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Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0

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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 (30 January 2023) | Viewed by 29177

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Dr. Valli De Re

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Immunopathology and Oncological Biomarkers (IBO) Lab, Department of Translational Research and Advanced Diagnostics of Tumors (DRDT), Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
Interests: biology of cancers of the gastrointestinal tract; Hodgkin's lymphoma, with a focus on infectious and autoimmune related factors
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues "Molecular Features Distinguishing Gastric Cancer Subtypes", "Molecular Pathways and Candidate Biomarkers" and "Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0".

Although there has been progress in gastric cancer and a worldwide decline in its pathology, gastric cancer remains a disease characterized by uncontrolled growth and high mortality mostly due to a delay in diagnosis. The epidemiology of gastric cancer has changed in the last 25 years, with a decline in the intestinal type and stomach antral localization but an increase in young people and the diffuse type. In recent decades, the introduction of high-throughput technologies that are able to analyse several gastric cancer from small biological samples has caused significant advances in the development of biomarkers in oncology. Molecular pathways and biomarkers molecules are potentially useful for GC diagnosis because they increase the accuracy of diagnosis (e.g., the nanomolecule used in confocal laser endomicroscopy) and can be used to select patients at risk for GC at an early stage (e.g., ABC pepsinogen test in japan), as well as to propose new GC classification (e.g., TCAG, ACRG). This research has produced important results that enable us to better understand gastric cancer pathogenesis and individualized important targetable molecules to achieve novel drug targets and new treatment strategies in advanced gastric cancer. Target therapies are now ongoing with moderate benefits in some subsets of gastric cancer, but several trials are ongoing to achieve an increase in the survival benefit of patients with gastric cancer. The aim of this Special Issue is to provide new findings regarding molecular pathways and biomarkers that could improve the diagnosis and/or the prognostic classification of gastric cancer, and to resume their potential application in GC detection and classification, or in clinics.

Dr. Valli De Re
Guest Editor

Manuscript Submission Information

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Keywords

gastric cancer
pathogenesis
immune response
Helicobacter pylori
genomics
proteomics
diagnostic marker
prognostic marker

Related Special Issues

Molecular Features Distinguishing Gastric Cancer Subtypes in International Journal of Molecular Sciences (20 articles)
Gastric Cancers: Molecular Pathways and Candidate Biomarkers in International Journal of Molecular Sciences (9 articles)
Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0 in International Journal of Molecular Sciences (10 articles)
Gastric Cancer: Molecular Pathways and Candidate Biomarkers 5.0 in International Journal of Molecular Sciences (1 article)

Published Papers (9 papers)

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Research

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16 pages, 2845 KiB

Open AccessArticle

Could Toll-like Receptor 2 Serve as Biomarker to Detect Advanced Gastric Cancer?

by Marek Majewski, Kamil Torres, Paulina Mertowska, Sebastian Mertowski, Izabela Korona-Głowniak, Jan Korulczyk, Witold Zgodziński and Ewelina Grywalska

Int. J. Mol. Sci. 2023, 24(6), 5824; https://doi.org/10.3390/ijms24065824 - 18 Mar 2023

Cited by 1 | Viewed by 1650

Abstract

Gastric cancer is one of the five most common types of cancer worldwide. Due to the heterogeneous course and the involvement of many risk factors, its treatment and diagnosis is an important challenge for modern medicine. Recent studies have emphasized the i role of Toll-like receptors (TLRs) expressed on selected cells of the immune system in the pathogenesis of gastric cancer. The aim of this study was to determine the prevalence of TLR2 on T lymphocytes, B lymphocytes, monocytes, and dendritic cells in patients diagnosed with gastric cancer, with particular emphasis on the stage of the disease. Based on the obtained results, we have shown that patients with gastric cancer are characterized by a higher percentage of all tested populations of peripheral blood immune cells expressing TLR2 in relation to patients from the control group. Moreover, a detailed analysis of the collected results showed a significant link between TLR2 and the stage of the disease. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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16 pages, 2949 KiB

Open AccessArticle

Short Telomere Lesions with Dysplastic Metaplasia Histology May Represent Precancerous Lesions of Helicobacter pylori-Positive Gastric Mucosa

by Rina Fujiwara-Tani, Tadataka Takagi, Shiori Mori, Shingo Kishi, Yukiko Nishiguchi, Takamitsu Sasaki, Masayuki Ikeda, Kenta Nagai, Ujjal Kumar Bhawal, Hitoshi Ohmori, Kiyomu Fujii and Hiroki Kuniyasu

Int. J. Mol. Sci. 2023, 24(4), 3182; https://doi.org/10.3390/ijms24043182 - 06 Feb 2023

Viewed by 1637

Abstract

Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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12 pages, 1775 KiB

Open AccessArticle

Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population

by Natalia Landeros, Alejandro H. Corvalan, Maher Musleh, Luis A. Quiñones, Nelson M. Varela and Patricio Gonzalez-Hormazabal

