Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

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.

Keywords: Axl; MerTK; TAM; Tyro3; chemoresistance; hepatocellular carcinoma; receptor tyrosine kinase; therapy; tumor microenvironment.

Figure 1

Hallmarks of Gas6-Pros1/TAM signaling. (A) Binding of high affinity ligands Gas6 or Pros1 to the immunoglobulin (Ig) domains of TAM receptors causes homo-dimerization and activation by phosphorylation of the intracellular protein kinase domain (PTK). (B) Interaction of Gas6 or Pros1 with TAM receptors and phosphatidylserine residues (PS) promotes phagocytosis of apoptotic cells. (C–E) Interaction of activated TAM receptors with interferon-α/β receptor (IFNAR) (C), integrin β3 (D), and the RTKs EGF-R, MET, PDGF-R, or FGFR-3 (E).

Figure 2

Regulation of TAM receptor expression and its role in HCC progression and EMT. (A) Transcriptional control of Axl expression in cancer cells of HCC (left arrow), immune cells (middle arrow), and various tumor entities (right arrow). FZD2, frizzled-2; NUAK, nuclear serine/threonine kinase; STAT3, signal transducer and activator of transcription 3, YAP1, yes-associated protein 1; Mzf1, myeloid zinc finger 1; HIF, hypoxia-inducible factor. (B) Molecular collaboration of Axl and TGF-β signaling in HCC switching from TGF-β-induced growth arrest to TGF-β-mediated cancer progression. Smad3L, linker region of Smad3. (C) HCC-specific role of TAM receptors in EMT. YAP, yes-associated protein; MAPK, mitogen-activated protein kinase; AFP, α-fetoprotein.

Figure 3

TAM receptor function in EMT and acquired chemoresistance. (Left panel) Epithelial cancer cells show sensitivity against drug treatment. EGF-Ri, inhibition of epidermal growth factor receptor; NFκBi, inhibition of nuclear factor κB; DDRi, inhibition of DNA damage response. (Right panel) EMT-transformed cancer cells having reduced levels of E-cadherin (red arrow) exhibit higher resistance to drug treatment by induced TAM expression (right panel). Inhibition of individual TAM receptors (TAMi) or treatment with soluble TAM decoy receptors that bind TAM ligands restore chemosensitivity.

Figure 4

Role of TAM receptor in the tumor microenvironment of HCC. (A) Immune cell infiltrated “hot” versus immune intermediate versus immune cell excluded HCC classes. NK cell, natural killer cell; KC, Kupffer cell; TREG, regulatory T cell; IFN-γ, interferon-gamma; PRF, perforin; GZMB, granzyme B; PD-L1, programmed death ligand 1. (B) TAM receptors during fibrogenesis. LSEC, liver sinusoidal endothelial cell. (C) Differential role of Gas6 and Pros1 in hemostasis and vessel integrity.