Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2019; 11(9): 686-704
Published online Sep 15, 2019. doi: 10.4251/wjgo.v11.i9.686
Tumor progression-dependent angiogenesis in gastric cancer and its potential application
Hsi-Lung Hsieh, Ming-Ming Tsai
Hsi-Lung Hsieh, Ming-Ming Tsai, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
Hsi-Lung Hsieh, Ming-Ming Tsai, Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
Hsi-Lung Hsieh, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Ming-Ming Tsai, Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
Author contributions: The author contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Supported by the Ministry of Science and Technology, Taiwan, No. MOST 106-2320-B-255-005 and No. MOST 107-2320-B-255-003; Chang Gung Medical Research Foundation, Taoyuan, Taiwan, No. CMRPF1G0011, No. CMRPF1G0251, No. CMRPF1I0031, No. CMRPF1H0051, and No. CMRPF1I0041; and Chang Gung University of Science and Technology, Taoyuan, Taiwan, No. ZRRPF3H0131.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ming-Ming Tsai, PhD, Associate Professor, Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, 261 Wen-hwa 1 Road, Taoyuan 333, Taiwan. mmtsai@mail.cgust.edu.tw
Telephone: +886-3-2118999 Fax: +886-3-2118866
Received: March 15, 2019
Peer-review started: March 18, 2019
First decision: June 5, 2019
Revised: July 5, 2019
Accepted: August 19, 2019
Article in press: August 19, 2019
Published online: September 15, 2019
Processing time: 181 Days and 18.6 Hours
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.