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Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New...
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Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 4213

Special Issue Editors

Dr. Serena Martinelli

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
Interests: oncology; metastasis; cell cultures; 3D models; cancer organoids; microbiota
Special Issues, Collections and Topics in MDPI journals
Dr. Elena Niccolai

E-Mail Website1 Website2
Guest Editor
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Interests: microbiome; immunology; gastrointestinal cancers; nutrition; gut-brain axis; neurodegeneration; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Malignant tumors that affect the gastrointestinal tract, known as gastrointestinal (GI) cancers, are widespread. Globally, GI cancers are estimated to be responsible for one in four cancer cases and one in three deaths. This Special Issue aims to elucidate potential areas of progress in the field of GI cancers, including the modulation of the microbiota and novel therapeutic approaches.

Research areas may include (but are not limited to) the following:

  • Modulation of the microbiota: role of the gut microbiome in influencing GI cancer development and response to treatment; manipulation of the microbiota through interventions such as probiotics, prebiotics, and fecal microbiota transplantation; and methods of modulating the microbiome to enhance response to immunotherapies, such as checkpoint inhibitors.
  • Immunotherapy: efficacy of checkpoint inhibitors, such as pembrolizumab and nivolumab, in various GI malignancies and the exploration of CAR-T potential in GI cancers.
  • Precision medicine: advances in molecular profiling and genomics, leading to the identification of specific biomarkers associated with GI cancers, and the development of liquid biopsy techniques for monitoring GI cancers.
  • Targeted therapies: identify additional targeted therapies for specific subtypes of GI cancers in addition to HER2 therapies.
  • Artificial intelligence in diagnostics: evaluation of machine learning algorithms to analyze medical images and to predict the prognosis and disease outcomes of GI cancers.

Dr. Serena Martinelli
Dr. Elena Niccolai
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • gastrointestinal cancers
  • microbiota
  • anticancer therapy
  • immunotherapy
  • precision medicine

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Published Papers (6 papers)

