Genetic background dictates pro-angiogenic factor production in preclinical models of colorectal cancer

Mutations such as BRAFV600E and PTEN-loss portend rapid tumor progression, treatment resistance, and overall impaired survival; on the other hand, tumor-stroma interactions are also a crucial determinant of tumor progression. Here we hypothesize that tumor genetic background may influence the surrounding microenvironment, through the production of chemokines and pro-angiogenic factors in ColoRectal Cancer (CRC) models. Here, we demonstrated that BRAFV600E, and to a lesser extent PTEN loss, were significantly associated with the production of higher levels of Interleukin (IL)-8 (p=0.004; p=0.05), whereas the other genetic alterations tested (RAS, PI3K) had no effect on IL-8 production. CRC cell lines BRAFV600E and PTEN-loss expressed the highest levels of IL-8 and a ROC curve-based prediction algorithm based on these two mutations had 68 % accuracy in predicting IL-8 production (p=0.002). On the other hand, IL-6 was almost never detected and Vascular Endothelial Growth Factor (VEGF) levels correlated with KRAS mutational status. Moreover, IL-8 is tightly controlled by activation of the MEK/ERK pathway, as MEK and ERK inhibitors profoundly suppressed its production regardless of the genetic background; the selective BRAF inhibitor downregulated IL-8 only in BRAFV600E contexts, but upregulated its production in parallel with ERK phosphorylation in BRAF-wt CRC cells. The PI3K/mTOR inhibitor had no effect on IL-8 production.