41 MET immunoreactivity and poor prognosis Introduction Head and neck cancers (HNCs) are a diverse group of malignant tumors that arise in various anatomical localizations of the upper aerodigestive tract (1). With an incidence of more than 680,000 cases worldwide (42,913 in Western Europe), it is the seventh most common cancer (2). Moreover, 90 to 95% percent of HNCs are squamous cell carcinoma (HNSCC). Despite the fact that numerous treatment platforms are available (3-5), relative 5-year survival rates remain poor for patients presenting with locoregionally advanced and recurrent and/or metastatic HNSCC (6-8). The current standard of care for patients diagnosed with advanced, unresectable HNSCC is concurrent chemoradiation (CRT) (9). Nevertheless successful, CRT is associated with substantial toxicity impeding its advances (10). Consequently, translational research has focused on the application of biologicals in the treatment of advanced HNSCC (10). This effort ultimately led to the approval of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (1, 10). Although adding cetuximab to radiotherapy (RT) improves locoregional control and reduces mortality compared to RT alone (11), there is no – prospective – evidence that the use of cetuximab plus RT in advanced HNSCC outperforms CRT (12, 13). However, adding cetuximab to chemotherapy in patients with recurrent and/or metastatic HNSCC does provide a small though significant survival benefit compared to chemotherapy alone (14, 15). To further improve treatment options for patients diagnosed with advanced and recurrent and/or metastatic HNSCC, the search for additional relevant molecular targets continues (16). One molecular target of interest is the receptor tyrosine kinase MET (1, 10, 16). MET is synthesized as a partially glycosylated 170 kDa single-chain intracellular precursor, which undergoes cleavage and further glycosylation to yield a mature, cell surface-associated 190 kDa disulphide linked heterodimer consisting of an extracellular 50 kDa a-chain and a transmembrane 145 kDa b-chain (17). MET is predominantly expressed on the surface of epithelial cells and is activated by its stromal ligand, the hepatocyte growth factor/scatter factor (HGF/SF) (18). Signaling via this receptor-ligand pair initiates the program of invasive growth, which is essential for physiological processes such as embryogenesis, tissue regeneration and wound healing as well as the pathological process of cancer cell invasion. 3
RkJQdWJsaXNoZXIy MTk4NDMw