Abstract
Simple SummaryTyro3, 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.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.
Highlights
TAM receptors emerge as promising therapeutic targets and biomarkers in chronic liver disease (CLD), consequences of TAM activation and intervention are contrasting what might have a severe impact on clinical efforts
Axl is essentially involved in hepatic stellate cells (HSCs) activation and fibrosis, while the role of MerTK is ambiguous [40,118,120,121]
MerTK single nucleotide polymorphism (SNP) rs4374383 GG/AG correlate with higher risk and severity of liver fibrosis compared to patients harboring the rs4374383 AA genotype, indicating either pro-fibrotic or hepatoprotective functions, respectively [26,122]
Summary
The receptor tyrosine kinases (RTKs) Tyro, Axl, and MerTK constitute the TAM family. The Gla domain of Gas or Pros can be γ-carboxylated in a vitamin K-dependent fashion, which is required for the interaction of TAM receptors with PtdSer residues exposed at—membranes of activated platelets and apoptotic cells (Figure 1B) [27]. The interaction of MerTK and Tyro with PtdSer-presenting membranes enhances their receptor activation, suggesting a major impact on the clearance of apoptotic cells [20]. Aggregation of platelets is dependent on TAM signaling in the presence of PtdSer residues, as shown by the Gas6/Axl-mediated tyrosine phosphorylation of integrin β3, which stabilizes thrombus formation by adhesion (Figure 1D) [32,33]. Gas6/TAM receptors enhance the pro-inflammatory activation of endothelial cells by upregulating expression of VCAM-1, ICAM-1, and P-selectin, which allows binding to P-selectin glycoprotein ligand 1 expressed by leukocytes, promoting leukocytes extravasation and inflammation [35]. A recent study revealed the upregulation of Axl after abrogation of ADAMTSL5, a crucial regulator of oncogenic signaling and chemoresistance in HCC, suggesting a role in the acquisition of chemosensitivity rather than in its escape from drug treatment [52]
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