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Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench...
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Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics

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

Deadline for manuscript submissions: 1 July 2024 | Viewed by 8701

Special Issue Editors

Prof. Dr. Shumei Song

E-Mail Website
Guest Editor
Coriell Institute for Medical Research, Cherry Hill, NJ, USA
Interests: gastroesophageal cancer; cancer stem cells; immunotherapy; tumor microenvironment; peritoneal metastases
Prof. Dr. Jaffer A. Ajani

E-Mail Website
Guest Editor
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, USA
Interests: gastroesophageal cancer; peritoneal carcinoma of GI origin; clinical trials; multidisciplinary care; multimodality therapy
Dr. Jiankang Jin

E-Mail Website
Guest Editor
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer, Houston, TX, USA
Interests: molecular biology, cancer genetics, CRISPR and gene editing; novel methodologies, tumor suppressors and oncogenes; gene regulation; gastric cancer

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue in MDPI Cancers (5-Year Impact
Factor: 6.886 (2021)) focusing on gastric cancers (GC). This Special Issue welcomes a broad spectrum of research, from very basic molecular biology to translational research, covering novel techniques/methods, novel onco-targets, and novel targets on tumor microenvironments, including tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAFs), as well as immunosuppressive myeloid cells that potentially translate into clinics. This Special Issue aims to cover multiple facets, from multidisciplinary research to clinical applications.

Novel techniques such as CRISPR-based genome-wide screening, de novo targets of genes and splice variants, new ideas and methodologies, and novel targets in TME, including CAFs and macrophages, are welcome. Immunotherapy has offered a great therapeutic potential for GC patients as well as in a broad spectrum of other cancers; however, further research is needed in novel immuno-target therapy. Crosstalk among tumor cells, immune cells, and stroma signaling may promise more positive therapeutic targets. New ideas and methodologies may open a new world for researchers to better understand neoplasm, oncogenesis, and metastasis.

We invite the submission of great works from basic scientists, basic/clinical researchers involved in translational studies, and clinicians.

We welcome original research papers and reviews focusing on gastric cancer. Research areas may include but are not limited to the following:

  • Discovery of new targets of gene, splice variants, RNAs;
  • Cancer/stroma, immune cells crosstalk, tumor microenvironment;
  • Immune biomarker and immunotherapy;
  • New therapeutic modality and clinical trials;
  • RNAseq, WES, exosomes, proteomics, organoids;
  • Epigenomics, spatial transcriptomics.

We look forward to receiving your contributions.

Prof. Dr. Shumei Song
Prof. Dr. Jaffer A. Ajani
Dr. Jiankang Jin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • novel oncogene targets
  • interplays among cancer, stroma, immune cells
  • tumor microenvironment (TME)
  • immune biomarker
  • immunotherapy
  • new therapeutic modality
  • translational research
  • clinical trials

Published Papers (5 papers)

