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Recent Advances in Gastrointestinal Cancer, 2nd Edition

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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: closed (20 April 2025) | Viewed by 13966

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Dr. Aneta Koronowicz

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Department of Human Nutrition and Dietetics, University of Agriculture in Krakow, A. Mickiewicz Av. 21, 31-120 Krakow, Poland
Interests: health prevention; human nutrition; nutrigenomics; nutrition and immunity; epigenetics; functional foods
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Special Issue Information

Dear Colleagues,

Gastrointestinal cancer is the most common human malignancy, with colorectal and gastric cancer accounting for the third and fifth highest global incidences, respectively. Despite the use of new and innovative chemotherapeutic agents and combinational treatment strategies, including chemotherapy, surgery, radiotherapy and targeted therapies, modern medicine still lacks a fully effective therapy approach. In addition, survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence cancer progression and the development of optimal therapeutic strategies for gastrointestinal cancer malignancies is urgently needed. Alongside the need for utilizing existing knowledge in the field of development and synthesizing new, potential chemotherapeutic agents characterized by an appropriate effectiveness of action on gastrointestinal cancer cells, it is also important to emphasize prevention, which may involve, for example, proper nutrition. Numerous studies show that natural plant-derived compounds may contribute to prevention and support the treatment of gastrointestinal cancer and other chronic diseases. The anticancer potential of compounds is often related to changes in the expression of genes that are implicated in cell cycle arrest and apoptotic death.

This Special Issue is supervised by Dr. Aneta Koronowicz and assisted by our Topical Advisory Panel Member Dr. Ewelina Piasna-Słupecka (University of Agriculture in Krakow). In this Special Issue, we will discuss recent advances and future directions of therapy for malignant tumors of the gastrointestinal system, and also describe innovative chemotherapeutic agents. In addition, we will discuss the biological properties of natural products and new and classical dietary bioactive compounds which may reduce the risk for gastrointestinal cancer diseases in the future.

More published papers can be found in the closed Special Issue “Recent Advances in Gastrointestinal Cancer”.

Dr. Aneta Koronowicz
Guest Editor

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Keywords

gastrointestinal cancer
chemotherapeutic agents
innovative therapies
human nutrition
nutrigenomics
nutrition and immunity
epigenetics
cytotoxicity
apoptosis

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Published Papers (9 papers)

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Research

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25 pages, 6294 KiB

Open AccessArticle

Increased Herpesvirus Entry Mediator Expression on Circulating Monocytes and Subsets Predicts Poor Outcomes in Pancreatic Ductal Adenocarcinoma Patients

by Isabelle Kuchenreuther, Finn-Niklas Clausen, Johanne Mazurie, Sushmita Paul, Franziska Czubayko, Anke Mittelstädt, Ann-Kathrin Koch, Alara Karabiber, Frederik J. Hansen, Lisa-Sophie Arnold, Nadine Weisel, Susanne Merkel, Maximilian Brunner, Christian Krautz, Julio Vera, Robert Grützmann, Georg F. Weber and Paul David

Int. J. Mol. Sci. 2025, 26(7), 2875; https://doi.org/10.3390/ijms26072875 - 21 Mar 2025

Viewed by 491

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with a 5-year survival rate of only 12.8%, and its increasing incidence in Western countries highlights the urgent need for better early-stage detection and treatment methods. Early diagnosis significantly improves the chances of survival, but non-specific symptoms and undetectable precursor lesions pose a major challenge. To date, there are no reliable screening tools to detect PDAC at an early stage. Herpesvirus entry mediator (HVEM) has already been proposed as a prognostic marker in numerous cancer types. Therefore, we investigated the role of HVEM in PDAC. Flow cytometry was used to analyze HVEM expression in immune cells and its inhibitory receptors (CD160 and BTLA) on T-cells, as well as its subsets in the peripheral blood of 57 diagnosed PDAC patients and 17 clinical controls. In addition, survival analyses were performed within the PDAC cohort, changes in HVEM expression were analyzed in relation to clinicopathological parameters, and a correlation analysis between HVEM expression and cytokine levels of IL-6 and IL-10 was conducted. Furthermore, HVEM expression on monocytes and their subsets was evaluated as a potential prognostic marker and compared with the prognostic utility of CA19-9. We found that HVEM expression is significantly elevated on immune cells, particularly on monocytes (p < 0.0001) and their subsets, in PDAC patients, and is associated with reduced survival (p = 0.0067) and clinicopathological features such as perineural, lymphovascular, and vascular invasion. Moreover, HVEM-expressing monocytes demonstrated superior predictive value compared to CA19-9, highlighting their potential as part of a combined screening tool for PDAC. In conclusion, HVEM on monocytes could serve as a novel prognostic marker for PDAC. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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19 pages, 3799 KiB

