Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

SIMPLE SUMMARY: Tyro3, Axl, and MerTK are receptor tyrosine kinases of the TAM family, which are activated by their ligands Gas6 and Protein S. TAM receptors have large physiological implications, including the removal of dead cells, activation of immune cells, and prevention of bleeding. In the last decade, TAM receptors have been suggested to play a relevant role in liver fibrogenesis and the development of hepatocellular carcinoma. The understanding of TAM receptor functions in tumor cells and their cellular microenvironment is of utmost importance to advances in novel therapeutic strategies that conquer chronic liver disease including hepatocellular carcinoma. ABSTRACT: Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.