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Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer

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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: 20 September 2026 | Viewed by 6770

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Dr. Daniel Gabriel Pons

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Guest Editor

1. Multidisciplinar Group in Traslational Oncology (GMOT), Balearic Islands University (UIB), 07122 Palma, Spain
2. Balearic Islands Health Research Institute (IdISBa), 07010 Palma, Spain
Interests: oxidative stress; estrogen; phytoestrogens; cancer cells; personalized treatment
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Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, necessitating advancements in understanding its underlying mechanisms and therapeutic strategies. This Special Issue, entitled “Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer”, aims to gather innovative research on the molecular and cellular processes driving the development, progression, and resistance of CRC to treatment. This Special Issue will particularly focus on novel biomarkers for early detection, the role of the tumor microenvironment, advancements in immunotherapy, and innovative therapeutic approaches that target signaling pathways. Contributions that explore precision medicine strategies, the potential application of phytochemicals or bioactive compounds as adjuvant therapies, and the use of extracellular vesicles for intercellular communication are particularly welcome. By integrating multidisciplinary perspectives, this Special Issue seeks to highlight breakthroughs that can translate into improved clinical outcomes for CRC patients.

Dr. Daniel Gabriel Pons
Guest Editor

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Keywords

colorectal cancer
tumor microenvironment
biomarkers
intercellular communication
therapeutic strategies

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Published Papers (5 papers)

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Research

34 pages, 5176 KB

Open AccessArticle

N-Substituted-2-(9H-Xanthen-9-yl)acetamide Derivatives Induce In Vitro Colon Cancer Cell Death via TASK-1 Inhibition: Lead Compounds for Further Optimization as TASK-1-Targeted Therapeutics in Colorectal Cancer

by Abdulaziz H. Al Khzem, S. M. El Rayes, Ibrahim A. I. Ali, Walid Fathalla, Mansour S. Alturki, Nada Tawfeeq, Saeed M. Tayeb, Abdulelah A. Alfattani, Saad M. Wali, Firdos A. Khan, Abdulmalik M. Alqarni, Faheem H. Pottoo, Dania Hussein and Mohamed S. Gomaa

Int. J. Mol. Sci. 2026, 27(9), 4069; https://doi.org/10.3390/ijms27094069 - 1 May 2026

Viewed by 493

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

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20 pages, 3082 KB

Open AccessArticle

Short-Duration HIPEC-Mimetic Mithramycin A Exposure Induces Durable Transcriptional Remodeling Involving Chromatin Regulatory Networks in Colorectal Cancer Models

by Olivia Coburn-Flynn, M. Virginia Butchy, Yazid Ghanem, Robert Emery, Vincent Verchio, Kristen Knapp, Jessica Collier, Sahil Jethi, Francis R. Spitz, Ping Zhang, Weam Othman Elbezanti and Young Ki Hong

Int. J. Mol. Sci. 2026, 27(8), 3580; https://doi.org/10.3390/ijms27083580 - 17 Apr 2026

Viewed by 949

Abstract

Hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal metastases relies primarily on DNA-damaging agents whose efficacy depends on sustained cytotoxic exposure. Whether brief treatment can induce durable transcriptional remodeling remains unclear. Mithramycin A (MA) is a GC-rich DNA-binding agent with transcriptional regulatory activity involving chromatin-associated pathways. Here, we investigated the molecular and functional consequences of a single 90-min HIPEC-mimetic MA exposure in colorectal cancer models. RNA sequencing revealed extensive and coordinated transcriptional remodeling, affecting a substantial fraction of expressed genes and producing a response qualitatively distinct from mitomycin C. MA selectively suppressed key chromatin-associated regulatory factors, including DNMT1, JARID2, and HDAC4, while coordinately activating canonical cyclin-dependent kinase inhibitors CDKN1A, CDKN1C, and CDKN2C. Gene set enrichment analysis demonstrated enrichment of G2/M checkpoint pathways and suppression of oncogenic gene networks. These molecular changes translated into sustained inhibition of clonogenic growth and activation of caspase-dependent apoptosis following drug washout, with hyperthermia potentiating apoptotic signaling. Collectively, these findings indicate that brief MA exposure induces selective modulation of chromatin regulators and durable transcriptional reorganization, supporting modulation of chromatin regulatory networks as a potential therapeutic strategy for HIPEC-based colorectal cancer therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

