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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 (31 December 2023) | Viewed by 20722

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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: cancer research; human nutrition; nutrigenomics; nutrition and immunity; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gastrointestinal cancer is the most common human malignancy. Colorectal as well as gastric cancer are listed third and fifth, respectively, in terms of incidence around the world. Despite the use of new and innovative chemotherapeutic agents, combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, modern medicine is still struggling to identify a fully effective therapy approach. In addition, the 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 are urgently needed. Therefore, there is a strong need not only to use the existing knowledge in the field of development and synthesis of new, potential chemotherapeutic agents, which would be characterized by an appropriate effectiveness of action on gastrointestinal cancer cells. It is also important to place appropriate emphasis on prevention, which may involve, among others, proper nutrition. Numerous pieces of evidence 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.

Dr. Aneta Koronowicz
Guest Editor

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

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

Published Papers (10 papers)

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Research

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13 pages, 4100 KiB

Open AccessArticle

Sodium Butyrate Inhibits the Expression of Thymidylate Synthase and Induces Cell Death in Colorectal Cancer Cells

by Nayeon Kim and Changwon Yang

Int. J. Mol. Sci. 2024, 25(3), 1572; https://doi.org/10.3390/ijms25031572 - 26 Jan 2024

Viewed by 851

Abstract

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU). Inhibition of thymidylate synthase (TYMS) expression appears to be a promising strategy to overcome the decreased sensitivity to 5-FU caused by high expression of TYMS, which can be induced by 5-FU treatment. Several compounds have been shown to potentially inhibit the expression of TYMS, but it is unclear whether short-chain fatty acids (SCFAs), which are naturally produced by bacteria in the human intestine, can regulate the expression of TYMS. Sodium butyrate (NaB) is the most widely known SCFA for its beneficial effects. Therefore, we investigated the enhancing effects on inhibition of cell viability and induction of apoptosis after co-treatment of NaB with 5-FU in two CRC cell lines, HCT116 and LoVo. This study suggests that the effect of NaB in improving therapeutic sensitivity to 5-FU in CRC cells may result from a mechanism that strongly inhibits the expression of TYMS. This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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13 pages, 2669 KiB

Open AccessArticle

Downregulation of γ-Catenin by miR-195-5p Inhibits Colon Cancer Progression, Regulating Desmosome Function

by Emanuele Piccinno, Viviana Scalavino, Nicoletta Labarile, Giusy Bianco, Maria Teresa Savino, Raffaele Armentano, Gianluigi Giannelli and Grazia Serino

Int. J. Mol. Sci. 2024, 25(1), 494; https://doi.org/10.3390/ijms25010494 - 29 Dec 2023

Viewed by 761

Abstract

Desmosomes are essential structures for ensuring tissue functions, and their deregulation is involved in the development of colorectal cancer (CRC). JUP (γ-catenin) is a desmosome adhesion component that also acts as a signaling hub, suggesting its potential involvement in CRC progression. In this context, we recently demonstrated that miR-195-5p regulated JUP and desmosome cadherins expression. In addition, miR-195-5p gain of function indirectly modulated the expression of key effectors of the Wnt pathway involved in JUP-dependent signaling. Here, our purpose was to demonstrate the aberrant expression of miR-195-5p and JUP in CRC patients and to functionally characterize the role of miR-195-5p in the regulation of desmosome function. First, we showed that miR-195-5p was downregulated in CRC tumors compared to adjacent normal tissue. Then, we demonstrated that JUP expression was significantly increased in CRC tissues compared to adjacent normal tissues. The effects of miR-195-5p on CRC progression were assessed using in vitro transient transfection experiments and in vivo miRNA administration. Increased miR-195-5p in colonic epithelial cells strongly inhibits cell proliferation, viability, and invasion via JUP. In vivo gain of function of miR-195-5p reduced the numbers and sizes of tumors and significantly ameliorated the histopathological changes typical of CRC. In conclusion, our findings indicate a potential pharmacological target based on miR-195-5p replacement as a new therapeutic approach in CRC. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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19 pages, 8396 KiB

Open AccessArticle

A Risk Model for Prognosis and Treatment Response Prediction in Colon Adenocarcinoma Based on Genes Associated with the Characteristics of the Epithelial-Mesenchymal Transition

by Hongyu Huang, Tianyou Li, Ziqi Meng, Xueqian Zhang, Shanshan Jiang, Mengying Suo and Na Li

Int. J. Mol. Sci. 2023, 24(17), 13206; https://doi.org/10.3390/ijms241713206 - 25 Aug 2023

