New Molecular Insights for GC Characterization and Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 22057

Special Issue Editor


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Guest Editor
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G.B. Morgagni, 50-50134 Firenze, Italy
Interests: molecular features of gastric cancer; deregulation of signal transduction in cancer cells; molecular mechanisms of chemoresistance; IRES-mediated transcription modulation
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Special Issue Information

Dear Colleagues,

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. Surgical resection, possibly combined with neoadjuvant chemotherapy, is the elective approach. The high lethality rate is due to late diagnosis and lack of effective treatments. When the tumor is in an advanced stage, or in the presence of cancer relapse or metastases, multi-line chemotherapy strategy according to standard guidelines is the only option. However, the effects on the overall survival are modest, and the most common phenomenon responsible for the treatment failure is innate or acquired resistance to chemotherapy agents. Traditional subdivision based on epidemiological, macroscopical, and histological classifications, is ineffective to understand the complex gastric cancer biology and to determine patient prognosis. Thanks to the advances in the diagnostic tools and to the next-generation sequencing technology, we may currently approach cancers from a molecular point of view, to stratify patients for targeted diagnosis and therapy. Anyway, inter-individual variability of drug response together with tumor heterogeneity are particularly hard to overcome when treating gastric cancer.

Even if alterations in multiple single genes and complex copy number and gene expression profiles have been identified, their significance in gastric carcinogenesis, tumor progression, and patient survival remains to be determined. So far, only CDH1 mutation is indicated as a preventive marker to monitor patients with hereditary GC, and HER2 overexpression as a predictive marker for response to trastuzumab treatment.

Furthermore, differences in development and response to treatments have been observed among ethnically diverse populations. In spite of major incidence, GC Asian patients have a better prognosis and response to treatments than Caucasian ones. Studies on the molecular mechanisms underlying gastric cancer are limited by the lack of in vitro experimental models, such as cell cultures, especially from Caucasian subjects. Most of the studies on GC have been conducted on Asian patients; however, it remains questionable whether they can be fully extrapolated to Caucasian populations, as assessed, i.e., by difference in the somatic mutation rates of several driver genes.

This Special Issue seeks reviews and original papers covering the more recent studies related to gastric cancer biology, molecular biology, models for preclinical studies, identification of molecular markers suitable for diagnosis, and markers to target patients for personalized treatment strategies.

Dr. Lucia Magnelli
Guest Editor

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Keywords

  • gastric cancer
  • chemoresistance
  • preclinical experimental models
  • gene therapy
  • precision medicine

Published Papers (7 papers)

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Research

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20 pages, 7006 KiB  
Article
Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells
by Sarah Bacon, Lornella Seeneevassen, Alison Fratacci, Faustine Rose, Camille Tiffon, Elodie Sifré, Maria M. Haykal, Maya M. Moubarak, Astrid Ducournau, Lucie Bruhl, Stéphane Claverol, Caroline Tokarski, Alina-Roxani Gouloumi, Ioannis S. Pateras, Thomas Daubon, Philippe Lehours, Christine Varon and Océane C. B. Martin
Cancers 2022, 14(17), 4316; https://doi.org/10.3390/cancers14174316 - 02 Sep 2022
Cited by 2 | Viewed by 2172
Abstract
Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of [...] Read more.
Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. Methods: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. Results: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients’ gastric mucosa infected with H. pylori. Conclusions: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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13 pages, 1093 KiB  
Article
Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas
by Marie-Isabelle Glückstein, Sebastian Dintner, Tim Tobias Arndt, Dmytro Vlasenko, Gerhard Schenkirsch, Abbas Agaimy, Gernot Müller, Bruno Märkl and Bianca Grosser
Cancers 2021, 13(15), 3894; https://doi.org/10.3390/cancers13153894 - 02 Aug 2021
Cited by 12 | Viewed by 2396
Abstract
The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance [...] Read more.
The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases. Genes encoding subunits of the SWI/SNF complex are mutated in approximately 20% of all human tumors. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of immunohistochemical expression of proteins of the SWI/SNF complexes, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. Complete loss of SMARCA4 was detected in three cases (0.6%) and was associated with adverse clinical characteristics. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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Review