Open AccessArticle

High p53 Protein Level Is a Negative Prognostic Marker for Pancreatic Adenocarcinoma

by Sebastian M. Klein, Maria Bozko, Astrid Toennießen, Dennis Rangno and Przemyslaw Bozko

Int. J. Mol. Sci. 2024, 25(22), 12307; https://doi.org/10.3390/ijms252212307 - 16 Nov 2024

Viewed by 942

Abstract

Pancreatic adenocarcinoma is one of the most aggressive types of cancer. Among different mechanisms generally believed to be important for the development of cancer, aberrant regulation of the p53 protein is a well-known and common feature for many cancer entities. Our work aims to analyze the impact of p53 deregulation and proteins encoded by p53 target genes on the survival of patients suffering from pancreatic adenocarcinoma. We, therefore, focused on the analysis of the selected collective for the TP53 mutation status, the p53 protein level, their correlation, and possible impacts on the prognosis/survival. We compared and analyzed a set of 123 patients. We have extracted information regarding the TP53 mutation status, p53 protein levels, the level of proteins encoded by prominent p53 target genes, and information on the overall survival. Survival analyses were displayed by Kaplan–Meier plots, using the log-rank test, in order to check for statistical significance. Protein levels were compared using the Mann–Whitney Test. We did not find any statistically significant correlation between the TP53 mutation status and the survival of the patients. Moreover, we have not found any significant correlation between the protein amount of prominent p53 target genes and the patients’ survival. However, we see a significant correlation between the p53 protein level in cancer samples and the overall survival of pancreatic adenocarcinoma patients: patients having tumors with a p53 protein level within the upper quartile of all measured cases show a significantly reduced survival compared to the rest of the patients. Thus, in pancreatic adenocarcinoma, the p53 protein level is a relevant marker for prognosis, and cancers having a high p53 protein amount show a shortened patients’ survival. In contrast, for this cancer entity, the TP53 mutation status or the protein amount of prominent p53 target genes on their own seems not to have a significant impact on survival. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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18 pages, 1941 KiB

Open AccessArticle

Layer Analysis Based on RNA-Seq Reveals Molecular Complexity of Gastric Cancer

by Pablo Perez-Wert, Sara Fernandez-Hernandez, Angelo Gamez-Pozo, Marina Arranz-Alvarez, Ismael Ghanem, Rocío López-Vacas, Mariana Díaz-Almirón, Carmen Méndez, Juan Ángel Fresno Vara, Jaime Feliu, Lucia Trilla-Fuertes and Ana Custodio

Int. J. Mol. Sci. 2024, 25(21), 11371; https://doi.org/10.3390/ijms252111371 - 22 Oct 2024

Viewed by 1305

Abstract

Gastric adenocarcinoma (GA) is a significant global health issue with poor prognosis, despite advancements in treatment. Although molecular classifications, such as The Cancer Genome Atlas (TCGA), provide valuable insights, their clinical utility remains limited. We performed a multi-layered functional analysis using TCGA RNA sequencing data to better define molecular subtypes and explore therapeutic implications. We reanalyzed TCGA RNA-seq data from 142 GA patients with localized disease who received adjuvant chemotherapy. Our approach included probabilistic graphical models and recurrent sparse k-means/consensus cluster algorithms for layer-based analysis. Our findings revealed survival differences among TCGA groups, with the GS subtype showing the poorest prognosis. We identified twelve functional nodes and seven biological layers, each with distinct functions. The combined molecular layer (CML) classification identified three prognostic groups that align with TCGA subtypes. CML2 (GS-like) displayed gene expression related to lipid metabolism, correlating with worse survival. Transcriptomic heterogeneity within the CIN subtype revealed clusters tied to proteolysis and lipid metabolism. We identified a subset of CIN tumors with profiles similar to MSI, termed CIN-MSI-like. Claudin-18, a key gene in proteolysis, was overexpressed across TCGA subtypes, suggesting it is a potential therapeutic target. Our study advances GA biology, enabling refined stratification and personalized treatment. Further studies are needed to translate these findings into clinical practice. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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20 pages, 6889 KiB

Open AccessArticle

Diagnostic Potential of miR-143-5p, miR-143-3p, miR-551b-5p, and miR-574-3p in Chemoresistance of Locally Advanced Gastric Cancer: A Preliminary Study

by Marlena Janiczek-Polewska, Tomasz Kolenda, Paulina Poter, Joanna Kozłowska-Masłoń, Inga Jagiełło, Katarzyna Regulska, Julian Malicki and Andrzej Marszałek

Int. J. Mol. Sci. 2024, 25(15), 8057; https://doi.org/10.3390/ijms25158057 - 24 Jul 2024

