Brief Definit ive Report

Constitutive activation of the PI3K pathway is very common in cancer, and PI3K inhibitors are currently progressing through oncology tri-als (Rodon et al., 2013). At present, the role of PI3K in the tumor microenvironment, such as in cancer-associated fibroblasts, endothelial cells (ECs), mural cells, and immune cells, is largely unexplored. With the exception of white blood cells, where p110 and p110 both play impor-tant roles (including in cancer; p110; Schmid et al., 2011), the ubiquitously expressed p110 is likely to be a critical PI3K isoform in non-leukocyte stromal cell types, based on the no-tion that p110 plays a nonredundant key role in vascular development (Lelievre et al., 2005; Graupera et al., 2008) and fibroblast prolifera-tion (Foukas et al., 2006; Zhao et al., 2006). However, the role of p110 in the tumor stroma is unknown. To assess the importance of the p110 PI3K axis in the cancer stromal com-partment, we manipulated this pathway in syn-geneic mouse cancer models. RESULTS AND DISCUSSION Systemic pharmacological blockade of p110 and p110 in mice leads to decreased B16F1 melanoma growth and aberrant angiogenesis In vitro treatment of B16F1 cells with PI3Ki-A/D, a small molecule inhibitor with selectivity for p110 and p110 (Edgar et al., 2010), reduced Akt phosphorylation (Fig. 1 A), without affecting cell proliferation (Fig. 1 B) or survival (Fig. 1 C). This compound also reduced in vitro production of vascular endothelial growth factor (VEGF