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Research

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21 pages, 25714 KiB  
Article
Long Non-Coding RNA LOC339059 Attenuates IL-6/STAT3-Signaling-Mediated PDL1 Expression and Macrophage M2 Polarization by Interacting with c-Myc in Gastric Cancer
by Haibo Han, Guangyu Ding, Shanshan Wang, Junling Meng, Yunwei Lv, Wei Yang, Hong Zhang, Xianzi Wen and Wei Zhao
Cancers 2023, 15(22), 5313; https://doi.org/10.3390/cancers15225313 - 07 Nov 2023
Cited by 1 | Viewed by 1233
Abstract
Background: Long non-coding RNA (lncRNA) was identified as a novel diagnostic biomarker in gastric cancer (GC). However, the functions of lncRNAs in immuno-microenvironments have not been comprehensively explored. In this study, we explored a critical lncRNA, LOC339059, that can predict the clinical prognosis [...] Read more.
Background: Long non-coding RNA (lncRNA) was identified as a novel diagnostic biomarker in gastric cancer (GC). However, the functions of lncRNAs in immuno-microenvironments have not been comprehensively explored. In this study, we explored a critical lncRNA, LOC339059, that can predict the clinical prognosis in GC related to the modulation of PD-L1 and determined its influence upon macrophage polarization via the IL-6/STAT3 pathway. Methods: To date, accumulating evidence has demonstrated that the dysregulation of LOC339059 plays an important role in the pathological processes of GC. It acts as a tumor suppressor, regulating GC cell proliferation, migration, invasion, tumorigenesis, and metastasis. A flow cytometry assay showed that the loss of LOC339059 enhanced PDL1 expression and M2 macrophage polarization. RNA sequencing, RNA pull-down, RNA immunoprecipitation, Chip-PCR, and a luciferase reporter assay revealed the pivotal role of signaling alternation between LOC339059 and c-Myc. Results: A lower level of LOC339059 RNA was found in primary GC tissues compared to adjacent tissues, and such a lower level is associated with a poorer survival period (2.5 years) after surgery in patient cohorts. Moreover, we determined important immunological molecular biomarkers. We found that LOC339059 expression was correlated with PD-L1, CTLA4, CD206, and CD204, but not with TIM3, FOXP3, CD3, C33, CD64, or CD80, in a total of 146 GC RNA samples. The gain of LOC339059 in SGC7901 and AGS inhibited biological characteristics of malignancy, such as proliferation, migration, invasion, tumorigenesis, and metastasis. Furthermore, our data gathered following the co-culture of THP-1 and U937 with genomic GC cells indicate that LOC339059 led to a reduction in the macrophage cell ratio, in terms of CD68+/CD206+, to 1/6, whereas the selective knockdown of LOC339059 promoted the abovementioned malignant cell phenotypes, suggesting that it has a tumor-suppressing role in GC. RNA-Seq analyses showed that the gain of LOC339059 repressed the expression of the interleukin family, especially IL-6/STAT3 signaling. The rescue of IL-6 in LOC339059-overexpressing cells reverted the inhibitory effects of the gain of LOC339059 on malignant cell phenotypes. Our experiments verified that the interaction between LOC339059 and c-Myc resulted in less c-Myc binding to the IL-6 promoter, leading to the inactivation of IL-6 transcription. Conclusions: Our results establish that LOC339059 acts as a tumor suppressor in GC by competitively inhibiting c-Myc, resulting in diminished IL-6/STAT3-signaling-mediated PDL1 expression and macrophage M2 polarization. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics)
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20 pages, 3158 KiB  
Article
Effects of Co-Culture EBV-miR-BART1-3p on Proliferation and Invasion of Gastric Cancer Cells Based on Exosomes
by Mengyao Lin, Shun Hu, Tianyi Zhang, Jiezhen Li, Feng Gao, Zhenzhen Zhang, Ke Zheng, Guoping Li, Caihong Ren, Xiangna Chen, Fang Guo and Sheng Zhang
Cancers 2023, 15(10), 2841; https://doi.org/10.3390/cancers15102841 - 19 May 2023
Cited by 1 | Viewed by 1742
Abstract
Aim: EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore [...] Read more.
Aim: EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore the mechanism of miR-BART1-3p transmission through the exosome pathway and its influence on tumor cell proliferation and invasion. Materials and methods: Exosomes of EBV-positive and EBV-negative gastric cancer cells were characterized by transmission electron microscopy. NanoSight and Western blotting, and miRNA expression profiles in exosomes were sequenced with high throughput. Exosomes with high or low expression of miR-BART1-3p were co-cultured with AGS cells to study the effects on proliferation, invasion, and migration of gastric cancer cells. The target genes of EBV-miR-BART1-3p were screened and predicted by PITA, miRanda, RNAhybrid, virBase, and DIANA-TarBase v.8 databases, and the expression of the target genes after co-culture was detected by qPCR. Results: The exosomes secreted by EBV-positive and negative gastric cancer cells range in diameter from 30 nm to 150 nm and express the exosomal signature proteins CD9 and CD63. Small RNA sequencing showed that exosomes expressed some human miRNAs, among which hsa-miR-23b-3p, hsa-miR-320a-3p, and hsa-miR-4521 were highly expressed in AGS-exo; hsa-miR-21-5p, hsa-miR-148a-3p, and hsa-miR-7-5p were highly expressed in SNU-719-exo. All EBV miRNAs were expressed in SNU-719 cells and their exosomes, among which EBV-miR-BART1-5p, EBV-miR-BART22, and EBV-miR-BART16 were the highest in SNU-719 cells; EBV-miR-BART1-5p, EBV-miR-BART10-3p, and EBV-miR-BART16 were the highest in SNU-719-exo. After miR-BART1-3p silencing in gastric cancer cells, the proliferation, healing, migration, and invasion of tumor cells were significantly improved. Laser confocal microscopy showed that exosomes could carry miRNA into recipient cells. After co-culture with miR-BART1-3p silenced exosomes, the proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved. The target gene of miR-BART1-3p was FAM168A, MACC1, CPEB3, ANKRD28, and USP37 after screening by a targeted database. CPEB3 was not expressed in all exosome co-cultured cells, while ANKRD28, USP37, MACC1, and FAM168A were all expressed to varying degrees. USP37 and MACC1 were down-regulated after up-regulation of miR-BART1-3p, which may be the key target genes for miR-BART1-3p to regulate the proliferation of gastric cancer cells through exosomes. Conclusions: miR-BART1-3p can affect the growth of tumor cells through the exosome pathway. The proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved after co-culture with exosomes of miR-BART1-3p silenced expression. USP37 and MACC1 may be potential target genes of miR-BART1-3p in regulating cell proliferation. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics)
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Review