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Abstract

Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Although the incidence is decreasing in developed countries, the treatment results are still unsatisfactory. The standard treatment for locally advanced gastric cancer (LAGC) is gastrectomy with perioperative chemotherapy. The association of selected microRNAs (miRNAs) with chemoresistance was assessed using archival material of patients with LAGC. Histological material was obtained from each patient via a biopsy performed during gastroscopy and then after surgery, which was preceded by four cycles of neoadjuvant chemotherapy (NAC) according to the FLOT or FLO regimen. The expression of selected miRNAs in the tissue material was assessed, including miRNA-21-3p, miRNA-21-5p, miRNA-106a-5p, miRNA-122-3p, miRNA-122-5p, miRNA-143-3p, miRNA-143-5p, miRNA-203a-3p, miRNA-203-5p, miRNA-551b-3p, miRNA-551b-5p, and miRNA-574-3p. miRNA expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The response to NAC was assessed using computed tomography of the abdomen and chest and histopathology after gastrectomy. The statistical analyses were performed using GraphPad Prism 9. The significance limit was set at p < 0.05. We showed that the expression of miR-143-3p, miR-143-5p, and miR-574-3p before surgery, and miR-143-5p and miR-574-3p after surgery, decreased in patients with GC. The expression of miR-143-3p, miR-143-5p, miR-203a-3p, and miR-551b-5p decreased in several patients who responded to NAC. The miRNA most commonly expressed in these cases was miRNA-551b-5p. Moreover, it showed expression in a patient whose response to chemotherapy was inconsistent between the histopathological results and computed tomography. The expression of miR-143-3p, miR-143-5p, miR-203a-3p, and miR-551b-5p in formalin-fixed paraffin-embedded tissue (FFPET) samples can help differentiate between the responders and non-responders to NAC in LAGC. miR-143-3p, miR-143-5p, and miR-574-3p expression may be used as a potential diagnostic tool in GC patients. The presence of miR-551b-5p may support the correct assessment of a response to NAC in GC via CT. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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20 pages, 2677 KiB

Open AccessArticle

Comprehensive Analysis of the Function and Prognostic Value of TAS2Rs Family-Related Genes in Colon Cancer

by Suzhen Bi, Jie Zhu, Liting Huang, Wanting Feng, Lulu Peng, Liangqi Leng, Yin Wang, Peipei Shan, Weikaixin Kong and Sujie Zhu

Int. J. Mol. Sci. 2024, 25(13), 6849; https://doi.org/10.3390/ijms25136849 - 21 Jun 2024

Cited by 1 | Viewed by 2154

Abstract

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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14 pages, 3542 KiB

Open AccessArticle

Identification of a Novel miR-195-5p/PNN Axis in Colorectal Cancer

by Emanuele Piccinno, Viviana Scalavino, Nicoletta Labarile, Lucia De Marinis, Raffaele Armentano, Gianluigi Giannelli and Grazia Serino

Int. J. Mol. Sci. 2024, 25(11), 5980; https://doi.org/10.3390/ijms25115980 - 30 May 2024

Cited by 5 | Viewed by 1567

Abstract

Pinin (PNN) is a desmosome-associated protein that reinforces the organization of keratin intermediate filaments and stabilizes the anchoring of the cytoskeleton network to the lateral surface of the plasma membrane. The aberrant expression of PNN affects the strength of cell adhesion as well as modifies the intracellular signal transduction pathways leading to the onset of CRC. In our previous studies, we characterized the role of miR-195-5p in the regulation of desmosome junctions and in CRC progression. Here, with the aim of investigating additional mechanisms related to the desmosome complex, we identified PNN as a miR-195-5p putative target. Using a public data repository, we found that PNN was a negative prognostic factor and was overexpressed in colon cancer tissues from stage 1 of the disease. Then, we assessed PNN expression in CRC tissue specimens, confirming the overexpression of PNN in tumor sections. The increase in intracellular levels of miR-195-5p revealed a significant decrease in PNN at the mRNA and protein levels. As a consequence of PNN regulation by miR-195-5p, the expression of KRT8 and KRT19, closely connected to PNN, was affected. Finally, we investigated the in vivo effect of miR-195-5p on PNN expression in the colon of AOM/DSS-treated mice. In conclusion, we have revealed a new mechanism driven by miR-195-5p in the regulation of desmosome components, suggesting a potential pharmacological target for CRC therapy. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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17 pages, 1553 KiB

Open AccessArticle

Expression of Calcitonin Gene-Related Peptide and Calcitonin Receptor-like Receptor in Colorectal Adenocarcinoma

by Robert-Emmanuel Șerban, Mioara-Desdemona Stepan, Dan Nicolae Florescu, Mihail-Virgil Boldeanu, Mirela-Marinela Florescu, Mircea-Sebastian Șerbănescu, Mihaela Ionescu, Liliana Streba, Nicoleta-Alice-Marinela Drăgoescu, Pavel Christopher, Vasile-Cosmin Obleagă, Cristian Constantin and Cristin Constantin Vere

