FIGURE 4.

TGF‐β signaling in the pre‐metastatic niche. Primary tumors secrete cytokines and exosomes that home to the liver and trigger transforming growth factor (TGF)‐β signaling in liver cells. Exosomes containing migration inhibitory factor (MIF) triggered TGF‐β release by kupffer cells, resulting hepatic stellate cell (HSC) activation. MIF can also be secreted by liver sinusoid endothelial cells (LSECs), which increases tumor cell adhesion to LSECs. miR‐92a, present in exosomes secreted by bone marrow derived cells, represses mothers against decapentaplegic homolog(SMAD)7 in HSCs, sensitizing HSCs toward TGF‐β mediated activation. The result of TGF‐β induced HSC activation is a fibrotic niche of collagen‐1 and fibronectin, which promotes recruitment of suppressive bone marrow derived cells (BMDCs), and metastatic outgrowth. Migration of tumor cells toward the liver can be increased by TGF‐β induced interaction between tumor cells and fibroblasts