Cited by 2 | Viewed by 1327

Abstract

The epithelial-mesenchymal transition (EMT) is an important process during metastasis in various tumors, including colorectal cancer (CRC). Thus, the study of its characteristics and related genes is of great significance for CRC treatment. In this study, 26 EMT-related gene sets were used to score each sample from The Cancer Genome Atlas program (TCGA) colon adenocarcinoma (COAD) database. Based on the 26 EMT enrichment scores for each sample, we performed unsupervised cluster analysis and classified the TCGA-COAD samples into three EMT clusters. Then, weighted gene co-expression network analysis (WGCNA) was used to investigate the gene modules that were significantly associated with these three EMT clusters. Two gene modules that were strongly positively correlated with the EMT cluster 2 (worst prognosis) were subjected to Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Then, a prognosis-related risk model composed of three hub genes GPRC5B, LSAMP, and PDGFRA was established. The TCGA rectal adenocarcinoma (READ) dataset and a CRC dataset from the Gene Expression Omnibus (GEO) were used as the validation sets. A novel nomogram that incorporated the risk model and clinicopathological features was developed to predict the clinical outcomes of the COAD patients. The risk model served as an independent prognostic factor. It showed good predictive power for overall survival (OS), immunotherapy efficacy, and drug sensitivity in the COAD patients. Our study provides a comprehensive evaluation of the clinical relevance of this three-gene risk model for COAD patients and a deeper understanding of the role of EMT-related genes in COAD. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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24 pages, 4956 KiB

Open AccessArticle

Iodine-Biofortified Lettuce Can Promote Mitochondrial Dependent Pathway of Apoptosis in Human Gastrointestinal Cancer Cells

by Olga Sularz, Aneta Koronowicz, Sylwester Smoleń, Cayla Boycott and Barbara Stefanska

Int. J. Mol. Sci. 2023, 24(12), 9869; https://doi.org/10.3390/ijms24129869 - 7 Jun 2023

Cited by 2 | Viewed by 1425

Abstract

Previously, our research provided evidence that exposure of gastric and colon cancer cells to extracts from iodine-biofortified lettuce leads to a reduction of cell viability and proliferation through cell cycle arrest and upregulation of pro-apoptotic genes. The aim of the present study was to determine the potential cellular mechanisms of induction of cell death in human gastrointestinal cancer cell lines after treatment with iodine-biofortified lettuce. We demonstrated that extracts from lettuce enriched with iodine induce apoptosis in gastric AGS and colon HT-29 cancer cells and the mechanism of programmed cell death may be triggered and executed through different signaling pathways, depending on the type of cells. Western blot analysis revealed that iodine-fortified lettuce leads to cell death through the release of cytochrome c to the cytosolic fraction and activation of the primary drivers of apoptosis: caspase-3, caspase-7, and caspase-9. Furthermore, we have reported that apoptotic effects of lettuce extracts may be mediated by poly (ADP-ribose) polymerase (PARP) and activation of pro-apoptotic Bcl-2 family proteins such as Bad, Bax, and BID. We also observed mitochondrial dysfunction with the dissipation of the mitochondrial membrane potential in cells exposed to lettuce extracts. Taken together, these results indicate that the organic form of iodine such as 5-ISA and 3,5-diISA is an important factor in the activation of intrinsic mitochondrial apoptotic pathway in AGS and HT-29 cancer cells in a p53-independent manner. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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12 pages, 4041 KiB

Open AccessArticle

Targeting the Sequences of Circulating Tumor DNA of Cholangiocarcinomas and Its Applications and Limitations in Clinical Practice

by Kyung-Hee Kim, Hyon-Seung Yi, Hyunjung Lee, Go-Eun Bae and Min-Kyung Yeo

Int. J. Mol. Sci. 2023, 24(8), 7512; https://doi.org/10.3390/ijms24087512 - 19 Apr 2023

Viewed by 1686

Abstract

Cholangiocarcinoma is a malignant epithelial tumor arising from bile ducts that is frequently fatal. Diagnosis is difficult due to tumor location in the biliary tract. Earlier diagnosis requires less invasive methods of identifying effective biomarkers for cholangiocarcinoma. The present study investigated the genomic profiles of cell-free DNA (cfDNA) and DNA from corresponding primary cholangiocarcinomas using a targeted sequencing panel. Somatic mutations in primary tumor DNA and circulating tumor DNA (ctDNA) were compared and clinical applications of ctDNA validated in patients with cholangiocarcinoma. A comparison of primary tumor DNA and ctDNA identified somatic mutations in patients with early cholangiocarcinomas that showed clinical feasibility for early screening. The predictive value of single-nucleotide variants (SNVs) of preoperative plasma cfDNA positive for somatic mutations of the primary tumor was 42%. The sensitivity and specificity of postoperative plasma SNVs in detecting clinical recurrence were 44% and 45%, respectively. Targetable fibroblast growth factor receptor 2 (FGFR2) and Kirsten rat sarcoma virus (KRAS) mutations were detected in 5% of ctDNA samples from patients with cholangiocarcinoma. These findings showed that genomic profiling of cfDNA was useful in clinical evaluation, although ctDNA had limited ability to detect mutations in cholangiocarcinoma patients. Serial monitoring of ctDNA is important clinically and in assessing real-time molecular aberrations in cholangiocarcinoma patients. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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Review

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15 pages, 426 KiB

Open AccessReview

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review

by Matthew J. Hadfield, Kathryn DeCarli, Kinan Bash, Grace Sun and Khaldoun Almhanna

