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Special Issue "Gastric Cancers: Molecular Pathways and Candidate Biomarkers"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 August 2019).

Special Issue Editor

Special Issue Information

Dear colleagues,

This Special Issue is the continuation of our previous special issue "Molecular Features Distinguishing Gastric Cancer Subtypes".

Although there has been progress in gastric cancer and a worldwide decline in pathology, gastric cancer remains a disease characterized by an uncontrolled growth and a high mortality mostly due to a delay in diagnosis. The epidemiology of gastric cancer changed in the last 25 years, with a decline of the intestinal type and stomach antral localization but an increase in young people and the diffuse type. The introduction of high-throughput technologies in recent decades 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

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Published Papers (9 papers)

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Research

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Article
Correlations between Genetic Polymorphisms in Long Non-Coding RNA PRNCR1 and Gastric Cancer Risk in a Korean Population
Int. J. Mol. Sci. 2019, 20(13), 3355; https://doi.org/10.3390/ijms20133355 - 08 Jul 2019
Cited by 8 | Viewed by 1006
Abstract
We evaluated the association between prostate cancer non-coding RNA 1 (PRNCR1) polymorphisms and the risk of developing gastric cancer (GC) and GC subgroups in Korea. A case–control study was conducted with 437 GC patients and 357 healthy controls using a TaqMan [...] Read more.
We evaluated the association between prostate cancer non-coding RNA 1 (PRNCR1) polymorphisms and the risk of developing gastric cancer (GC) and GC subgroups in Korea. A case–control study was conducted with 437 GC patients and 357 healthy controls using a TaqMan genotyping assay. A chi-squared test, binary logistic regression, and genetic models were used to explore the association between five PRNCR1 polymorphisms and GC risk. After adjusting for gender and age, overall analyses using the recessive model indicated that the rs13252298 GG genotype was significantly associated with increased risk of intestinal-type gastric cancer (IGC). In the stratification analyses, the recessive model indicated that the rs1016343 TT genotype was significantly associated with decreased GC risk in individuals aged <60 years showing lymph node metastasis (LNM)-negative results. The rs13252298 GG genotype in the recessive model showed increased GC risk in subjects aged ≥60 years showing LNM-positive results and those aged ≥60 years in tumor stage III. In the dominant model, the rs16901946 combined genotype (AG/GG) was significantly associated with increased GC risk in subjects aged <60 years with tumor stage III. In the recessive model, the rs16901946 GG genotype was associated with decreased risk of GC and IGC in males aged ≥60 years. Thus, genetic variations in PRNCR1 may contribute to susceptibility to GC. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
Article
Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis
Int. J. Mol. Sci. 2018, 19(12), 3983; https://doi.org/10.3390/ijms19123983 - 11 Dec 2018
Cited by 15 | Viewed by 1413
Abstract
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new [...] Read more.
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new therapies is a highly necessary clinical need. Angiogenesis is a promising target for this tumor type, however clinical trials with the use of anti-angiogenic drugs have so far not met expectations. Therefore, it is important to better characterize the expression of molecules whose expression levels may impact on the efficacy of the treatments. In this study the characteristics of the gastric tumor associated blood vessels were first assessed by endomicroscopy. Next, we analyzed the expression of Multimerin-2, EMILIN-2 and EMILIN-1, three molecules of the EMI Domain ENdowed (EDEN) protein family. These molecules play important functions in the tumor microenvironment, affecting cancer progression both directly and indirectly impinging on angiogenesis and lymphangiogenesis. All the molecules were highly expressed in the normal mucosa whereas in a number of patients their expression was altered. We consider that better characterizing the gastric tumor microenvironment and the quality of the vasculature may achieve effective patient tailored therapies. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Article
IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling
Int. J. Mol. Sci. 2018, 19(11), 3616; https://doi.org/10.3390/ijms19113616 - 16 Nov 2018
Cited by 7 | Viewed by 1493
Abstract
The assembly and maintenance of cilia depend on intraflagellar transport (IFT) proteins, which play an important role in development and homeostasis. IFT80 is a newly defined IFT protein and partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy [...] Read more.
The assembly and maintenance of cilia depend on intraflagellar transport (IFT) proteins, which play an important role in development and homeostasis. IFT80 is a newly defined IFT protein and partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III, both characterized by abnormal skeletal development. However, the role and mechanism of IFT80 in the invasion of gastric cancer is unknown. We established SGC-7901 and MKN-45 gastric cancer cell lines that stably overexpressed IFT80, as verified by quantitative reverse transcription-PCR, Western blot, and immunofluorescence. Matrix metalloproteinase-9 (MMP9) plays an important role in tumor invasion, and its expression was assessed by quantitative reverse transcription-PCR, Western blotting, and immunofluorescence. The invasion ability of IFT80 on SGC-7901 and MKN-45 cells was examined by the Matrigel invasion assay. The relationship between p75NGFR, and the p75NGFR antagonists, PD90780 and IFT80, were detected by quantitative reverse transcription-PCR and Western blotting. We first detected an IFT80 expression pattern, and found that IFT80 was highly expressed in gastric cancer clinical samples. Overexpression of IFT80 in the gastric cancer cell lines, SGC-7901 and MKN-45, led to lengthening cilia. Additionally, overexpression of IFT80 significantly improved proliferation and invasion, but inhibited apoptosis, in gastric cancer cells. We further found that overexpression of IFT80 increased p75NGFR and MMP9 mRNA and protein expression. Treatment with the p75NGFR antagonist PD90780 inhibited the increased invasion ability resulting from overexpression of IFT80 in SGC-7901 and MKN-45 gastric cancer cells. Thus, these results suggest that IFT80 plays an important role in invasion of gastric cancer through regulating the ift80/p75NGFR/MMP9 signal pathways. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Article
Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis
Int. J. Mol. Sci. 2018, 19(11), 3389; https://doi.org/10.3390/ijms19113389 - 29 Oct 2018
Cited by 19 | Viewed by 2541
Abstract
The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription factor-4 (ATF4) pathway-mediated [...] Read more.
The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Article
Distribution Patterns of Cocaine- and Amphetamine-Regulated Transcript- and/or Galanin-Containing Neurons and Nerve Fibers Located in the Human Stomach Wall Affected by Tumor
Int. J. Mol. Sci. 2018, 19(11), 3357; https://doi.org/10.3390/ijms19113357 - 26 Oct 2018
Cited by 3 | Viewed by 1186
Abstract
The aim of the study was to investigate the distribution patterns of cocaine- and amphetamine-regulated transcript- (CART-) and galanin-immunoreactive (GAL-IR) neuronal structures in the human stomach wall, focusing on differences observed in regions directly affected by the cancer process, and those from the [...] Read more.
The aim of the study was to investigate the distribution patterns of cocaine- and amphetamine-regulated transcript- (CART-) and galanin-immunoreactive (GAL-IR) neuronal structures in the human stomach wall, focusing on differences observed in regions directly affected by the cancer process, and those from the surgical margin. Samples from the stomach wall were collected from 10 patients (3 women and 7 men, the mean age 67.0 ± 11.9). Next, triple-immunofluorescence staining was used to visualize the changes in the frequency of neurons inside myenteric plexi and intramural fibers containing CART and/or GAL, as well as protein gene product 9.5 (as panneuronal marker). Tumor into the stomach wall caused a decrease in the number of CART-positive (+) nerve fibers in the longitudinal (LML) and circular muscle layers (CML). Notable changes in the dense network of CART+/GAL+ nerve fibers (an increase) were observed in the LML and lamina muscularis mucosae (LMM) within carcinoma-affected areas of the human stomach. Additionally, an elevated number of these nerve fibers from LMM were accompanied by an increase in the number of fibers containing GAL in the vicinity of the neoplastic proliferation. Obtained results suggest that a carcinoma invasion may affect the innervation pattern of the human stomach wall and their function(s). Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Review

