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

Abstract

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.

The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

“…One different anti-angiogenic strategy encompasses therapies targeting the angiogenic VEGF-mediated pathway, which is considered critical not only for the regulation of tumor angiogenesis but also for the degradation and remodeling of the ECM [191]. Significant evidence awards VEGF/VEGFR2 signaling an important role in gastric cancer pathogenesis, and indeed, gastric cancer patients were reported to display significantly higher plasma or serum VEGF levels than healthy control subjects [192]. The monoclonal anti-VEGF antibody Bevacizumab, which was the first drug targeting the VEGF pathway, did not reach promising results in overall survival of gastric cancer patients in the AVAGAST clinical trial, however, it is now approved for first-and/or second-line treatment of a variety of tumors including colorectal cancer [191].…”

Angiogenesis-Related Gene Expression Signatures Predicting Prognosis in Gastric Cancer Patients

“…Substantial evidence suggests that angiogenesis is involved in processes of carcinogenesis, progression, and metastasis of GC. Moreover, results from translational research on angiogenesis in GC indicate that several angiogenesis-related factors might be prognostically relevant [ 9 , 15 , 16 , 17 ]. Although analyzing the expression levels of a single angiogenetic gene is convenient with immunohistochemistry and ELISA [ 17 , 18 ], multiple gene signature analysis reflects the complex interaction of various parameters affecting angiogenesis in tumor pathology.…”

“…Angiogenesis is an essential process in tumorigenesis, because its induction is indispensable to deliver nutrients and evacuate metabolic waste [ 8 ]. During cancer development, several proangiogenic cytokines are released by tumor cells, such as vascular endothelial growth factor A (VEGFA), fibroblast growth factor (FGF) and hypoxia-inducible factor-1 (HIF-1), which contributes to the sprout and formation of neovasculature in the tumor microenvironment (TME) [ 9 ]. Thus, it had been demonstrated that anti-angiogenic therapies significantly improved prognosis in GC patients [ 10 , 11 ].…”

ITRAQ-based Bioinformatics Analysis Reveals the Potential Anticancer Effects of ATP4B in Gastric Cancer

“…The initiation and development of GC is a multi-stage, heterogeneous and multifactorial pathology process involving numerous genetic, epigenetic and environmental factors alterations [22]. Recently, studies have reported that the ATP4B gene is downregulated in GC, which plays a negative role in the progression of GC [6,15].…”