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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2016; 22(8): 2434-2440
Published online Feb 28, 2016. doi: 10.3748/wjg.v22.i8.2434
Emerging molecular basis of hematogenous metastasis in gastric cancer
Jing Zhong, Yan Chen, Liang-Jing Wang
Jing Zhong, Yan Chen, Liang-Jing Wang, Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine and Institute of Gastroenterology, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
Author contributions: Zhong J and Chen Y contributed to the literature searching and the writing of the manuscript; Wang LJ contributed to the original idea, polishing and final proof of the manuscript.
Supported by National Natural Science Foundation of China, No. 81472214 and No. 81302070; Science and Technology Innovation Team Fund of Zhejiang Province, No. 2013TD13; Natural Science Foundation of Zhejiang Province, No. LY13H160019; and Science and Technology Fund of Zhejiang Province, No. 2012C37105.
Conflict-of-interest statement: The authors have no conflict of interest to report.
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/
Correspondence to: Dr. Liang-Jing Wang, Professor, Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China. wanglj76@hotmail.com
Telephone: +86-571-87783715 Fax: +86-571-86006788
Received: April 28, 2015
Peer-review started: May 7, 2015
First decision: October 14, 2015
Revised: October 29, 2015
Accepted: November 19, 2015
Article in press: November 19, 2015
Published online: February 28, 2016
Abstract

Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the “seed and soil hypothesis” a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ‘‘metastatic intermediates’’ between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future.

Keywords: Gastric cancer, Metastasis, Molecular mechanism

Core tip: The premetastatic niche is a novel predictor of cancer metastasis. The following steps including local invasion, intravasation into vessel lumen, survival in the circulation and extravasation also contribute to gastric cancer progression through a variety of mechanisms. This review provides an overview of the complex interaction between tumors and their microenvironment in hematogenous metastasis cascade.