Int. J. Mol. Sci. 2022, 23(1), 467; https://doi.org/10.3390/ijms23010467 - 31 Dec 2021

Cited by 1 | Viewed by 1751

Abstract

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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14 pages, 7621 KiB

Open AccessArticle

Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line

by Sara Peri, Alessio Biagioni, Giampaolo Versienti, Elena Andreucci, Fabio Staderini, Giuseppe Barbato, Lisa Giovannelli, Francesco Coratti, Nicola Schiavone, Fabio Cianchi, Laura Papucci and Lucia Magnelli

Int. J. Mol. Sci. 2021, 22(14), 7698; https://doi.org/10.3390/ijms22147698 - 19 Jul 2021

Cited by 10 | Viewed by 2881

Abstract

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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19 pages, 5200 KiB

Open AccessArticle

Cortactin Is Required for Efficient FAK, Src and Abl Tyrosine Kinase Activation and Phosphorylation of Helicobacter pylori CagA

by Jakob Knorr, Irshad Sharafutdinov, Florian Fiedler, Delara Soltan Esmaeili, Manfred Rohde, Klemens Rottner, Steffen Backert and Nicole Tegtmeyer

Int. J. Mol. Sci. 2021, 22(11), 6045; https://doi.org/10.3390/ijms22116045 - 03 Jun 2021

Cited by 7 | Viewed by 3123

Abstract

Cortactin is a well-known regulatory protein of the host actin cytoskeleton and represents an attractive target of microbial pathogens like Helicobacter pylori. H. pylori manipulates cortactin’s phosphorylation status by type-IV secretion-dependent injection of its virulence protein CagA. Multiple host tyrosine kinases, like FAK, Src, and Abl, are activated during infection, but the pathway(s) involved is (are) not yet fully established. Among them, Src and Abl target CagA and stimulate tyrosine phosphorylation of the latter at its EPIYA-motifs. To investigate the role of cortactin in more detail, we generated a CRISPR/Cas9 knockout of cortactin in AGS gastric epithelial cells. Surprisingly, we found that FAK, Src, and Abl kinase activities were dramatically downregulated associated with widely diminished CagA phosphorylation in cortactin knockout cells compared to the parental control. Together, we report here a yet unrecognized cortactin-dependent signaling pathway involving FAK, Src, and Abl activation, and controlling efficient phosphorylation of injected CagA during infection. Thus, the cortactin status could serve as a potential new biomarker of gastric cancer development. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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16 pages, 3469 KiB

Open AccessArticle

Role of Glycated High Mobility Group Box-1 in Gastric Cancer

by Shingo Kishi, Yukiko Nishiguchi, Kanya Honoki, Shiori Mori, Rina Fujiwara-Tani, Takamitsu Sasaki, Kiyomu Fujii, Isao Kawahara, Kei Goto, Chie Nakashima, Akira Kido, Yasuhito Tanaka, Yi Luo and Hiroki Kuniyasu

Int. J. Mol. Sci. 2021, 22(10), 5185; https://doi.org/10.3390/ijms22105185 - 13 May 2021

Cited by 10 | Viewed by 2660

Abstract

Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. N^ε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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Review

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35 pages, 1676 KiB

Open AccessReview

The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer

by Aadil Javed, Mahdieh Yarmohammadi, Kemal Sami Korkmaz and Teresa Rubio-Tomás

Int. J. Mol. Sci. 2023, 24(3), 2848; https://doi.org/10.3390/ijms24032848 - 02 Feb 2023

Cited by 5 | Viewed by 3680

Abstract

Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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17 pages, 1783 KiB

Open AccessReview

Sirtuins (SIRTs) As a Novel Target in Gastric Cancer

by Agata Poniewierska-Baran, Paulina Warias and Katarzyna Zgutka

Int. J. Mol. Sci. 2022, 23(23), 15119; https://doi.org/10.3390/ijms232315119 - 01 Dec 2022

Cited by 7 | Viewed by 2141

Abstract

Gastric cancer is a major health burden worldwide. Among all neoplasms, gastric cancer is the fifth most common and the third most deadly type of cancer. It is known that sirtuins (SIRTs), are NAD⁺-dependent histone deacetylases regulating important metabolic pathways. High expression of SIRTs in the human body can regulate metabolic processes; they prevent inflammation but also resist cell death and aging processes. The seven members of this family enzymes can also play a fundamental role in process of carcinogenesis by influencing cell viability, apoptosis and metastasis. This review collects and discusses the role of all seven sirtuins (SIRT1–SIRT7) in the pathogenesis of gastric cancer (GC). Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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25 pages, 2168 KiB

Open AccessReview

Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies

by Lornella Seeneevassen, Emilie Bessède, Francis Mégraud, Philippe Lehours, Pierre Dubus and Christine Varon

Int. J. Mol. Sci. 2021, 22(7), 3418; https://doi.org/10.3390/ijms22073418 - 26 Mar 2021

Cited by 69 | Viewed by 8506

Abstract

Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis. Full article

(This article belongs to the Special Issue Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0)

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