Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis

In the last 10 years, evidence has accumulated that overexpression of Met p rotein is a distinguishing feature of almost every case of well-differentia ted papillary carcinoma. Increased expression of the protein is probably du e to enhanced transcription of the MET gene and/or to post-transcriptional mechanisms. So far, alterations of the MET gene have not been recognized, b ut evidence has been provided that activated R.-IS and RET can cause accumu lation of MET RNA. Thus, the possibility exists that dysregulation of MET i s the final result of different molecular pathways capable of inducing thyr oid cell transformation; RET rearrangements might account for some of the c ases, but the demonstration that the majority of papillary carcinomas do no t have recognized alterations of the RET gene strongly suggests that MET ge ne dysregulation can also be achieved through other molecular pathways. Dys regulation of MET causes marked accumulation of Met protein in tumour cells that is promptly detected by immunohistochemistry. Thus, overexpression of Met protein might represent an immunohistochemical marker of papillary car cinoma, potentially helpful in problematic cases, but caution is required; moderate expression of Met protein is observed in non-neoplastic thyroid di seases, such as Graves' and Hashimoto's thyroiditis, and reagents active on paraffin sections may have a low affinity and/or low specificity for Met p rotein, leading to artifactual staining. Met protein-positive papillar? car cinoma cells may produce hepatocyte growth factor (HGF) and may activate HG F through the urokinase-type plasminogen activator (uPA) bound to urokinase -type plasminogen activator receptor (uPA-R), Thus, papillary carcinoma cel ls possess the molecular machinery necessary for a productive HGF/ Met inte raction. In vitro studies have demonstrated that HGF enhances the motility and invasiveness of tumour cells and induces the synthesis and release of c hemokines active in the recruitment of dendritic cells. These observations provide a rational basis for the understanding of two distinguishing featur es of papillary carcinoma. First, the tumour is often characterized by earl y metastatic spread to regional lymph nodes and by multifocal involvement o f the gland, which suggests highly invasive behaviour. Second, a prominent peritumoral inflammatory reaction is often observed, which suggests cross-t alk between tumour cells and the immune system. Copyright (C) 2001 John Wil ey & Sons, Ltd.