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33 pages, 4093 KB

Open AccessArticle

Association of TIGIT and CD155 with KRAS, NRAS, BRAF, PIK3CA, and AKT Gene Mutations, MSI Status, and Cytokine Profiles in Colorectal Cancer

by Błażej Ochman, Piotr Limanówka, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Dorota Hudy, Monika Szrot, Jerzy Piecuch, Zenon Czuba, Dariusz Waniczek and Elżbieta Świętochowska

Int. J. Mol. Sci. 2026, 27(2), 937; https://doi.org/10.3390/ijms27020937 - 17 Jan 2026

Cited by 2 | Viewed by 989

Abstract

TIGIT and its ligand CD155 (PVR) are emerging immune checkpoints in colorectal cancer (CRC), but their associations with mutational subtypes and the tumor immune milieu remain unclear. We quantified TIGIT and CD155 proteins by ELISA in paired CRC tumors and matched surgical margins (n = 131) and evaluated associations with clinicopathological features, MSI status, and KRAS/NRAS/BRAF/PIK3CA/AKT1 mutations (n = 104). Both TIGIT and CD155 were significantly elevated in tumor tissue versus margins (p < 0.0001) and showed no association with TNM stage, clinical stage, grade, or tumor location. TIGIT levels were higher in MSI than MSS tumors and in BRAF-mutant compared to BRAF wild-type tumors, while CD155 expression showed no consistent MSI- or mutation-dependent differences. Cytokine profiling identified IFN-g as the only shared positive associate of TIGIT and CD155; CD155 additionally associated with TRAIL, IL-1Ra, M-CSF, and PDGF-bb. In external transcriptomic validation (TCGA-CRC), GSEA indicated enrichment of interferon/inflammatory programs in TIGIT-high tumors, while CD155-high tumors preferentially showed proliferation-related MYC/E2F/G2M signatures. Together, these findings support tumor-wide upregulation of the TIGIT/CD155 axis in CRC and suggest that TIGIT, more than CD155, tracks with MSI/BRAF-associated immune activation, providing a rationale for patient stratification in checkpoint-directed immunotherapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

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18 pages, 6015 KB

Open AccessArticle

Biomarker Identification via Spatial Transcriptomics Profiling of Colorectal Cancer and Colorectal Cancer with Liver Metastasis Stem Cells

by Minho Lee, Seoin Han, Hak Chun Kim, Yujun Jung, Jeong-An Gim, Chang-Jin Kim and Dongjun Jeong

Int. J. Mol. Sci. 2025, 26(22), 11045; https://doi.org/10.3390/ijms262211045 - 14 Nov 2025

Cited by 1 | Viewed by 1794

Abstract

Colorectal cancer (CRC) demonstrates favorable clinical outcomes when diagnosed at an early stage; however, the prognosis declines substantially following recurrence or distant metastasis. Increasing evidence indicates that cancer stem cells (CSCs) are pivotal contributors to tumor recurrence, metastatic dissemination, and therapeutic resistance. The present study aimed to identify CSC-associated biomarkers through spatial transcriptomic profiling of normal colonic mucosa, primary CRC, and liver metastatic tissues, and to evaluate their functional relevance in CRC progression. Spatial transcriptomic analysis revealed that CCN2 was preferentially enriched within CSC clusters of primary CRC tissues, whereas APOC2 was predominantly upregulated in liver-metastatic CSCs. Functional validation of CCN2 was performed by establishing CCN2-knockout HCT116 cell lines using the CRISPR-Cas9 system. Loss of CCN2 expression markedly attenuated cell proliferation, migration, invasion, and oxaliplatin resistance compared with control cells. Furthermore, immunohistochemical analysis of tissue microarrays demonstrated a significant positive correlation between CCN2 expression and CSC markers SOX2 and Nestin. Collectively, these findings suggest that CCN2 functions as a central regulator of stemness and malignant potential in CRC and may represent a promising therapeutic target to prevent recurrence and metastasis. Additional mechanistic studies are warranted to further elucidate the molecular pathways of CCN2 and to validate the role of APOC2 in liver-metastatic CRC stem cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

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22 pages, 4133 KB

Open AccessArticle

Multiomics Signature Reveals Network Regulatory Mechanisms in a CRC Continuum

by Juan Carlos Higareda-Almaraz, Francesco Mattia Mancuso, Pol Canal-Noguer, Kristi Kruusmaa and Arianna Bertossi

Int. J. Mol. Sci. 2025, 26(15), 7077; https://doi.org/10.3390/ijms26157077 - 23 Jul 2025

Cited by 1 | Viewed by 1478

Abstract

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)

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