Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF.

Cancer Research

PubMedID: 24366884

Wang Y, Han G, Wang K, Liu G, Wang R, Xiao H, Li X, Hou C, Shen B, Guo R, Li Y, Chen G. Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF. Cancer Res. 2014;74(3):716-26.
Chronic inflammation is a major driving force for the development of colitis-associated cancer (CAC). Elevated production of granulocyte macrophage colony-stimulating factor (GMCSF) has been observed in mucosa of patients with inflammatory bowel disease (IBD). Its actions in the progression from colitis to cancer, however, remain poorly understood. Herein, we demonstrated that colonic epithelial cells (CEC) were a major cellular source of GMCSF and its production was significantly augmented when CAC model was established by administration of azoxymethane and dextran sulfate sodium. Furthermore, we showed that GMCSF was a driver for VEGF release by CEC in autocrine and/or paracrine manners through extracellular regulated protein kinase (ERK)-dependent pathway. Blocking GMCSF activity in vivo significantly decreased epithelial release of VEGF, thereby abrogated CAC formation. In vitro treatment of transformed CEC with recombinant GMCSF dramatically augmented its invasive potentials, largely in VEGF-dependent fashion. Furthermore, commensal microbiota-derived lipopolysaccharides (LPS) was identified a trigger for GMCSF expression in CEC, as antibiotics treatment or toll like receptor 4 (TLR4) ablation considerably impaired its epithelial expression. Overall, these findings may have important implications for understanding of mechanisms underlying CAC pathogenesis and the therapeutic potentials of regimens targeting GMCSF or VEGF in clinic.