Combination curcumin and (−)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway

Tumor microenvironment has a crucial role in cancer development and progression, whereas the mechanism of how it regulates angiogenesis is unclear. In this study, we simulated the colorectal carcinoma microenvironment by conditioned medium (CM) of colorectal carcinoma cell lines (SW620, HT-29, HCT116) supernatant or colorectal carcinoma tissue homogenate supernatant to induce normal endothelial cells (NECs). We found that colorectal carcinoma CM promoted tumor angiogenesis by coercing NECs toward tumor endothelial cells (TECs) with the activation of the JAK/STAT3 signaling pathway. Antibody array analysis showed HT-29 supernatant contained numerous angiogenesis-related proteins, especially IL-8. Interestingly, the production of IL-8 in NECs induced by HT-29 CM was also increased. We also verified the crucial role of IL-8 in promoting the CM-induced angiogenesis, as IL-8 repression by neutralizing antibody abolished the transition of NECs toward TECs. Curcumin and (−)-epigallocatechin-3-gallate (EGCG) are broadly investigated in cancer chemoprevention. However, poor bioavailability hurdles their application alone, and the mechanism of their anti-angiogenesis still need to be illuminated. Here, we found that curcumin combination with EGCG attenuated the tumor CM-induced transition of NECs toward TECs by inhibiting JAK/STAT3 signaling pathway. Furthermore, the combination of curcumin and EGCG markedly reduced tumor growth and angiogenesis in the colorectal carcinoma PDX mouse model, and the combined anti-angiogenic effect was better than that of curcumin or EGCG alone. Taken together, our findings provide a new mechanism of tumor angiogenesis, and the combination of curcumin and EGCG represents a potential anti-angiogenic therapeutic method for colorectal carcinoma.