in defining CRC progression and paves the way for “tailored” therapy.

Starting from the adenoma to carcinoma transition, several more detailed findings have enriched our knowledge of CRC pathogenesis, allowing CRC disease’s stratification in different prognostic classes associated to both different molecular subgroups and genomic signatures, making it possible to predict CRC outcome. However, molecular characterization and DNA methylation alone do not appear sufficient to drive further improvements of therapeutic regimens, and additional studies taking into account epigenetic changes and interactions with the tumor microenvironment are needed to identify the best therapeutic approach and the potential role of novel therapies.

It is urgent to identify early diagnosis biomarkers through the identification of new biological and molecular “signatures” and the integration of morphological and immunophenotypical features able to improve the prognosis and efficacy of the therapeutic response.

This Special Issue will also be dedicated to gastroenteropancreatic neuroendocrine neoplasms—a rare and heterogeneous population of tumors whose incidence rate has increased dramatically over the past several years.

We warmly welcome the submission of original research papers and reviews.

Prof. Dr. Massimo Milione
Prof. Dr. Matteo Fassan
Dr. Federica Morano
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
gastroenteropancreatic neuroendocrine neoplasms
familial/hereditary forms
surgical pathology
molecular pathology
new markers
microRNAs
tumor microenvironment
novel therapies

Published Papers (7 papers)

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Research

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18 pages, 2314 KiB

Open AccessArticle

Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-κB and a New Tumor Suppressor in Colorectal Cancer

by Matthew Martin, Rasika Mundade, Antja-Voy Hartley, Guanglong Jiang, Jiamin Jin, Steven Sun, Ahmad Safa, George Sandusky, Yunlong Liu and Tao Lu

Int. J. Mol. Sci. 2022, 23(5), 2732; https://doi.org/10.3390/ijms23052732 - 01 Mar 2022

Cited by 5 | Viewed by 2468

Abstract

Since nuclear factor (NF) κB plays pivotal roles in inflammation and cancer, understanding its regulation holds great promise for disease therapy. Using the powerful validation-based insertional mutagenesis (VBIM) technique established by us previously, we discovered armadillo repeat-containing protein 4 (ARMC4)/outer dynein arm docking complex subunit 2 (ODAD2), a rarely studied protein known to date, as a novel negative regulator of NF-κB in colorectal cancer (CRC). High expression of ARMC4 downregulated the expression of NF-κB-dependent genes, dramatically reduced NF-κB activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and significantly decreased xenograft tumor growth in vivo. Co-immunoprecipitation experiments demonstrated that ARMC4 forms a complex with NF-κB. Importantly, the lower ARMC4 expression in patient tumors than normal tissues indicates its potential tumor suppressor function in CRC. Collectively, we uncovered a completely new facet of ARMC4 function by identifying it as a novel NF-κB negative regulator, thus uncovering ARMC4 as a potential new therapeutic target in CRC. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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20 pages, 8183 KiB

Open AccessArticle

p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy

by Jörg Kumbrink, Pan Li, Agnes Pók-Udvari, Frederick Klauschen, Thomas Kirchner and Andreas Jung

Int. J. Mol. Sci. 2021, 22(22), 12364; https://doi.org/10.3390/ijms222212364 - 16 Nov 2021

Cited by 1 | Viewed by 2138

Abstract

p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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18 pages, 3747 KiB

Open AccessArticle

YY1 Silencing Induces 5-Fluorouracil-Resistance and BCL2L15 Downregulation in Colorectal Cancer Cells: Diagnostic and Prognostic Relevance

by Silvia Vivarelli, Luca Falzone, Saverio Candido, Benjamin Bonavida and Massimo Libra

Int. J. Mol. Sci. 2021, 22(16), 8481; https://doi.org/10.3390/ijms22168481 - 06 Aug 2021

Cited by 8 | Viewed by 1823

Abstract

Colorectal cancer (CRC) is characterized by genetic heterogeneity and is often diagnosed at an advanced stage. Therefore, there is a need to identify novel predictive markers. Yin Yang 1 (YY1) is a transcription factor playing a dual role in cancer. The present study aimed to investigate whether YY1 expression levels influence CRC cell response to therapy and to identify the transcriptional targets involved. The diagnostic and prognostic values of YY1 and the identified factor(s) in CRC patients were also explored. Silencing of YY1 increased the resistance to 5-Fluorouracil-induced cytotoxicity in two out of four CRC cells with different genotypes. BCL2L15/Bfk pro-apoptotic factor was found selectively expressed in the responder CRC cells and downregulated upon YY1 knockdown. CRC dataset analyses corroborated a tumor-suppressive role for both YY1 and BCL2L15 whose expressions were inversely correlated with aggressiveness. CRC single-cell sequencing dataset analyses demonstrated higher co-expression levels of both YY1 and BCL2L15 within defined tumor cell clusters. Finally, elevated levels of YY1 and BCL2L15 in CRC patients were associated with larger relapse-free survival. Given their observed anti-cancer role, we propose YY1 and BCL2L15 as candidate diagnostic and prognostic CRC biomarkers. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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14 pages, 13562 KiB

