International Journal of Molecular Sciences

Editorial

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6 pages, 166 KiB

Open AccessEditorial

Molecular Features Distinguish Gastric Cancer Subtypes

by Valli De Re

Int. J. Mol. Sci. 2018, 19(10), 3121; https://doi.org/10.3390/ijms19103121 - 11 Oct 2018

Cited by 21 | Viewed by 4705

Abstract

Gastric cancer (GC) is a leading cause of cancer deaths [...] Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

Research

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23 pages, 3508 KiB

Open AccessArticle

The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors

by Irene Gullo, Joana Carvalho, Diana Martins, Diana Lemos, Ana Rita Monteiro, Marta Ferreira, Kakoli Das, Patrick Tan, Carla Oliveira, Fátima Carneiro and Patrícia Oliveira

Int. J. Mol. Sci. 2018, 19(7), 2079; https://doi.org/10.3390/ijms19072079 - 17 Jul 2018

Cited by 29 | Viewed by 6084

Abstract

Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and [...] Read more.

Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1^high/PD-L1^low, PD-1^high/PDL1^high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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12 pages, 2263 KiB

Open AccessArticle

Molecular and Pathological Features of Gastric Cancer in Lynch Syndrome and Familial Adenomatous Polyposis

by Mara Fornasarig, Raffaella Magris, Valli De Re, Ettore Bidoli, Vincenzo Canzonieri, Stefania Maiero, Alessandra Viel and Renato Cannizzaro

Int. J. Mol. Sci. 2018, 19(6), 1682; https://doi.org/10.3390/ijms19061682 - 6 Jun 2018

Cited by 26 | Viewed by 7243

Abstract

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are autosomal dominant hereditary diseases caused by germline mutations leading to the development of colorectal cancer. Moreover, these mutations result in the development of a spectrum of different tumors, including gastric cancers (GCs). Since the [...] Read more.

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are autosomal dominant hereditary diseases caused by germline mutations leading to the development of colorectal cancer. Moreover, these mutations result in the development of a spectrum of different tumors, including gastric cancers (GCs). Since the clinical characteristics of GCs associated with LS and FAP are not well known, we investigated clinical and molecular features of GCs occurring in patients with LS and FAP attending our Institution. The Hereditary Tumor Registry was established in 1994 at the Department of Oncologic Gastroenterology, CRO Aviano National Cancer Institute, Italy. It includes 139 patients with LS and 86 patients with FAP. Patients were recruited locally for prospective surveillance. Out of 139 LS patients, 4 developed GC—3 in the presence of helicobacter pylori infection and 1 on the background of autoimmune diseases. All GCs displayed a high microsatellite instability (MSI-H) and loss of related mismatch repair (MMR) protein. One of the FAP patients developed a flat adenoma, displaying low-grade dysplasia at the gastric body, and another poorly differentiated adenocarcinoma with signet ring cells like Krukenberg without HP infection. LS carriers displayed a risk of GC. The recognition of HP infection and autoimmune diseases would indicate those at higher risk for an endoscopic surveillance. Regarding FAP, the data suggested the need of suitable endoscopic surveillance in long survivals with diffuse fundic gland polyps. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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10 pages, 11655 KiB

Open AccessArticle

Molecular Characterization of Gastric Epithelial Cells Using Flow Cytometry

by Kevin A. Bockerstett, Chun Fung Wong, Sherri Koehm, Eric L. Ford and Richard J. DiPaolo

Int. J. Mol. Sci. 2018, 19(4), 1096; https://doi.org/10.3390/ijms19041096 - 6 Apr 2018

Cited by 7 | Viewed by 6020

Abstract

The ability to analyze individual epithelial cells in the gastric mucosa would provide important insight into gastric disease, including chronic gastritis and progression to gastric cancer. However, the successful isolation of viable gastric epithelial cells (parietal cells, neck cells, chief cells, and foveolar [...] Read more.