Int. J. Mol. Sci. 2024, 25(1), 543; https://doi.org/10.3390/ijms25010543 - 30 Dec 2023

Cited by 1 | Viewed by 1288

Abstract

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody–drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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14 pages, 1475 KiB

Open AccessReview

Inflammation and Digestive Cancer

by Helge Waldum and Reidar Fossmark

Int. J. Mol. Sci. 2023, 24(17), 13503; https://doi.org/10.3390/ijms241713503 - 31 Aug 2023

Cited by 4 | Viewed by 1721

Abstract

Chronic inflammation is linked to carcinogenesis, particularly in the digestive organs, i.e., the stomach, colon, and liver. The mechanism of this effect has, however, only partly been focused on. In this review, we focus on different forms of chronic hepatitis, chronic inflammatory bowel disease, and chronic gastritis, conditions predisposing individuals to the development of malignancy. Chronic inflammation may cause malignancy because (1) the cause of the chronic inflammation is itself genotoxic, (2) substances released from the inflammatory cells may be genotoxic, (3) the cell death induced by the inflammation induces a compensatory increase in proliferation with an inherent risk of mutation, (4) changes in cell composition due to inflammation may modify function, resulting in hormonal disturbances affecting cellular proliferation. The present review focuses on chronic gastritis (Helicobacter pylori or autoimmune type) since all four mechanisms may be relevant to this condition. Genotoxicity due to the hepatitis B virus is an important factor in hepatocellular cancer and viral infection can similarly be central in the etiology and malignancy of inflammatory bowel diseases. Helicobacter pylori (H. pylori) is the dominating cause of chronic gastritis and has not been shown to be genotoxic, so its carcinogenic effect is most probably due to the induction of atrophic oxyntic gastritis leading to hypergastrinemia. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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16 pages, 2297 KiB

Open AccessReview

Total Neoadjuvant Treatment for Locally Advanced Rectal Cancer Patients: Where Do We Stand?

by Valentina Daprà, Marco Airoldi, Michela Bartolini, Roberta Fazio, Giuseppe Mondello, Maria Chiara Tronconi, Maria Giuseppina Prete, Giuseppe D’Agostino, Caterina Foppa, Antonino Spinelli, Alberto Puccini and Armando Santoro

Int. J. Mol. Sci. 2023, 24(15), 12159; https://doi.org/10.3390/ijms241512159 - 29 Jul 2023

Cited by 3 | Viewed by 4636

Abstract

The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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12 pages, 819 KiB

Open AccessReview

Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer

by Daniele Lavacchi, Giandomenico Roviello, Alessia Guidolin, Silvia Romano, Jacopo Venturini, Enrico Caliman, Agnese Vannini, Elisa Giommoni, Elisa Pellegrini, Marco Brugia, Serena Pillozzi and Lorenzo Antonuzzo

Int. J. Mol. Sci. 2023, 24(6), 5840; https://doi.org/10.3390/ijms24065840 - 19 Mar 2023

Cited by 4 | Viewed by 2975

Abstract

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China’s National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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18 pages, 520 KiB

Open AccessReview

Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing

by Daniele Lavacchi, Sara Fancelli, Eleonora Buttitta, Gianmarco Vannini, Alessia Guidolin, Costanza Winchler, Enrico Caliman, Agnese Vannini, Elisa Giommoni, Marco Brugia, Fabio Cianchi, Serena Pillozzi, Giandomenico Roviello and Lorenzo Antonuzzo

Int. J. Mol. Sci. 2023, 24(5), 4877; https://doi.org/10.3390/ijms24054877 - 2 Mar 2023

Cited by 7 | Viewed by 2694

Abstract

Resectable gastric or gastroesophageal (G/GEJ) cancer is a heterogeneous disease with no defined molecularly based treatment strategy. Unfortunately, nearly half of patients experience disease recurrence despite standard treatments (neoadjuvant and/or adjuvant chemotherapy/chemoradiotherapy and surgery). In this review, we summarize the evidence of potential tailored approaches in perioperative treatment of G/GEJ cancer, with a special focus on patients with human epidermal growth factor receptor-2(HER2)-positive and microsatellite instability-high (MSI-H) tumors. In patients with resectable MSI-H G/GEJ adenocarcinoma, the ongoing INFINITY trial introduces the concept of non-operative management for patients with complete clinical-pathological-molecular response, and this could be a novel and potential practice changing strategy. Other pathways involving vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), claudin18 isoform 2 (CLDN18.2), and DNA damage repair proteins are also described, with limited evidence until now. Although tailored therapy appears to be a promising strategy for resectable G/GEJ cancer, there are several methodological issues to address: inadequate sample size for pivotal trials, underestimation of subgroup effects, and choice of primary endpoint (tumor-centered vs. patient-centered endpoints). A better optimization of G/GEJ cancer treatment allows maximizing patient outcomes. In the perioperative phase, although caution is mandatory, times are changing and tailored strategies could introduce new treatment concepts. Overall, MSI-H G/GEJ cancer patients possess the characteristics to be the subgroup that could receive the most benefit from a tailored approach. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer)

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