TGF-? signaling in myeloid cells is required for tumor metastasis.

ABSTRACT: TGF-? is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-? functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-?1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-? production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-? receptor II expression. Our studies show that myeloid-specific TGF-? signaling is an essential component of the metastasis-promoting puzzle of TGF-?. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.

SUBMITTER: Pang Y 

PROVIDER: S-EPMC4678771 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature