M-CSF from Cancer Cells Induces Fatty Acid Synthase and PPARβ/δ Activation in Tumor Myeloid Cells, Leading to Tumor Progression

We investigate crosstalk between cancer cells and stromal myeloid cells. We find that Lewis lung carcinoma cells significantly induce PPAR beta/delta activity in myeloid cells in vitro and in vivo. Myeloid cell-specific knockout of PPAR beta/delta results in impaired growth of implanted tumors, and this is restored by adoptive transfer of wild-type myeloid cells. We find that IL-10 is a downstream effector of PPAR beta/delta and facilitates tumor cell invasion and angiogenesis. This observation is supported by the finding that the CD11b(low)IL-10(+) pro-tumoral myeloid cell is scarcely detected in tumors from myeloid-cell-specific PPAR beta/delta knockout mice, where vessel densities are also decreased. Fatty acid synthase (FASN) is shown to be an upstream regulator of PPAR beta/delta in myeloid cells and is induced by M-CSF secreted from tumor cells. Our study gives insight into how cancer cells influence myeloid stromal cells to get a pro-tumoral phenotype.