The ability to analyze individual epithelial cells in the gastric mucosa would provide important insight into gastric disease, including chronic gastritis and progression to gastric cancer. However, the successful isolation of viable gastric epithelial cells (parietal cells, neck cells, chief cells, and foveolar cells) from gastric glands has been limited due to difficulties in tissue processing. Furthermore, analysis and interpretation of gastric epithelial cell flow cytometry data has been difficult due to the varying sizes and light scatter properties of the different epithelial cells, high levels of autofluorescence, and poor cell viability. These studies were designed to develop a reliable method for isolating viable single cells from the corpus of stomachs and to optimize analyses examining epithelial cells from healthy and diseased stomach tissue by flow cytometry. We performed a two stage enzymatic digestion in which collagenase released individual gastric glands from the stromal tissue of the corpus, followed by a Dispase II digestion that dispersed these glands into greater than 1 × 10⁶ viable single cells per gastric corpus. Single cell suspensions were comprised of all major cell lineages found in the normal gastric glands. A method describing light scatter, size exclusion, doublet discrimination, viability staining, and fluorescently-conjugated antibodies and lectins was used to analyze individual epithelial cells and immune cells. This technique was capable of identifying parietal cells and revealed that gastric epithelial cells in the chronically inflamed mucosa significantly upregulated major histocompatibility complexes (MHC) I and II but not CD80 or CD86, which are costimulatory molecules involved in T cell activation. These studies describe a method for isolating viable single cells and a detailed description of flow cytometric analysis of cells from healthy and diseased stomachs. These studies begin to identify effects of chronic inflammation on individual gastric epithelial cells, a critical consideration for the study of gastric cancer. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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21 pages, 6573 KiB

Open AccessArticle

Quantitative Proteomic Approach Targeted to Fibrinogen β Chain in Tissue Gastric Carcinoma

by Ombretta Repetto, Stefania Maiero, Raffaella Magris, Gianmaria Miolo, Maria Rita Cozzi, Agostino Steffan, Vincenzo Canzonieri, Renato Cannizzaro and Valli De Re

Int. J. Mol. Sci. 2018, 19(3), 759; https://doi.org/10.3390/ijms19030759 - 7 Mar 2018

Cited by 15 | Viewed by 4271

Abstract

Elevated plasma fibrinogen levels and tumor progression in patients with gastric cancer (GC) have been largely reported. However, distinct fibrinogen chains and domains have different effects on coagulation, inflammation, and angiogenesis. The aim of this study was to characterize fibrinogen β chain (FGB) [...] Read more.

Elevated plasma fibrinogen levels and tumor progression in patients with gastric cancer (GC) have been largely reported. However, distinct fibrinogen chains and domains have different effects on coagulation, inflammation, and angiogenesis. The aim of this study was to characterize fibrinogen β chain (FGB) in GC tissues. Retrospectively we analyzed the data of matched pairs of normal (N) and malignant tissues (T) of 28 consecutive patients with GC at diagnosis by combining one- and two-dimensional electrophoresis (1DE and 2DE) with immunoblotting and mass spectrometry together with two-dimensional difference in gel electrophoresis (2D-DIGE). 1DE showed bands of the intact FGB at 50 kDa and the cleaved forms containing the fragment D at ~37–40 kDa, which corresponded to 19 spots in 2DE. In particular, spot 402 at ~50 kDa and spots 526 and 548 at ~37 kDa were of interest by showing an increased expression in tumor tissues. A higher content of spot 402 was associated with stomach antrum, while spots 526 and 548 amounts correlated with corpus and high platelet count (>208 × 10⁹/L). The quantification of FGB and cleaved products may help to further characterize the interconnections between GC and platelet/coagulation pathways. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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13 pages, 3518 KiB

Open AccessArticle

Use of Metabolomics as a Complementary Omic Approach to Implement Risk Criteria for First-Degree Relatives of Gastric Cancer Patients

by Giuseppe Corona, Renato Cannizzaro, Gianmaria Miolo, Laura Caggiari, Mariangela De Zorzi, Ombretta Repetto, Agostino Steffan and Valli De Re

Int. J. Mol. Sci. 2018, 19(3), 750; https://doi.org/10.3390/ijms19030750 - 7 Mar 2018

Cited by 30 | Viewed by 4697

Abstract

A positive family history is a strong and consistently reported risk factor for gastric cancer (GC). So far, it has been demonstrated that serum pepsinogens (PGs), and gastrin 17 (G17) are useful for screening individuals at elevated risk to develop atrophic gastritis but [...] Read more.