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Review
Mechanotransduction and Cytoskeleton Remodeling Shaping YAP1 in Gastric Tumorigenesis
Int. J. Mol. Sci. 2019, 20(7), 1576; https://doi.org/10.3390/ijms20071576 - 29 Mar 2019
Cited by 9 | Viewed by 1974
Abstract
The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 [...] Read more.
The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 (YAP1) and WW domain that contain transcription regulator 1 (TAZ), two transcriptional co-activators with a PDZ-binding motif, function as critical effectors negatively regulated by the Hippo pathway. Previous studies indicate the involvement of YAP1/TAZ in mechanotransduction by crosstalking with the extracellular matrix (ECM) and the F-actin cytoskeleton associated signaling network. In gastric cancer (GC), YAP1/TAZ functions as an oncogene and transcriptionally promotes tumor formation by cooperating with TEAD transcription factors. Apart from the classic role of Hippo-YAP1 cascade, in this review, we summarize the current investigations to highlight the prominent role of YAP1/TAZ as a mechanical sensor and responder under mechanical stress and address its potential prognostic and therapeutic value in GC. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Review
From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer
Int. J. Mol. Sci. 2019, 20(1), 13; https://doi.org/10.3390/ijms20010013 - 20 Dec 2018
Cited by 40 | Viewed by 3830
Abstract
Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice [...] Read more.
Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Review
Types of Gastric Carcinomas
Int. J. Mol. Sci. 2018, 19(12), 4109; https://doi.org/10.3390/ijms19124109 - 18 Dec 2018
Cited by 23 | Viewed by 3440
Abstract
Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, [...] Read more.
Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for Helicobacter pylori as well as the recently described increased risk of gastric cancer due to proton pump inhibitor treatment. Therefore, it is essential to determine the role of the gastrin target cell, the ECL cell, in gastric carcinogenesis. Clinical trials with gastrin antagonists could improve prognoses in those with gastrin receptor positive tumours. However, further studies on gastric carcinomas applying relative available methods and with the highest sensitivity are warranted to improve our knowledge of gastric carcinogenesis. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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Review
Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review
Int. J. Mol. Sci. 2018, 19(11), 3388; https://doi.org/10.3390/ijms19113388 - 29 Oct 2018
Cited by 26 | Viewed by 2474
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies [...] Read more.
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new targeted therapies. Those CSCs express biomarkers such as cluster of differentiation 44 (CD44) and display high aldehyde dehydrogenase activity that converts vitamin A-derived retinal into retinoic acids. All-trans retinoic acid (ATRA), which has pro-differentiating properties, has revolutionized the prognosis of acute promyelotic leukemia by increasing its remission rate from 15% to 85%. Recent studies have started to show that ATRA also has an anti-tumoral role on solid cancers such as GC. The purpose of this review is therefore to summarize the work that evaluated the effects of ATRA in GC and to evaluate whether its anti-cancerous action involves gastric CSCs targeting. It has been demonstrated that ATRA can block the cell cycle, enhance apoptosis, and decrease gastric CSCs properties in GC cell lines, tumorspheres, and patient-derived xenograft mice models. Therefore, retinoids and new synthetic retinoids seem to be a promising step forward in targeted therapy of gastric CSC in combination with existing chemotherapies. Future studies should probably focus on these points. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers)
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