Metastasis is one of the main cause of death of cancer patients. Tumors are composed of a combination of cancer cells and stromal cells whose communication is crucial in their function. Endothelial cells play a role in the extravasation step of metastasis. Immune cells are part of the tumor infiltrate and are implicated in all the steps of metastasis. Myeloid derived cells such as monocytes, granulocytes and macrophages support tumor progression. TGFβ is a cytokine that control several physiological processes, such as cell proliferation, differentiation, and angiogenesis. In cancer, it switches from an inhibitory effect in early carcinogenesis to a promoting effect in late cancer progression. We used an experimental and spontaneous metastasis mouse model to assess the role of TGFβ signaling in myeloid and endothelial cells during metastasis.
Mice with Tgfbr2 deficiency in myeloid cells (LysMCreTR2fl/fl -TR2myeloKO) had lower number of liver and lung metastasis. Decreased metastasis associated with decreased number of monocytes and neutrophils in the metastatic liver and lower number of macrophages in the early metastatic lung. The accumulation of myeloid derived cells in the liver foci was absent in TR2myeloKO mice. In the early metastatic liver and lung the monocytes unresponsive to TGFβ had a more M1 anti-tumorigenic phenotype. The decreased lung but not liver metastasis in TR2myeloKO mice was dependent on CD8 T cells.
TGFβ signaling in endothelial cells is critical in embryonic development. We used a tamoxifen inducible mouse model for endothelial specific deficiency of TGFβRII (VECadCreERT2/TRIIfl/fl). Treated mice had lower number of lung metastasis in a spontaneous model. An immortalized mouse brain endothelial cell line showed increased phosphorylation of proteins associated with contractility. The increased phosphorylation suggests that decreased endothelial contraction and vascular permeability could be responsible for decreased lung metastasis in mice with temporal endothelial deficiency of TGFβ signaling. We showed that myeloid and endothelial TGFβ signaling is crucial for lung and liver metastasis and represent a valuable therapeutic target.