Abstract
Tumor angiogenesis plays a crucial role in colorectal cancer development. Dysregulation of the receptor for the advanced glycation end-products (RAGE) transmembrane signaling mediates inflammation, resulting in various cancers. However, the mechanism of the RAGE signaling pathway in modulating development of colorectal cancer has not been explored. In this study, an aptamer-based RAGE antagonist (Apt-RAGE) was used to inhibit interaction between RAGE and S100B, thus blocking downstream NFκB-mediated signal transduction. In vitro results showed that Apt-RAGE effectively inhibited S100B-dependent and S100B-independent RAGE/NFκB activation in colorectal HCT116 cancer cells, thus decreasing proliferation and migration of cells. Notably, expression and secretion of VEGF-A were inhibited, implying that Apt-RAGE can be used as an antiangiogenesis agent in tumor therapy. Moreover, Apt-RAGE inhibited tumor growth and microvasculature formation in colorectal tumor-bearing mice. Inhibition of angiogenesis by Apt-RAGE was positively correlated with suppression of the RAGE/NFκB/VEGF-A signaling. The findings of this study show that Apt-RAGE antagonist is a potential therapeutic agent for treatment of colorectal cancer.
Highlights
Colorectal cancer is a multifactorial disease that affects over four million people worldwide [1]
These findings imply that development of colorectal cancer may be mediated by receptor for advanced glycation end-products (RAGE)/NFκB/vascular endothelial growth factor (VEGF)-A axis, which plays a role in promoting tumor angiogenesis
Development of colorectal cancer is associated with aberrant RAGE activation through angiogenesis-promoting tumor microenvironment (TME) inflammation
Summary
Colorectal cancer is a multifactorial disease that affects over four million people worldwide [1]. Previous studies report that the development of colorectal cancer is highly correlated with tumor angiogenesis [2] which is implicated in the pathological process of many critical diseases [3]. Inhibition of angiogenesis is associated with alleviation of cancer progression and metastasis [4, 5]. New blood vessels formed during angiogenesis may contribute to inflammation-associated carcinogenesis, inducing tumor progression and tumor metastasis [6, 7]. Unregulated release of different inflammatory mediators in the tumor microenvironment (TME) activates growth, proliferation, and migration of colorectal cancer cells [8]. Inflammation mediators in TME induce abnormal angiogenesis by increasing secretion of vascular endothelial growth factor (VEGF).
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