A positive family history is a strong and consistently reported risk factor for gastric cancer (GC). So far, it has been demonstrated that serum pepsinogens (PGs), and gastrin 17 (G17) are useful for screening individuals at elevated risk to develop atrophic gastritis but they are suboptimal biomarkers to screen individuals for GC. The main purpose of this study was to investigate serum metabolomic profiles to find additional biomarkers that could be integrated with serum PGs and G17 to improve the diagnosis of GC and the selection of first-degree relatives (FDR) at higher risk of GC development. Serum metabolomic profiles included 188 serum metabolites, covering amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexoses. Serum metabolomic profiles were performed with tandem mass spectrometry using the Biocrates AbsoluteIDQ p180 kit. The initial cohort (training set) consisted of n = 49 GC patients and n = 37 FDR. Differential metabolomic signatures among the two groups were investigated by univariate and multivariate partial least square differential analysis. The most significant metabolites were further selected and validated in an independent group of n = 22 GC patients and n = 17 FDR (validation set). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic power and the optimal cut-off for each of the discriminant markers. Multivariate analysis was applied to associate the selected serum metabolites, PGs, G17 and risk factors such as age, gender and Helicobacter pylori (H. pylori) infection with the GC and FDR has been performed and an integrative risk prediction algorithm was developed. In the training set, 40 metabolites mainly belonging to phospholipids and acylcarnitines classes were differentially expressed between GC and FDR. Out of these 40 metabolites, 9 were further confirmed in the validation set. Compared with FDR, GC patients were characterized by lower levels of hydroxylated sphingomyelins (SM(OH)22:1, SM(OH)22:2, SM(OH)24:1) and phosphatidylcholines (PC ae 40:1, PC ae 42:2, PC ae 42:3) and by higher levels of acylcarnitines derivatives (C2, C16, C18:1). The specificity and sensitivity of the integrative risk prediction analysis of metabolites for GC was 73.47% and 83.78% respectively with an area under the curve of the ROC curve of 0.811 that improves to 0.90 when metabolites were integrated with the serum PGs. The predictive risk algorithm composed of the C16, SM(OH)22:1 and PG-II serum levels according to the age of individuals, could be used to stratify FDR at high risk of GC development, and then this can be addressed with diagnostic gastroscopy. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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1226 KiB

Open AccessArticle

Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype

by Laura Caggiari, Gianmaria Miolo, Angela Buonadonna, Debora Basile, Davide A. Santeufemia, Antonio Cossu, Giuseppe Palmieri, Mariangela De Zorzi, Mara Fornasarig, Lara Alessandrini, Vincenzo Canzonieri, Giovanni Lo Re, Fabio Puglisi, Agostino Steffan, Renato Cannizzaro and Valli De Re

Int. J. Mol. Sci. 2018, 19(1), 47; https://doi.org/10.3390/ijms19010047 - 23 Dec 2017

Cited by 15 | Viewed by 4963

Abstract

The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target [...] Read more.

The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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Review

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13 pages, 668 KiB

Open AccessReview

Molecular Mechanisms of H. pylori-Induced DNA Double-Strand Breaks

by Dawit Kidane

Int. J. Mol. Sci. 2018, 19(10), 2891; https://doi.org/10.3390/ijms19102891 - 23 Sep 2018

Cited by 25 | Viewed by 5472

Abstract

Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis has not been fully elucidated. H. pylori-associated chronic inflammation is linked to [...] Read more.

Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori-induced double strand breaks (DSBs). Furthermore, we provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to DSBs. We review recent studies on how H. pylori infection triggers NF-κB/inducible NO synthase (iNOS) versus NF-κB/nucleotide excision repair (NER) axis-mediated DSBs to drive genomic instability. This review discusses current research findings that are related to mechanisms of DSBs and repair during H. pylori infection. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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21 pages, 287 KiB

Open AccessReview

What’s New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives

by Giuseppe Tirino, Luca Pompella, Angelica Petrillo, Maria Maddalena Laterza, Annalisa Pappalardo, Marianna Caterino, Michele Orditura, Fortunato Ciardiello, Gennaro Galizia and Ferdinando De Vita

Int. J. Mol. Sci. 2018, 19(9), 2659; https://doi.org/10.3390/ijms19092659 - 7 Sep 2018

Cited by 44 | Viewed by 5352

Abstract

Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved [...] Read more.

Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called “precision medicine” even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

19 pages, 1801 KiB

Open AccessReview

Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity

by Shamshul Ansari, Boldbaatar Gantuya, Vo Phuoc Tuan and Yoshio Yamaoka

Int. J. Mol. Sci. 2018, 19(8), 2424; https://doi.org/10.3390/ijms19082424 - 16 Aug 2018

Cited by 66 | Viewed by 8701

Abstract

Gastric cancer is the third leading cause of cancer-related deaths and ranks as the fifth most common cancer worldwide. Incidence and mortality differ depending on the geographical region and gastric cancer ranks first in East Asian countries. Although genetic factors, gastric environment, and [...] Read more.

Gastric cancer is the third leading cause of cancer-related deaths and ranks as the fifth most common cancer worldwide. Incidence and mortality differ depending on the geographical region and gastric cancer ranks first in East Asian countries. Although genetic factors, gastric environment, and Helicobacter pylori infection have been associated with the pathogenicity and development of intestinal-type gastric cancer that follows the Correa’s cascade, the pathogenicity of diffuse-type gastric cancer remains mostly unknown and undefined. However, genetic abnormalities in the cell adherence factors, such as E-cadherin and cellular activities that cause impaired cell integrity and physiology, have been documented as contributing factors. In recent years, H. pylori infection has been also associated with the development of diffuse-type gastric cancer. Therefore, in this report, we discuss the host factors as well as the bacterial factors that have been reported as associated factors contributing to the development of diffuse-type gastric cancer. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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15 pages, 2688 KiB

Open AccessReview

The Reprimo Gene Family: A Novel Gene Lineage in Gastric Cancer with Tumor Suppressive Properties

by Julio D. Amigo, Juan C. Opazo, Roddy Jorquera, Ignacio A. Wichmann, Benjamin A. Garcia-Bloj, Maria Alejandra Alarcon, Gareth I. Owen and Alejandro H. Corvalán

Int. J. Mol. Sci. 2018, 19(7), 1862; https://doi.org/10.3390/ijms19071862 - 25 Jun 2018

Cited by 14 | Viewed by 4953

Abstract

The reprimo (RPRM) gene family is a group of single exon genes present exclusively within the vertebrate lineage. Two out of three members of this family are present in humans: RPRM and RPRM-Like (RPRML). RPRM induces cell cycle arrest [...] Read more.

The reprimo (RPRM) gene family is a group of single exon genes present exclusively within the vertebrate lineage. Two out of three members of this family are present in humans: RPRM and RPRM-Like (RPRML). RPRM induces cell cycle arrest at G2/M in response to p53 expression. Loss-of-expression of RPRM is related to increased cell proliferation and growth in gastric cancer. This evidence suggests that RPRM has tumor suppressive properties. However, the molecular mechanisms and signaling partners by which RPRM exerts its functions remain unknown. Moreover, scarce studies have attempted to characterize RPRML, and its functionality is unclear. Herein, we highlight the role of the RPRM gene family in gastric carcinogenesis, as well as its potential applications in clinical settings. In addition, we summarize the current knowledge on the phylogeny and expression patterns of this family of genes in embryonic zebrafish and adult humans. Strikingly, in both species, RPRM is expressed primarily in the digestive tract, blood vessels and central nervous system, supporting the use of zebrafish for further functional characterization of RPRM. Finally, drawing on embryonic and adult expression patterns, we address the potential relevance of RPRM and RPRML in cancer. Active investigation or analytical research in the coming years should contribute to novel translational applications of this poorly understood gene family as potential biomarkers and development of novel cancer therapies. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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20 pages, 899 KiB

Open AccessReview

Proposed Molecular and miRNA Classification of Gastric Cancer

by Lara Alessandrini, Melissa Manchi, Valli De Re, Riccardo Dolcetti and Vincenzo Canzonieri

Int. J. Mol. Sci. 2018, 19(6), 1683; https://doi.org/10.3390/ijms19061683 - 6 Jun 2018

Cited by 71 | Viewed by 10665

Abstract

Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with [...] Read more.

Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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19 pages, 479 KiB

Open AccessReview

The Pattern of Signatures in Gastric Cancer Prognosis

by Julita Machlowska, Ryszard Maciejewski and Robert Sitarz

Int. J. Mol. Sci. 2018, 19(6), 1658; https://doi.org/10.3390/ijms19061658 - 4 Jun 2018

Cited by 63 | Viewed by 6583

Abstract

Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which [...] Read more.

Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which finally lead to the occurrence of a malignancy. These genes have diversified roles regarding cancer development. Intracellular pathways are assigned to the expression of different genes, signal transduction, cell-cycle supervision, genomic stability, DNA repair, and cell-fate destination, like apoptosis, senescence. Extracellular pathways embrace tumour invasion, metastasis, angiogenesis. Altered expression patterns, leading the different clinical responses. This review highlights the list of molecular biomarkers that can be used for prognostic purposes and provide information on the likely outcome of the cancer disease in an untreated individual. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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24 pages, 1167 KiB

Open AccessReview

Immunotherapy for Gastric Cancer: Time for a Personalized Approach?

by Riccardo Dolcetti, Valli De Re and Vincenzo Canzonieri

Int. J. Mol. Sci. 2018, 19(6), 1602; https://doi.org/10.3390/ijms19061602 - 29 May 2018

Cited by 50 | Viewed by 10341

Abstract

Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is [...] Read more.

Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is rapidly evolving. Recently, multi-platform molecular analyses of GC have proposed a new classification of this heterogeneous group of tumors, highlighting subset-specific features that may more reliably inform therapeutic choices, including the use of new immunotherapeutic drugs. The clinical benefit and improved survival observed in GC patients treated with immunotherapeutic strategies and their combination with conventional therapies highlighted the importance of the immune environment surrounding the tumor. A thorough investigation of the tumor microenvironment and the complex and dynamic interaction between immune cells and tumor cells is a fundamental requirement for the rational design of novel and more effective immunotherapeutic approaches. This review summarizes the pre-clinical and clinical results obtained so far with immunomodulatory and immunotherapeutic treatments for GC and discusses the novel combination strategies that are being investigated to improve the personalization and efficacy of GC immunotherapy. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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16 pages, 3032 KiB

Open AccessReview

Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer

by Donatella Aldinucci and Naike Casagrande

Int. J. Mol. Sci. 2018, 19(5), 1477; https://doi.org/10.3390/ijms19051477 - 16 May 2018

Cited by 110 | Viewed by 13273

Abstract

Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its [...] Read more.

Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its progression, and its resistance to therapy. The interactions of chemokines, also known as chemotactic cytokines, with their receptors regulate immune and inflammatory responses. However, updated research demonstrates that cancer cells subvert the normal chemokine role, transforming them into fundamental constituents of the tumor microenvironment (TME) with tumor-promoting effects. C-C chemokine ligand 5 (CCL5) is a chemotactic cytokine, and its expression and secretion are regulated in T cells. C-C chemokine receptor type 5 (CCR5) is expressed in T cells, macrophages, other leukocytes, and certain types of cancer cells. The interaction between CCL5 and CCR5 plays an active role in recruiting leukocytes into target sites. This review summarizes recent information on the role of the CCL5 chemokine and its receptor CCR5 in GC cell proliferation, metastasis formation, and in the building of an immunosuppressive TME. Moreover, it highlights the development of new therapeutic strategies to inhibit the CCL5/CCR5 axis in different ways and their possible clinical relevance in the treatment of GC. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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9 pages, 372 KiB

Open AccessReview

Is There a Role for the Non-Helicobacter pylori Bacteria in the Risk of Developing Gastric Cancer?

by Jackie Li and Guillermo I. Perez Perez

Int. J. Mol. Sci. 2018, 19(5), 1353; https://doi.org/10.3390/ijms19051353 - 3 May 2018

Cited by 25 | Viewed by 5920

Abstract

Helicobacter pylori is the most abundant bacterium in the gastric epithelium, and its presence has been associated with the risk of developing gastric cancer. As of 15 years ago, no other bacteria were associated with gastric epithelial colonization; but thanks to new methodologies, [...] Read more.

