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Evolving Perspectives in Colon Cancer Treatment and Research
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Evolving Perspectives in Colon Cancer Treatment and Research

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

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 25116

Special Issue Editor

Dr. Francesca Negri

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Guest Editor
Gastroenterology and Endoscopy Unit, University Hospital of Parma, 43121 Parma, Italy
Interests: colon cancer; rectal cancer; angiogenesis; biomarker; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Precision medicine is increasingly developing therapy algorithms through the identification and characterization of markers according to their involvement in distinct cancer pathways.

Regarding the early stage of the disease, one major question concerns the risk of recurrence and minimal residual disease: when is staging based on pathologic features adequate for shared therapeutic evaluation? Could circulating tumor DNA (ctDNA) prove useful in relapse-risk stratification? These are the main issues concerning future developments.

A revolution in colon cancer therapy has been brewing. The efficacy of PD-1 blockade for MSI-H-dMMR advanced colon cancer has been established and is the new standard of care for MSI-H tumors. Moreover, new data are emerging on the combination of immune checkpoint inhibitors (PD-1, CTLA4) in MSS tumors in different settings.

While the amount of biomarker testing in colon cancer has significantly increased over time, we have also been witness to an evolution from negative selection options (i.e., the presence of RAS mutation and the use of anti-EGFR inhibitors) to positive ones. There has been unprecedented achievement in patients with BRAFV600E mutant colon cancer when disease had previously progressed after prior regimens. Encouraging results have also been obtained in RAS mutant tumors with activating KRAS codon 12 mutations or in heavily pretreated HER-2-expressing colon cancers. As numerous biomarkers are being studied according to a histology-agnostic approach, the number of potentially actionable ones could increase.

This Special Issue aims to provide an overview of the main achievements in the field of colon cancer treatment, providing prospective lines of research. We also would like to provide comprehensive overviews over important aspects of the molecular events in the Colon cancer life cycle, disease development and the current state of Colon cancer treatment.

Dr. Francesca Virginia Negri
Guest Editor

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Keywords

  • Colon cancer
  • Staging
  • Therapy
  • Predictive markers

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Published Papers (7 papers)