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22 pages, 553 KiB  
Review
Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View
by Justus Körfer, Florian Lordick and Ulrich T. Hacker
Cancers 2021, 13(20), 5216; https://doi.org/10.3390/cancers13205216 - 18 Oct 2021
Cited by 15 | Viewed by 4188
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition [...] Read more.
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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9 pages, 634 KiB  
Review
Beyond Chemotherapy, PD-1, and HER-2: Novel Targets for Gastric and Esophageal Cancer
by Ali Zubair Siddiqui and Khaldoun Almhanna
Cancers 2021, 13(17), 4322; https://doi.org/10.3390/cancers13174322 - 27 Aug 2021
Cited by 6 | Viewed by 2913
Abstract
Together, gastric cancer and esophageal cancer (EC) possess two of the highest incidence rates amongst all cancers. They exhibit poor prognoses in which the 5-year survival rate is dismal. In addition to cytotoxic chemotherapy, treatment efforts have been geared toward targeting human epidermal [...] Read more.
Together, gastric cancer and esophageal cancer (EC) possess two of the highest incidence rates amongst all cancers. They exhibit poor prognoses in which the 5-year survival rate is dismal. In addition to cytotoxic chemotherapy, treatment efforts have been geared toward targeting human epidermal growth factor receptor 2 (HER-2), vascular endothelial growth factor (VEGF), and programmed death ligand-1 (PD-1). Although ample success has been recorded with these agents, gastric and esophageal cancer remain lethal, and further research into potential treatment alternatives is needed. In this article, we will review some of the targets at the forefront of investigation such as claudin, Dickkopf-related protein 1 (DKK-1), fibroblast growth factor receptor (FGFR), and matrix metalloproteinases (MMPs). These innovative target pathways are in the midst of clinical trials to be implemented in the treatment algorithm for this patient population. Ultimately, exploiting the oncogenic tendencies of these potential biomarkers creates an opportunity for precise treatment and improved prognosis for these cancers. Lastly, research aimed toward reversing PD-1 antibodies resistance by combining it with other novel agents or other treatment modalities is underway in order to expand existing treatment options for this patient population. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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15 pages, 637 KiB  
Review
Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond
by Robin Park, Laercio Lopes Da Silva and Anwaar Saeed
Cancers 2021, 13(7), 1715; https://doi.org/10.3390/cancers13071715 - 05 Apr 2021
Cited by 17 | Viewed by 3554
Abstract
Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in [...] Read more.
Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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Other

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25 pages, 3800 KiB  
Systematic Review
Molecularly Targeted Therapies for Gastric Cancer. State of the Art
by Rossella Reddavid, Simona Dagatti, Caterina Franco, Lucia Puca, Mariano Tomatis, Simona Corso, Silvia Giordano and Maurizio Degiuli
Cancers 2021, 13(16), 4094; https://doi.org/10.3390/cancers13164094 - 14 Aug 2021
Cited by 11 | Viewed by 3420
Abstract
Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs [...] Read more.
Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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9 pages, 4140 KiB  
Commentary
Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?
by Angela Dalia Ricci, Alessandro Rizzo, Fabiola Lorena Rojas Llimpe, Francesca Di Fabio, Dario De Biase and Karim Rihawi
Cancers 2021, 13(7), 1664; https://doi.org/10.3390/cancers13071664 - 01 Apr 2021
Cited by 63 | Viewed by 2619
Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive [...] Read more.
Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive GC patients with advanced disease. However, subsequent studies on HER2 targeted therapies in this setting failed to meet their primary endpoints, and not all HER2-positive GC patients benefit from targeted approaches. More recently, novel HER2-directed treatments have been investigated, including trastuzumab deruxtecan (T-Dxd); following the results of the DESTINY-Gastric01 study, T-Dxd received its first U.S. Food and Drug Administration (FDA) approval on 15 January 2021 for the treatment of adults with unresectable, locally advanced, or metastatic GC who have received a prior trastuzumab-based regimen. In this review, we discuss the current HER2-targeted treatments for GC in the advanced disease setting, mainly focusing on emerging new treatments and future research directions. Full article
(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)
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