Gastric cancer is one of the most frequent malignancies worldwide. Despite improvements in diagnosis and therapy, the overall prognosis remains poor. In the last decade, several anti-angiogenic drugs for cancer treatment have been approved and lately also introduced to gastric cancer treatment. While the initial trials focused only on unresectable or metastatic cancer, anti-angiogenic treatment is now also investigated in the perioperative and neoadjuvant setting. In this review, an overview of the role of angiogenesis and angiogenic factors in gastric cancer as well as anti-angiogenic treatment of gastric cancer is provided. Findings from in vitro and animal studies are summarized and put in a context with translational data on angiogenesis in gastric cancer. The most important angiogenic factors and their effect in gastric cancer are highlighted and clinical trials including anti-angiogenic drugs are discussed. Finally, an outlook of biomarkers for predicting response to anti-angiogenic treatment is presented, the ongoing trials on this topic are discussed and current challenges of anti-angiogenic therapy are outlined.

https://www.mdpi.com/1422-0067/19/1/43/pdf

Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer.

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

N6‐methyladenosine (m6A) is the addition of a methyl group on the N6 position of adenosine and is the most prevalent and abundant epigenetic modification in eukaryote mRNA. m6A marks are added to mRNA by the m6A methyltransferase complex (“writers”), removed by m6A demethylases (“erasers”), and recognized by m6A‐binding proteins (“readers”). Recent evidence has shown that the m6A modification plays a crucial role in the pathogenic mechanism and malignant progression of pancreatic cancer, with roles in cell survival, proliferation, migration, invasion, tumor metastasis, and drug resistance.

Research advances of N6‐methyladenosine in diagnosis and therapy of pancreatic cancer

Gastric adenocarcinoma (GC) is a devastating disease and is the third leading cause of cancer deaths worldwide. This heterogeneous disease has several different classification systems that consider histological appearance and genomic alterations. Understanding the etiology of GC, including infection, hereditary conditions, and environmental factors, is of particular importance and is discussed in this review. To improve survival in GC, we also must improve our therapeutic strategies. Here, we discuss new targets that warrant further exploration.

Molecular pathogenesis and emerging targets of gastric adenocarcinoma

RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy. 

Emerging role of RNA modification and long noncoding RNA interaction in cancer.

This study investigated the inhibitory effects of bevacizumab monoclonal antibodies in combination with chemotherapy in different time sequences on a human gastric cancer cell line (MGC-803). Cultured MGC-803 human gastric cancer cells were treated with bevacizumab in combination with chemotherapy treatment in different time sequences. The effects on cell growth inhibition were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle distribution and the rate of cell apoptosis were determined by propidium iodide staining followed by flow cytometry. Drug administration for different time sequences significantly inhibited the growth of MGC-803 cells. Based on group comparisons (P < 0.01), the effect of 24 h bevacizumab treatment prior to combination 5-fluorouracil and cisplatin (FP) was the strongest (F = 241.313, 246.856, all P values <0.001). Treating MGC-803 cells with bevacizumab for 24 h before combination FP induced significant G2/M phase arrest (F = 231.991, P < 0.001) and significantly increased gastric cancer cell apoptosis. Bevacizumab in combination with chemotherapy significantly inhibits the proliferation of MGC-803 gastric cancer cells. The mechanism may be related to cell cycle arrest at S phase and the induction of apoptosis in MGC-803 gastric cancer cells.

Inhibitory effects of bevacizumab monoclonal antibodies in combination with chemotherapy in different time sequences on a human gastric carcinoma cell line.

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Research advances of N6‐methyladenosine in diagnosis and therapy of pancreatic cancer

Inhibitory effects of bevacizumab monoclonal antibodies in combination with chemotherapy in different time sequences on a human gastric carcinoma cell line.