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Research

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18 pages, 2646 KiB  
Article
The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids
by Corinna Boden, Laura K. Esser, Leona Dold, Bettina Langhans, Taotao Zhou, Dominik J. Kaczmarek, Maria A. Gonzalez-Carmona, Tobias J. Weismüller, Glen Kristiansen, Jörg C. Kalff, Michael Hölzel, Hanno Matthaei, Marieta I. Toma and Vittorio Branchi
Biomedicines 2025, 13(5), 1083; https://doi.org/10.3390/biomedicines13051083 (registering DOI) - 29 Apr 2025
Abstract
Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as [...] Read more.
Background/Objectives: Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. Methods: Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. Results: We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma Conclusions: The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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18 pages, 11059 KiB  
Article
Prognostic Significance of CLDN1, INHBA, and CXCL12 in Colon Adenocarcinoma: A Multi-Omics and Single-Cell Approach
by Jaehwan Cheon, Sang Hyun Kim, Jaehyung Park and Tae Hoon Kim
Biomedicines 2025, 13(5), 1035; https://doi.org/10.3390/biomedicines13051035 - 24 Apr 2025
Viewed by 201
Abstract
Background/Objectives: Colon adenocarcinoma (COAD), the most prevalent form of colorectal cancer, remains a leading cause of cancer-related mortality. Advances in various treatments for COAD have significantly improved treatment outcomes. However, therapeutic limitations persist, highlighting the need for personalized strategies driven by novel [...] Read more.
Background/Objectives: Colon adenocarcinoma (COAD), the most prevalent form of colorectal cancer, remains a leading cause of cancer-related mortality. Advances in various treatments for COAD have significantly improved treatment outcomes. However, therapeutic limitations persist, highlighting the need for personalized strategies driven by novel biomarkers. The aim was to identify key hub genes that could be potential biomarkers of COAD using comprehensive bioinformatic analyses. Methods: Differentially expressed genes (DEGs) and co-DEGs were identified from COAD gene expression datasets. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were performed. Hub genes were extracted from protein–protein interaction (PPI) networks and validated epigenetically using microRNA (miRNA) and DNA methylation datasets. Their expression patterns were further examined via single-cell RNA sequencing (scRNA-seq) and immune cell infiltration analysis. Prognostic relevance was assessed based on tumor metastasis and survival outcomes. Results: Gene expression profiling identified 118 co-DEGs, with GO and KEGG pathway analyses revealing significant pathway enrichment. PPI network analysis pinpointed 27 key co-DEGs. Epigenetic profiling indicated that both miRNA interference and DNA methylation regulate CLDN1, INHBA, and CXCL12 expression levels. scRNA-seq analysis showed elevated CLDN1 expression in epithelial cells and INHBA in myeloid cells, and reduced CXCL12 expression in stromal cells. Prognostic analysis further demonstrated that CLDN1 and INHBA are significantly associated with poor COAD outcomes. Conclusions: We identified some potential prognostic biomarkers for patients with COAD. Further experimental validation is required to translate these findings into precision medicine for COAD. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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12 pages, 991 KiB  
Article
Real-World Comparison of Trifluridine–Tipiracil with or Without Bevacizumab in Patients with Refractory Metastatic Colorectal Cancer
by Hyunho Kim, Kabsoo Shin, Ho Jung An, In-Ho Kim, Jung Hoon Bae, Yoon Suk Lee, In Kyu Lee, MyungAh Lee and Se Jun Park
Biomedicines 2025, 13(4), 976; https://doi.org/10.3390/biomedicines13040976 - 16 Apr 2025
Viewed by 163
Abstract
Background/Objectives: Patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy face limited treatment options. While trifluridine–tipiracil (FTD–TPI) and regorafenib have shown modest efficacy in prior clinical trials, recent data from the SUNLIGHT trial demonstrated that combining FTD–TPI with bevacizumab (FTD–TPI+BEV) [...] Read more.
Background/Objectives: Patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy face limited treatment options. While trifluridine–tipiracil (FTD–TPI) and regorafenib have shown modest efficacy in prior clinical trials, recent data from the SUNLIGHT trial demonstrated that combining FTD–TPI with bevacizumab (FTD–TPI+BEV) may improve overall survival compared to FTD–TPI alone. However, supporting evidence from real-world populations remains scarce. Methods: This retrospective study assessed the real-world effectiveness and safety of FTD–TPI+BEV versus FTD–TPI monotherapy in patients with refractory mCRC treated at two institutions from June 2020 to October 2024. Results: A total of 106 patients were included, with 47 treated with FTD–TPI+BEV and 59 with FTD–TPI alone. Median progression-free survival (PFS) was significantly longer with FTD–TPI+BEV compared to FTD–TPI alone (4.1 vs. 2.1 months; HR = 0.56; p = 0.004), while median overall survival showed a non-significant trend favoring FTD–TPI+BEV (8.4 vs. 6.3 months; HR = 0.74; p = 0.189). The disease control rate was also significantly higher with FTD–TPI+BEV (59.6% vs. 25.4%, p = 0.001). Subgroup analyses showed consistent PFS benefits. Grade 3–5 adverse events occurred at comparable rates between groups. Conclusions: FTD–TPI+BEV may represent a preferred salvage treatment option for refractory mCRC. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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15 pages, 1729 KiB  
Article
Demographic Characteristics and Survival in Young-Onset Colorectal Neuroendocrine Neoplasms
by Deepak Vadehra, Sahithi Sonti, Beas Siromoni, Mrinalini Ramesh, Debduti Mukhopadhyay, Adrienne Groman, Renuka Iyer and Sarbajit Mukherjee
Biomedicines 2024, 12(10), 2411; https://doi.org/10.3390/biomedicines12102411 - 21 Oct 2024
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Abstract
Background/Objectives: Recent epidemiological studies have revealed an upward trend in young-onset colorectal cancer (YOCRC) overall, whereas specific data on young-onset colorectal neuroendocrine neoplasms (YONEN) remain limited. This study investigated the demographic characteristics and survival trends in YONEN and compared these with those of [...] Read more.
Background/Objectives: Recent epidemiological studies have revealed an upward trend in young-onset colorectal cancer (YOCRC) overall, whereas specific data on young-onset colorectal neuroendocrine neoplasms (YONEN) remain limited. This study investigated the demographic characteristics and survival trends in YONEN and compared these with those of young-onset colorectal adenocarcinoma (YOADC), the most common histologic subtype of YOCRC. Methods: A retrospective analysis was conducted from 2000 to 2019 using the Surveillance, Epidemiology, and End Results (SEER) database. Survival outcomes were assessed using univariate and multivariable Cox proportional models, with demographic differences evaluated via Wilcoxon rank sum and Chi-square tests. Results: Out of 61,705 patients aged 20–49 with colorectal cancer, 8% had NEN, and 92% had adenocarcinoma. The YONEN cohort had a higher proportion of Black patients and a lower proportion of White patients than the YOADC cohort (21% vs. 13% and 44% vs. 57%, respectively). NEN was more commonly found in the rectum (79%), and adenocarcinoma was mostly colonic (57%) in origin. YONEN patients had better survival than YOADC patients. Multivariate analysis in YONEN patients revealed that Hispanic patients had better overall survival compared to White patients (HR 0.67, 95% CI 0.47–0.95, p = 0.024). Conclusions: Racial disparities should be investigated further to aid in policymaking and targeted interventions. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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17 pages, 2030 KiB  
Article
The Interplay among Wnt/β-catenin Family Members in Colorectal Adenomas and Surrounding Tissues
by Domenica Lucia D’Antonio, Fabiana Fantini, Carmelo Moscatello, Alessio Ferrone, Stefano Scaringi, Rosa Valanzano, Ferdinando Ficari, Konstantinos Efthymakis, Matteo Neri, Gitana Maria Aceto and Maria Cristina Curia
Biomedicines 2024, 12(8), 1730; https://doi.org/10.3390/biomedicines12081730 - 2 Aug 2024
Cited by 1 | Viewed by 1648
Abstract
Background: The colorectal adenoma undergoes neoplastic progression via the normal epithelium–adenoma–adenocarcinoma sequence as reported in the Vogelgram. The hazard of developing a tumor is deeply associated with the number and size of adenomas and their subtype. Adenomatous polyps are histologically categorized as follows: [...] Read more.
Background: The colorectal adenoma undergoes neoplastic progression via the normal epithelium–adenoma–adenocarcinoma sequence as reported in the Vogelgram. The hazard of developing a tumor is deeply associated with the number and size of adenomas and their subtype. Adenomatous polyps are histologically categorized as follows: approximately 80–90% are tubular, 5–15% are villous, and 5–10% are tubular/villous. Given the higher risk of a malignant transformation observed in tubular/villous adenomas, patients diagnosed with adenomatous polyposis are at an improved risk of developing CRC. The Wnt/β-catenin pathway plays a key role in the onset of colorectal adenoma; in particular, intestinal cells first acquire loss-of-function mutations in the APC gene that induce the formation of adenomas. Methods: Wnt/β-catenin pathway APC, Wnt3a, Wnt5a, LEF1, and BCL9 genes and protein expression analyses were conducted by qRT-PCR and western blot in 68 colonic samples (polyps and adjacent mucosa) from 41 patients, of which 17 were affected by FAP. Ten normal colonic mucosal samples were collected from 10 healthy donors. Results: In this study, both the APC gene and protein were less expressed in the colon tumor compared to the adjacent colonic mucosa. Conversely, the activated β-catenin was more expressed in polyps than in the adjacent mucosa. All results confirmed the literature data on carcinomas. A statistically significant correlation between Wnt3a and BCL9 both in polyps and in the adjacent mucosa underlines that the canonical Wnt pathway is activated in early colon carcinogenesis and that the adjacent mucosa is already altered. Conclusion: This is the first study analyzing the difference in expression of the Wnt/β-catenin pathway in human colorectal adenomas. Understanding the progression from adenomas to colorectal carcinomas is essential for the development of new therapeutic strategies and improving clinical outcomes with the use of APC and β-catenin as biomarkers. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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Review

