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

ABSTRACT

We investigate crosstalk between cancer cells and stromal myeloid cells. We find that Lewis lung carcinoma cells significantly induce PPARß/δ activity in myeloid cells in vitro and in vivo. Myeloid cell-specific knockout of PPARß/δ 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 PPARß/δ and facilitates tumor cell invasion and angiogenesis. This observation is supported by the finding that the CD11blowIL-10+ pro-tumoral myeloid cell is scarcely detected in tumors from myeloid-cell-specific PPARß/δ knockout mice, where vessel densities are also decreased. Fatty acid synthase (FASN) is shown to be an upstream regulator of PPARß/δ 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.