Open AccessArticle

Low-Molecular-Weight Fucoidan as Complementary Therapy of Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer

by Ching-Wen Huang, Yen-Cheng Chen, Tzu-Chieh Yin, Po-Jung Chen, Tsung-Kun Chang, Wei-Chih Su, Cheng-Jen Ma, Ching-Chun Li, Hsiang-Lin Tsai and Jaw-Yuan Wang

Int. J. Mol. Sci. 2021, 22(15), 8041; https://doi.org/10.3390/ijms22158041 - 27 Jul 2021

Cited by 9 | Viewed by 2463

Abstract

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-–5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal–epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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Review

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13 pages, 469 KiB

Open AccessReview

Relationship between VEGF Family Members, Their Receptors and Cell Death in the Neoplastic Transformation of Colorectal Cancer

by Dominika Dakowicz, Monika Zajkowska and Barbara Mroczko

Int. J. Mol. Sci. 2022, 23(6), 3375; https://doi.org/10.3390/ijms23063375 - 21 Mar 2022

Cited by 35 | Viewed by 2793

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer death in the world. Both modifiable and nonmodifiable risk factors play a significant role in the pathogenesis of this tumor. The diagnosis is usually made late due to limitations of screening tests; therefore, the scientists are looking for new diagnostic tools such as gene or miRNA expression or different proteins’ concentrations, e.g., vascular endothelial growth factor (VEGF) family members. The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D and PlGF) plays a key role in the processes of blood vessel formation in embryonic development as well as in pathological angiogenesis and lymphangiogenesis, which allow the tumor to grow exponentially. Blockage of VEGF-related pathways seems to be a valid therapeutic target. It was suggested in recent studies, that besides already used drugs, e.g., bevacizumab, there are other agents with potential usefulness in anticancer activity such as miRNAs, TMEA, granzyme K, baicalein and arginine. Moreover, VEGF proteins were assessed to induce the expression of anti-apoptotic proteins such as BCL-2 and BAX. Therefore, investigations concerning the usefulness of VEGF family members, not only in the development but also in the therapy of CRC, in order to fully elucidate their role in carcinogenesis, are extremely important. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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23 pages, 1205 KiB

Open AccessReview

Cell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells

by Cristina Aparicio, Marina Belver, Lucía Enríquez, Francisco Espeso, Lucía Núñez, Ana Sánchez, Miguel Ángel de la Fuente and Margarita González-Vallinas

Int. J. Mol. Sci. 2021, 22(21), 11781; https://doi.org/10.3390/ijms222111781 - 29 Oct 2021

Cited by 33 | Viewed by 6556

Abstract

Colorectal cancer (CRC) is a global public health problem as it is the third most prevalent and the second most lethal cancer worldwide. Major efforts are underway to understand its molecular pathways as well as to define the tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) or neoantigens, in order to develop an effective treatment. Cell therapies are currently gaining importance, and more specifically chimeric antigen receptor (CAR)-T cell therapy, in which genetically modified T cells are redirected against the tumour antigen of interest. This immunotherapy has emerged as one of the most promising advances in cancer treatment, having successfully demonstrated its efficacy in haematological malignancies. However, in solid tumours, such as colon cancer, it is proving difficult to achieve the same results due to the shortage of TSAs, on-target off-tumour effects, low CAR-T cell infiltration and the immunosuppressive microenvironment. To address these challenges in CRC, new approaches are proposed, including combined therapies, the regional administration of CAR-T cells and more complex CAR structures, among others. This review comprehensively summarises the current landscape of CAR-T cell therapy in CRC from the potential tumour targets to the preclinical studies and clinical trials, as well as the limitations and future perspectives of this novel antitumour strategy. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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20 pages, 20858 KiB

Open AccessReview

The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

by Chien-An Chu, Yi-Wen Wang, Yi-Lin Chen, Hui-Wen Chen, Jing-Jing Chuang, Hong-Yi Chang, Chung-Liang Ho, Chen Chang, Nan-Haw Chow and Chung-Ta Lee

Int. J. Mol. Sci. 2021, 22(20), 10964; https://doi.org/10.3390/ijms222010964 - 11 Oct 2021

Cited by 7 | Viewed by 3126

Abstract

Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2022)

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