Hepatocyte Growth Factor/C-Met Axis in Thyroid Cancer: From Diagnostic Biomarker to Therapeutic Target

Abstract

The hepatocyte growth factor (HGF)/c-met axis plays a crucial role in cancer development by promoting cellular proliferation, motility, and morphogenesis, as well as angiogenesis. Different cellular distributions of both the ligand and the receptor in benign vs malignant lesions indicate this biological system as a candidate for a diagnostic biomarker of malignancy occurring in endocrine glands, such as the thyroid and pituitary. Furthermore, the HGF/c-met expression may help to identify a subset of patients eligible for potential targeted therapies with HGF/c-met inhibitors or antagonists in thyroid tumour, as well as in other malignancies. This may be relevant for iodine-refractory cancers, the treatment of which is still a major challenge. With this in mind, HGF/c-met expression in thyroid cancer tissue may be useful for prognostic and therapeutic stratification of patients.

Keywords: HGF/c-met axis; diagnostic biomarker; therapeutic target; thyroid cancer.

Figure 1.

HGF/c-met axis. HGF/c-met interaction leads to c-met dimerization as well as phosphorylation of 2 tyrosine residues, Tyr 1349 and Tyr1356, both located in the C-terminal tail and responsible for docking sites for multiple substrates showing SH2 domain. Through SH2 domain, Ras, PI3K, and STAT3 effectors are triggered to induce cellular growth through Rho activation, scattering effect by AKT recruitment, and morphogenetic response by migration of STAT3 to nucleus and subsequent to its binding to SIE. AKT indicates protein kinase B; HGF, hepatocyte growth factor; met, mesenchymal epithelial transition factor; PI3K, phosphatidyl inositol-4,5-bisphosphate 3-kinase; Ras, rat sarcoma; Rho, rhodopsin; SH2, Src homology 2; SIE, sis-inducible element; STAT3, signal transducer and activator of transcription 3.

Figure 2.

Immunoreactions of hepatocyte growth factor (HGF) in cases of benign colloid goitre and papillary thyroid carcinoma (PTC). (A) Unstained HGF follicular thyroid cells (grey arrow) and HGF stain located on membrane and cytoplasm of stromal cells (black arrow) surrounding thyrocytes, respectively (original magnification ×400). (B) HGF cytoplasmic and membranous immunostaining in PTC follicular cells (black arrow) and unstained HGF stromal cells (grey arrow), respectively (original magnification ×400).