Figure 3. Proinflammatory paracrine signaling as a potential target for the treatment of Pik3ca^H1047R-driven microcystic LM.

In a mouse model of LM, expression of oncogenic Pik3ca^H1047R (black stars) in LECs (green vessels) leads to lymphatic vessel overgrowth (blue vessels). This overgrowth is associated with a proinflammatory phenotype of LECs, promoting the recruitment of macrophages that, in turn, produce prolymphangiogenic VEGF-C and drive progressive vessel growth. In addition to PI3K pathway inhibitors, the use of antiinflammatory therapy, such as COX2 inhibitor celecoxib, and VEGF-C blockade has proven effective in limiting Pik3ca-driven lymphatic overgrowth in mice (51).