Int. J. Mol. Sci. 2024, 25(8), 4461; https://doi.org/10.3390/ijms25084461 - 18 Apr 2024

Cited by 3 | Viewed by 1974

Abstract

Colorectal cancer is one of the most widespread types of cancer that still causes many deaths worldwide. The development of new diagnostic and prognostic markers, as well as new therapeutic methods, is necessary. The calcitonin gene-related peptide (CGRP) neuropeptide alongside its receptor calcitonin receptor-like receptor (CRLR) could represent future biomarkers and a potential therapeutic target. Increased levels of CGRP have been demonstrated in thyroid, prostate, lung, and breast cancers and may also have a role in colorectal cancer. At the tumor level, it acts through different mechanisms, such as the angiogenesis, migration, and proliferation of tumor cells. The aim of this study was to measure the level of CGRP in colorectal cancer patients’ serum by enzyme-linked immunosorbent assay (ELISA) and determine the level of CGRP and CRLR at the tumor level after histopathological (HP) and immunohistochemical (IHC) analysis, and then to correlate them with the TNM stage and with different tumoral characteristics. A total of 54 patients with newly diagnosed colorectal adenocarcinoma were evaluated. We showed that serum levels of CGRP, as well as CGRP and CRLR tumor level expression, correlate with the TNM stage, with local tumor extension, the presence of lymph node metastasis, and distant metastasis, and also with the tumor differentiation degree. CGRP is present in colorectal cancer from the incipient TNM stage, with levels increasing with the stage, and can be used as a diagnostic and prognostic marker and may also represent a potentially new therapeutic target. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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Review

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24 pages, 2259 KiB

Open AccessReview

Geographic and Viral Etiology Patterns of TERT Promoter and CTNNB1 Exon 3 Mutations in Hepatocellular Carcinoma: A Comprehensive Review

by Mariana Leonardo Terra, Thaís Barbosa Ferreira Sant’Anna, José Junior França de Barros and Natalia Motta de Araujo

Int. J. Mol. Sci. 2025, 26(7), 2889; https://doi.org/10.3390/ijms26072889 - 22 Mar 2025

Viewed by 619

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Genetic alterations play a critical role in hepatocarcinogenesis, with mutations in the telomerase reverse transcriptase promoter (TERTp) and CTNNB1 exon 3 representing two of the most frequently reported somatic events in HCC. However, the frequency and distribution of these mutations vary across geographic regions and viral etiologies, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to assess the global distribution and etiological associations of TERTp and CTNNB1 exon 3 mutations in HCC through a comprehensive literature review. Our analysis, encompassing over 4000 HCC cases, revealed that TERTp mutations were present in 49.2% of tumors, with C228T being the predominant variant (93.3% among mutated cases). A striking contrast was observed between viral etiologies: TERTp mutations were detected in 31.6% of HBV-related HCCs, compared to 66.2% in HCV-related cases. CTNNB1 exon 3 mutations were identified in 23.1% of HCCs, showing a similar association with viral etiology, being more common in HCV-related cases (30.7%) than in HBV-related tumors (12.8%). Geographically, both mutations exhibited comparable patterns, with higher frequencies in Europe, Japan, and the USA, while lower rates were observed in China, Taiwan, and South Korea. Our findings underscore the distinct molecular profiles of HCC according to viral etiology and geographic origin, highlighting the need for region- and etiology-specific approaches to HCC prevention, diagnosis, and targeted therapy. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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14 pages, 862 KiB

Open AccessReview

The CpG Island Methylator Phenotype Status in Synchronous and Solitary Primary Colorectal Cancers: Prognosis and Effective Therapeutic Drug Prediction

by Yun-Yun Weng and Ming-Yii Huang

Int. J. Mol. Sci. 2024, 25(10), 5243; https://doi.org/10.3390/ijms25105243 - 11 May 2024

Cited by 2 | Viewed by 2190

Abstract

Synchronous colorectal cancer (sCRC) is characterized by the occurrence of more than one tumor within six months of detecting the first tumor. Evidence suggests that sCRC might be more common in the serrated neoplasia pathway, marked by the CpG island methylator phenotype (CIMP), than in the chromosomal instability pathway (CIN). An increasing number of studies propose that CIMP could serve as a potential epigenetic predictor or prognostic biomarker of sCRC. Therapeutic drugs already used for treating CIMP-positive colorectal cancers (CRCs) are reviewed and drug selections for sCRC patients are discussed. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 2nd Edition)

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