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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2015; 21(41): 11777-11792
Published online Nov 7, 2015. doi: 10.3748/wjg.v21.i41.11777
Pathophysiological mechanisms of death resistance in colorectal carcinoma
Ching-Ying Huang, Linda Chia-Hui Yu
Ching-Ying Huang, Linda Chia-Hui Yu, Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
Author contributions: All the authors contributed to this manuscript.
Supported by Ministry of Science and Technology, MOST 103-2811-B-002 -060 and MOST 102-2628-B-002-009-MY3; and National Taiwan University, No. NTU-CDP-104R7798.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
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: Linda Chia-Hui Yu, PhD, Associate Professor, Graduate Institute of Physiology, National Taiwan University College of Medicine, Suite 1020, 1 Jen-Ai Rd. Sec. I, Taipei 100, Taiwan. lchyu@ntu.edu.tw
Telephone: +886-2-23123456-88237 Fax: +886-2-23964350
Received: April 28, 2015
Peer-review started: May 7, 2015
First decision: June 2, 2015
Revised: June 18, 2015
Accepted: August 31, 2015
Article in press: August 31, 2015
Published online: November 7, 2015
Processing time: 189 Days and 4.5 Hours
Abstract

Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

Keywords: Colon cancer; Tumorigenesis; Anti-apoptosis; Chemoresistance; Anti-necroptosis; Cytoprotection

Core tip: The mechanisms underlying anti-death cytoprotection and tumor resistance bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. Autocrine, paracrine and exogenous factors within a tumor microenvironment may instigate apoptotic and necroptotic resistance in colon cancers. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharide will be highlighted. Targeting death resistance pathways in colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.