CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer

Abstract

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene α), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

“…PGE 2 induces the expression of a member of the epidermal growth factor family, amphiregulin, in colon cancer cells, which in turn stimulates cell proliferation and growth via an autocrine fashion (13,33). Chemokine CXCL1 (growth-regulated oncogene-␣) can be induced by PGE 2 in colon cancer cells, which then promotes neoangiogenesis in intestinal neoplasia via a paracrine pathway (37). Amphiregulin, hepatocyte growth factor, and VEGF are induced by PGE 2 in intestinal subepithelial myofibroblasts, which stimulate the growth of intestinal epithelial cells and promote angiogenesis through a paracrine mechanism (38).…”

Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways

“…34 CXCL1 (also known as growth-regulated oncogene-a or melanoma growth stimulatory activity, a) has been reported to be overexpressed in many cancers. 35,36 However, its presence has also been negatively associated with cancers, 37 attesting to its complex role in tumorigenesis and angiogenesis. Little information is available describing CXCL1 expression and function in human endothelial cells associated with tumors.…”

Custom Design of a GeXP Multiplexed Assay Used to Assess Expression Profiles of Inflammatory Gene Targets in Normal Colon, Polyp, and Tumor Tissue

“…A number of these previously have been reported to be increased in gut inflammation and or colon tumors. [13][14][15][16][17] They also have been reported to be involved in angiogenesis 27 and metastasis. 28,29 Notably, Table 1.…”

“…10.001. gut and have been reported to show altered expression in colon tumor tissue. [13][14][15][16][17] Inflammation is widely recognized as a component of cancer, with inflammatory bowel diseases known to lead to increased risk of colon carcinogenesis. 18,19 Hence, gastrointestinal inflammatory signaling pathways and their regulation present key targets for prevention and therapeutic intervention.…”