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15 pages, 539 KiB  
Review
G-Quadruplexes in Tumor Immune Regulation: Molecular Mechanisms and Therapeutic Prospects in Gastrointestinal Cancers
by Yunxia Zhou, Difei Xu, Ying Zhang and Huaixiang Zhou
Biomedicines 2025, 13(5), 1057; https://doi.org/10.3390/biomedicines13051057 - 27 Apr 2025
Viewed by 154
Abstract
G-quadruplex (G4) is a noncanonical nucleic acid secondary structure self-assembled by guanine-rich sequences. Recent studies have not only revealed the key role of G4 in gene regulation, DNA replication, and telomere maintenance but also showed that it plays a core role in regulating [...] Read more.
G-quadruplex (G4) is a noncanonical nucleic acid secondary structure self-assembled by guanine-rich sequences. Recent studies have not only revealed the key role of G4 in gene regulation, DNA replication, and telomere maintenance but also showed that it plays a core role in regulating the tumor immune microenvironment. G4 participates in tumor immune escape and the inhibition of immune response by regulating immune checkpoint molecules, cytokine expression, immune cell function, and their interaction network, thus significantly affecting the effect of tumor immunotherapy. This article systematically reviews the molecular mechanism of G4 in tumor immune regulation, especially gastrointestinal tumors, and explores the potential and application prospects of G4-targeted drug strategies in improving anti-tumor immunotherapy. Full article
(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancers: From Microbiota Modulation to New Therapeutic Approaches)
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