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.

Keywords: Gastric cancer, Angiogenesis, Vascular endothelial cell, Angiogenic phenotype switch, Anti-angiogenesis, Tumor dormancy

Core tip: Tumor angiogenesis in gastric cancer (GC) and antiangiogenic therapies for GC, including information from their preclinical and/or application to clinical trials, are discussed. The antiangiogenic strategies for advanced GC include decreasing the expression of proangiogenic ligands and their receptors, increasing the level of angiogenic inhibitors, and directly targeting the inner walls of endothelial cells. Here, the antiangiogenic strategies mainly focus on decreasing the expression of vascular endothelial growth factor-mediated pathway constituents for advanced GC in phase III clinical trials. Thus, this review provides a brief description of various tumor angiogenic factors for the purposes of diagnosis, prognosis and therapeutics and describes the antiangiogenic agents that are currently being investigated in preclinical and phase III clinical trials. Hopefully, according to the molecular mechanism of tumor angiogenesis, we highlight the accuracy of the diagnosis and prognosis and the selection of the most appropriate therapy for GC patients.