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Research

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17 pages, 1297 KiB  
Article
p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients
by Li Ching Ooi, Vincent Ho, Jing Zhou Zhu, Stephanie Lim, Liping Chung, Askar Abubakar, Tristan Rutland, Wei Chua, Weng Ng, Mark Lee, Matthew Morgan, Scott MacKenzie and Cheok Soon Lee
Int. J. Mol. Sci. 2024, 25(2), 725; https://doi.org/10.3390/ijms25020725 - 5 Jan 2024
Viewed by 1216
Abstract
The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer [...] Read more.
The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells’ behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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15 pages, 928 KiB  
Article
Artificial Diets with Altered Levels of Sulfur Amino Acids Induce Anticancer Activity in Mice with Metastatic Colon Cancer, Ovarian Cancer and Renal Cell Carcinoma
by Julio José Jiménez-Alonso, Emilio Guillén-Mancina, José Manuel Calderón-Montaño, Víctor Jiménez-González, Patricia Díaz-Ortega, Estefanía Burgos-Morón and Miguel López-Lázaro
Int. J. Mol. Sci. 2023, 24(5), 4587; https://doi.org/10.3390/ijms24054587 - 27 Feb 2023
Cited by 2 | Viewed by 3031
Abstract
Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role [...] Read more.
Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53−/− cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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11 pages, 984 KiB  
Article
New Histoprognostic Factors to Consider for the Staging of Colon Cancers: Tumor Deposits, Invasive Tumor Infiltration and High-Grade Budding
by Marc Riffet, Benoît Dupont, Maxime Faisant, Damiano Cerasuolo, Benjamin Menahem, Arnaud Alves, Fatémeh Dubois, Guénaëlle Levallet and Céline Bazille
Int. J. Mol. Sci. 2023, 24(4), 3573; https://doi.org/10.3390/ijms24043573 - 10 Feb 2023
Cited by 4 | Viewed by 1616
Abstract
Colorectal cancer is a major public health issue due to its high incidence and mortality. It is, therefore, essential to identify histological markers for prognostic purposes and to optimize the therapeutic management of patients. The main objective of our study was to analyze [...] Read more.
Colorectal cancer is a major public health issue due to its high incidence and mortality. It is, therefore, essential to identify histological markers for prognostic purposes and to optimize the therapeutic management of patients. The main objective of our study was to analyze the impact of new histoprognostic factors, such as tumor deposits, budding, poorly differentiated clusters, mode of infiltration, the intensity of inflammatory infiltrate and the type of tumor stroma, on the survival of patients with colon cancer. Two hundred and twenty-nine resected colon cancers were fully histologically reviewed, and survival and recurrence data were collected. Survival was analyzed using Kaplan–Meier curves. A univariate and multivariate Cox model was constructed to identify prognostic factors for overall survival and recurrence-free survival. The median overall survival of the patients was 60.2 months and the median recurrence-free survival was 46.9 months. Overall survival and recurrence-free survival were significantly worse in the presence of isolated tumor deposits (log rank = 0.003 and 0.001, respectively) and for an infiltrative type of tumor invasion (log rank = 0.008 and 0.02, respectively). High-grade budding was associated with a poor prognosis, with no significant difference. We did not find a significant prognostic impact of the presence of poorly differentiated clusters, the intensity of the inflammatory infiltrate or the stromal type. In conclusion, the analysis of these recent histoprognostic factors, such as tumor deposits, mode of infiltration, and budding, could be integrated into the results of pathological reports of colon cancers. Thus, the therapeutic management of patients could be adjusted by providing more aggressive treatments in the presence of some of these factors. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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15 pages, 2463 KiB  
Article
Modulation of Mismatch Repair and the SOCS1/p53 Axis by microRNA-155 in the Colon of Patients with Primary Sclerosing Cholangitis
by Monika Adamowicz, Iga Stukan, Piotr Milkiewicz, Andrzej Bialek, Malgorzata Milkiewicz and Agnieszka Kempinska-Podhorodecka
Int. J. Mol. Sci. 2022, 23(9), 4905; https://doi.org/10.3390/ijms23094905 - 28 Apr 2022
Cited by 4 | Viewed by 2634
Abstract
Deficient mismatch repair (MMR) proteins may lead to DNA damage and microsatellite instability. Primary sclerosing cholangitis (PSC) is a risk factor for colitis-associated colon cancer. MiR-155 is suggested to act as a key regulating node, linking inflammation and tumorigenesis. However, its involvement in [...] Read more.
