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.

GAS6/TAM Axis as Therapeutic Target in Liver Diseases

“…invasion and metastasis as well as poor clinical outcomes 125,126 . In HCC, high expression of AXL (54/246 of the cohort analyzed) has also been related to advanced disease stage, correlating with microvascular invasion and lower overall survival 127 .…”

“…Therefore, AXL activation is frequently associated with tumor invasion and metastasis as well as poor clinical outcomes. 125,126 In HCC, high expression of AXL (54/246 of the cohort analyzed) has also been related to advanced disease stage, correlating with microvascular invasion and lower overall survival. 127 Other studies showed a strong AXL expression in 60% of the HCC samples analyzed and validated the strong correlation between AXL and advanced stages, 128 as well as microvascular invasion.…”

Diagnostic Efficacy and Possible Underlying Mechanisms of Noninvasive Clinical Markers in Hepatocellular Carcinoma

“…The TAM receptor family of receptor tyrosine kinases comprises TYRO3, AXL, and MER, and specifically, AXL is mainly involved in regulating platelet aggregation and maintaining vascular integrity. 7 The upstream regulator of AXL, RAB10, is associated with an advanced stage and a large tumor size in patients with HCC, 8 and following AXL cleavage by a disintegrin and metalloproteinases 10 and 17 via a protein kinase C-dependent pathway, soluble AXL (sAXL) can be detected in serum. 9 Des-γ-carboxy prothrombin (DCP) is a prothrombin precursor produced in patients with HCC.…”

PRAME Is a Novel Target of Tumor-Intrinsic Gas6/Axl Activation and Promotes Cancer Cell Invasion in Hepatocellular Carcinoma

“…Upregulation of the receptor tyrosine kinase Axl, a member of the TAM receptor family together with Tyro3 and MerTK, associates with poor prognosis of HCC patients [6]. Nuclear serine/threonine kinases NUAK1/2, signal transducer and activator of transcription 3, yes-associated protein 1 and frizzled-2 are capable of inducing Axl expression in about 40% of HCC cases [6][7][8][9]. Axl can signal via MAPK, PI3K/Akt or Src among others favoring cell survival, proliferation, angiogenesis, epithelial-to-mesenchymal transition (EMT), cell invasion and drug resistance [10].…”

“…Axl can signal via MAPK, PI3K/Akt or Src among others favoring cell survival, proliferation, angiogenesis, epithelial-to-mesenchymal transition (EMT), cell invasion and drug resistance [10]. HCC cells frequently upregulate the expression of the EMT transcription factors (EMT-TFs) Snail, Slug, Twist and Zeb1/2 resulting in reprogramming to mesenchymal gene expression [7,11,12]. Axl is an important mediator of EMT in various malignancies associating with the expression of genes regulating stemness and metastasis [13,14].…”