TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling

TL;DR

This study shows how TIMP-1 helps liver cancer cells and stellate cells communicate through TGF-β and FAK signaling, and a drug called EW-7197 may be a promising treatment for liver cancer.

Contribution

The study identifies TIMP-1 as a mediator of TGF-β-dependent crosstalk between hepatic stellate and cancer cells, and validates EW-7197 as a potential anti-cancer therapy.

Findings

TIMP-1 mediates TGF-β-regulated crosstalk between hepatic stellate cells and HCC cells via FAK signaling.

EW-7197 inhibits TGF-β signaling, reducing HCC progression and metastasis in a mouse model.

EW-7197 blocks TIMP-1 secretion and downstream effects like proliferation and motility of HCC cells.

Abstract

Transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC. This study was undertaken to gain the proof of concept of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197 as a potent anti-cancer therapy for HCC. We identified tissue inhibitors of metalloproteinases-1 (TIMP-1) as one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-β-mediated crosstalk between HSCs and HCC cells. TGF-β signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-β signaling using EW-7197 significantly attenuated the progression and intrahepatic metastasis of HCC in an SK-HEP1-Luc orthotopic-xenograft mouse model. In addition, EW-7197 inhibited TGF-β-stimulated TIMP-1 secretion by HSCs as well as the TIMP-1-induced proliferation, motility, and survival of HCC cells. Further, EW-7197 interrupted TGF-β-mediated epithelial-to-mesenchymal transition and Akt signaling, leading to significant reductions in the motility and anchorage-independent growth of HCC cells. In conclusion, we found that TIMP-1 mediates TGF-β-regulated crosstalk between HSCs and HCC cells via FAK signaling. In addition, EW-7197 demonstrates potent in vivo anti-cancer therapeutic activity and may be a potential new anti-cancer drug of choice to treat patients with liver cancer.

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