Helicobacter pylori is the most abundant bacterium in the gastric epithelium, and its presence has been associated with the risk of developing gastric cancer. As of 15 years ago, no other bacteria were associated with gastric epithelial colonization; but thanks to new methodologies, many other non-H. pylori bacteria have been identified. It is possible that non-H. pylori may have a significant role in the development of gastric cancer. Here, we discuss the specific role of H. pylori as a potential trigger for events that may be conducive to gastric cancer, and consider whether or not the rest of the gastric microbiota represent an additional risk in the development of this disease. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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13 pages, 738 KiB

Open AccessReview

Common Variable Immunodeficiency and Gastric Malignancies

by Patrizia Leone, Angelo Vacca, Franco Dammacco and Vito Racanelli

Int. J. Mol. Sci. 2018, 19(2), 451; https://doi.org/10.3390/ijms19020451 - 2 Feb 2018

Cited by 35 | Viewed by 8289

Abstract

Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal manifestations and an increased risk of gastric carcinoma and lymphoma. This review discusses the latest advancements into the immunological, clinical and diagnostic aspects of gastric malignancies in patients with [...] Read more.

Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal manifestations and an increased risk of gastric carcinoma and lymphoma. This review discusses the latest advancements into the immunological, clinical and diagnostic aspects of gastric malignancies in patients with CVID. The exact molecular pathways underlying the relationships between CVID and gastric malignancies remain poorly understood. These include genetics, immune dysregulation and chronic infections by Helicobacter pylori. Further studies are needed to better stratify the risk for cancer in these patients, to elaborate surveillance programs aimed at preventing these complications, and to develop new and more effective therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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14 pages, 634 KiB

Open AccessReview

Autoimmunity and Gastric Cancer

by Nicola Bizzaro, Antonio Antico and Danilo Villalta

Int. J. Mol. Sci. 2018, 19(2), 377; https://doi.org/10.3390/ijms19020377 - 26 Jan 2018

Cited by 69 | Viewed by 11170

Abstract

Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin [...] Read more.

Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastric neoplasms: intestinal type and type I gastric carcinoid. Here, we review the association of autoimmune gastritis with gastric cancer and other autoimmune features present in gastric neoplasms. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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5467 KiB

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Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer

by Soraia Melo, Joana Figueiredo, Maria Sofia Fernandes, Margarida Gonçalves, Eurico Morais-de-Sá, João Miguel Sanches and Raquel Seruca

Int. J. Mol. Sci. 2017, 18(12), 2687; https://doi.org/10.3390/ijms18122687 - 12 Dec 2017

Cited by 40 | Viewed by 7877

Abstract

The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete [...] Read more.

The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete loss of E-cadherin associated with a well-established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E-cadherin function is not predictable. If a deleterious variant is identified, prophylactic surgery could be recommended. Therefore, over the last few years, intensive research has focused on evaluating the functional consequences of CDH1 missense variants and in assessing E-cadherin pathogenicity. In that context, our group has contributed to better characterize CDH1 germline missense variants and is now considered a worldwide reference centre. In this review, we highlight the state of the art methodologies to categorize CDH1 variants, as neutral or deleterious. This information is subsequently integrated with clinical data for genetic counseling and management of CDH1 variant carriers. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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Matrix-Assisted Laser Desorption/Ionisation Mass Spectrometry Imaging in the Study of Gastric Cancer: A Mini Review

by Andrew Smith, Isabella Piga, Manuel Galli, Martina Stella, Vanna Denti, Marina Del Puppo and Fulvio Magni

Int. J. Mol. Sci. 2017, 18(12), 2588; https://doi.org/10.3390/ijms18122588 - 1 Dec 2017

Cited by 29 | Viewed by 10014

Abstract

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide and the disease outcome commonly depends upon the tumour stage at the time of diagnosis. However, this cancer can often be asymptomatic during the early stages and remain undetected until [...] Read more.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide and the disease outcome commonly depends upon the tumour stage at the time of diagnosis. However, this cancer can often be asymptomatic during the early stages and remain undetected until the later stages of tumour development, having a significant impact on patient prognosis. However, our comprehension of the mechanisms underlying the development of gastric malignancies is still lacking. For these reasons, the search for new diagnostic and prognostic markers for gastric cancer is an ongoing pursuit. Modern mass spectrometry imaging (MSI) techniques, in particular matrix-assisted laser desorption/ionisation (MALDI), have emerged as a plausible tool in clinical pathology as a whole. More specifically, MALDI-MSI is being increasingly employed in the study of gastric cancer and has already elucidated some important disease checkpoints that may help us to better understand the molecular mechanisms underpinning this aggressive cancer. Here we report the state of the art of MALDI-MSI approaches, ranging from sample preparation to statistical analysis, and provide a complete review of the key findings that have been reported in the literature thus far. Full article

(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)

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