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34 pages, 1374 KiB  
Review
Chimeric Antigen Receptor-T Cell and Oncolytic Viral Therapies for Gastric Cancer and Peritoneal Carcinomatosis of Gastric Origin: Path to Improving Combination Strategies
by Courtney Chen, Audrey Jung, Annie Yang, Isabel Monroy, Zhifang Zhang, Shyambabu Chaurasiya, Supriya Deshpande, Saul Priceman, Yuman Fong, Anthony K. Park and Yanghee Woo
Cancers 2023, 15(23), 5661; https://doi.org/10.3390/cancers15235661 - 30 Nov 2023
Viewed by 1473
Abstract
Precision immune oncology capitalizes on identifying and targeting tumor-specific antigens to enhance anti-tumor immunity and improve the treatment outcomes of solid tumors. Gastric cancer (GC) is a molecularly heterogeneous disease where monoclonal antibodies against human epidermal growth factor receptor 2 (HER2), vascular endothelial [...] Read more.
Precision immune oncology capitalizes on identifying and targeting tumor-specific antigens to enhance anti-tumor immunity and improve the treatment outcomes of solid tumors. Gastric cancer (GC) is a molecularly heterogeneous disease where monoclonal antibodies against human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death 1 (PD-1) combined with systemic chemotherapy have improved survival in patients with unresectable or metastatic GC. However, intratumoral molecular heterogeneity, variable molecular target expression, and loss of target expression have limited antibody use and the durability of response. Often immunogenically “cold” and diffusely spread throughout the peritoneum, GC peritoneal carcinomatosis (PC) is a particularly challenging, treatment-refractory entity for current systemic strategies. More adaptable immunotherapeutic approaches, such as oncolytic viruses (OVs) and chimeric antigen receptor (CAR) T cells, have emerged as promising GC and GCPC treatments that circumvent these challenges. In this study, we provide an up-to-date review of the pre-clinical and clinical efficacy of CAR T cell therapy for key primary antigen targets and provide a translational overview of the types, modifications, and mechanisms for OVs used against GC and GCPC. Finally, we present a novel, summary-based discussion on the potential synergistic interplay between OVs and CAR T cells to treat GCPC. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics)
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23 pages, 2431 KiB  
Review
Gastric Cancer: Molecular Mechanisms, Novel Targets, and Immunotherapies: From Bench to Clinical Therapeutics
by Thais Baccili Cury Megid, Abdul Rehman Farooq, Xin Wang and Elena Elimova
Cancers 2023, 15(20), 5075; https://doi.org/10.3390/cancers15205075 - 20 Oct 2023
Cited by 1 | Viewed by 1650
Abstract
Gastric cancer is a global health concern, ranking fifth in cancer diagnoses and fourth in cancer-related deaths worldwide. Despite recent advancements in diagnosis, most cases are detected at advanced stages, resulting in poor outcomes. However, recent breakthroughs in genome analysis have identified biomarkers [...] Read more.
Gastric cancer is a global health concern, ranking fifth in cancer diagnoses and fourth in cancer-related deaths worldwide. Despite recent advancements in diagnosis, most cases are detected at advanced stages, resulting in poor outcomes. However, recent breakthroughs in genome analysis have identified biomarkers that hold positive clinical significance for GC treatment. These biomarkers and classifications offer the potential for more precise diagnostic and therapeutic approaches for GC patients. In this review, we explore the classification and molecular pathways in this disease, highlighting potential biomarkers that have emerged in recent studies including targeted therapies and immunotherapies. These advancements provide a promising direction for improving the management of GC. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics)
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18 pages, 3400 KiB  
Review
Challenges and Prospects of Patient-Derived Xenografts for Cancer Research
by Jiankang Jin, Katsuhiro Yoshimura, Matheus Sewastjanow-Silva, Shumei Song and Jaffer A. Ajani
Cancers 2023, 15(17), 4352; https://doi.org/10.3390/cancers15174352 - 31 Aug 2023
Cited by 4 | Viewed by 1348
Abstract
We discuss the importance of the in vivo models in elucidating cancer biology, focusing on the patient-derived xenograft (PDX) models, which are classic and standard functional in vivo platforms for preclinical evaluation. We provide an overview of the most representative models, including cell-derived [...] Read more.
We discuss the importance of the in vivo models in elucidating cancer biology, focusing on the patient-derived xenograft (PDX) models, which are classic and standard functional in vivo platforms for preclinical evaluation. We provide an overview of the most representative models, including cell-derived xenografts (CDX), tumor and metastatic cell-derived xenografts, and PDX models utilizing humanized mice (HM). The orthotopic models, which could reproduce the cancer environment and its progression, similar to human tumors, are particularly common. The standard procedures and rationales of gastric adenocarcinoma (GAC) orthotopic models are addressed. Despite the significant advantages of the PDX models, such as recapitulating key features of human tumors and enabling drug testing in the in vivo context, some challenges must be acknowledged, including loss of heterogeneity, selection bias, clonal evolution, stroma replacement, tumor micro-environment (TME) changes, host cell carryover and contaminations, human-to-host cell oncogenic transformation, human and host viral infections, as well as limitations for immunologic research. To compensate for these limitations, other mouse models, such as syngeneic and humanized mouse models, are currently utilized. Overall, the PDX models represent a powerful tool in cancer research, providing critical insights into tumor biology and potential therapeutic targets, but their limitations and challenges must be carefully considered for their effective use. Lastly, we present an intronic quantitative PCR (qPCR) method to authenticate, detect, and quantify human/murine cells in cell lines and PDX samples. Full article
(This article belongs to the Special Issue Gastric Cancers: Molecular Mechanisms, Novel Targets and Immunotherapies: From Bench to Clinical Therapeutics)
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