Deficient mismatch repair (MMR) proteins may lead to DNA damage and microsatellite instability. Primary sclerosing cholangitis (PSC) is a risk factor for colitis-associated colon cancer. MiR-155 is suggested to act as a key regulating node, linking inflammation and tumorigenesis. However, its involvement in the chronic colitis of PSC-UC patients has not been examined. We investigated the involvement of miR-155 in the dysregulation of MMR genes and colitis in PSC patients. Colon tissue biopsies were obtained from patients with PSC, PSC with concomitant ulcerative colitis (PSC-UC), uncomplicated UC, and healthy controls (n = 10 per group). In the ascending colon of PSC and PSC-UC patients, upregulated miR-155 promoted high microsatellite instability and induced signal transducer and activator of transcription 3 (STAT-3) expression via the inhibition of suppressors of cytokine signalling 1 (SOCS1). In contrast, the absence of miR-155 overexpression in the sigmoid colon of PSC-UC patients activated the Il-6/S1PR1 signalling pathway and imbalanced the IL17/FOXP3 ratio, which reinforces chronic colitis. Functional studies on human intestinal epithelial cells (HT-29 and NCM460D) confirmed the role of miR-155 over-expression in the inhibition of MMR genes and the modulation of p53. Moreover, those cells produced more TNFα upon a lipopolysaccharide challenge, which led to the suppression of miR-155. Additionally, exposure to bile acids induced upregulation of miR-155 in Caco-2 cell lines. Thus, under different conditions, miR-155 is involved in either neoplastic transformation in the ascending colon or chronic colitis in the sigmoid colon of patients with PSC. New insight into local modulation of microRNAs, that may alter the course of the disease, could be used for further research on potential therapeutic applications. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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17 pages, 3454 KiB  
Article
Evidence That β1-Integrin Is Required for the Anti-Viability and Anti-Proliferative Effect of Resveratrol in CRC Cells
by Aranka Brockmueller, Parviz Shayan and Mehdi Shakibaei
Int. J. Mol. Sci. 2022, 23(9), 4714; https://doi.org/10.3390/ijms23094714 - 25 Apr 2022
Cited by 17 | Viewed by 2212
Abstract
The β1-integrin receptor is broadly expressed on tumor and other cells in the tumor microenvironment (TME), and is an unfavorable prognostic factor for cancers. Nature-derived resveratrol has preventive and apoptotic effects on tumors, but whether resveratrol can exert its suppressive actions on TME-induced [...] Read more.
The β1-integrin receptor is broadly expressed on tumor and other cells in the tumor microenvironment (TME), and is an unfavorable prognostic factor for cancers. Nature-derived resveratrol has preventive and apoptotic effects on tumors, but whether resveratrol can exert its suppressive actions on TME-induced tumorigenesis through β1-integrin on the surface of CRC cells is still unknown. HCT116 or SW480 cells were exposed to inhibitory antibodies against β1-integrin, bacitracin (selective β1-integrin inhibitor), integrin-binding RGD (Arg-Gly-Asp) peptide, and/or resveratrol. We evaluated the anti-tumor actions and signaling impacts of resveratrol in colorectal cancer (CRC)-TME. We found that resveratrol completely altered the β1-integrin distribution pattern and expression on the surface of CRC cells in TME. Moreover, resveratrol down-regulated CRC cell proliferation, colony formation, viability, and up-regulated apoptosis in a concentration-dependent way. These actions of resveratrol were antagonized mainly by inhibitory antibodies against β1-integrin but not β5-integrin, and by an integrin-binding RGD peptide but not by RGE peptide, and by bacitracin in TME. Similarly, resveratrol-blocked TME-induced p65-NF-kB and its promoted gene markers linked to proliferation (cyclin D1), invasion (focal adhesion kinase, FAK), or apoptosis (caspase-3), were largely abrogated by anti-β1-integrin or RGD peptide, suggesting that β1-integrin is a potential transmission pathway for resveratrol/integrin down-stream signaling in CRC cells. The current results highlight, for the first time, the important gateway role of β1-integrins as signal carriers for resveratrol on the surfaces of HCT116 and SW480 cells, and their functional cooperation for the modulatory effects of resveratrol on TME-promoted tumorigenesis. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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Review

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21 pages, 8741 KiB  
Review
KRAS: A Druggable Target in Colon Cancer Patients
by Francesca Negri, Lorena Bottarelli, Gian Luigi de’Angelis and Letizia Gnetti
Int. J. Mol. Sci. 2022, 23(8), 4120; https://doi.org/10.3390/ijms23084120 - 8 Apr 2022
Cited by 23 | Viewed by 6167
Abstract
Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific [...] Read more.
Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered ‘undruggable’. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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22 pages, 1009 KiB  
Review
Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer
by Chiara Guarini, Teresa Grassi, Gaetano Pezzicoli and Camillo Porta
Int. J. Mol. Sci. 2021, 22(13), 6813; https://doi.org/10.3390/ijms22136813 - 24 Jun 2021
Cited by 21 | Viewed by 7176
Abstract
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not [...] Read more.
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2′s role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease. Full article
(This article belongs to the Special Issue Evolving Perspectives in Colon Cancer Treatment and Research)
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