Activation of Met signaling pathway drives cancer cells to acquire an invasive growth phenotype and promotes each of the stages of HNSCC metastasis. E-cadherin is an important cell adhesion molecule in epithelial cells and disruption of E-cadherin mediated cell-to-cell adhesion promotes detachment of cancer cells from their primary sites [96], which is the first step in tumor invasion process. is squamous cell carcinoma (HNSCC) originated from the squamous epithelium lining of upper aerodigestive tract. The most prominent contributors for the development of HNSCC include tobacco use, alcohol consumption, and human papillomavirus Flavoxate (HPV) infections [3,4]. High mortality rates and severe morbidity are two common features of HNSCC. HNSCC affects tongue, oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx and thus compromises essential functions such as speech and swallowing. Close to half of HNSCC patients will die from their disease within five years [5]. Despite advances in aggressive multidisciplinary treatments during the last two decades, the 5-year survival rate for HNSCC has not improved significantly and is lower than that for other major cancer types such as lymphoma, breast cancer, and malignant melanoma [6]. Rabbit polyclonal to AMOTL1 Traditional treatment for HNSCC has been extensive surgery, which often yields a poor functional outcome. In recent years, improved therapy has been developed involving intensity-modulated radiation and concurrent use of chemotherapy [7]. In addition, advances have been made in elucidating molecular mechanisms and tumor biology that are important for the development and progression of HNSCC. Flavoxate Evidence demonstrates the importance of epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways in tumorigenesis and progression of HNSCC. This information has led to application of therapeutic strategies that target EGFR. Indeed, cetuximab, a monoclonal anti-epidermal growth factor receptor (EGFR) antibody, has been shown to improve median survival, when combined with cytotoxic chemotherapy in treatment of advanced HNSCC [8]. Hepatocyte growth factor receptor (HGFR, also known as Met) pathway, is another important growth factor pathway that has been shown to Flavoxate be important for the development of HNSCC. A growing body of evidence suggests that Met pathway could function as a driving force for invasive growth and early metastasis of HNSCC, and may cooperate with EGFR to cause resistance against anti-EGFR therapy. Therefore, Met is an attractive therapeutic target for treatment of HNSCC [9]. == 2. The Met Signaling Pathway and Functions == Hepatocyte growth factor (HGF), also known as scatter factor, is active in numerous tissues [10]. HGF is synthesized and secreted by mesenchymal cells as a 90-kDa inactive single-chain polypeptide and then proteolytically cleaved into an active disulfide-linked heterodimer [11]. HGF participates in the regulation of organogenesis, tissue repair, angiogenesis and neural induction [11]. HGF is a unique growth factor that elicits multiple cellular responses. HGF is mitogenic in many Flavoxate normal cell types, including epithelial cells, vascular endothelial cells, and melanocytes. HGF can also function as a morphogen that induces transition of epithelial cells into a mesenchymal morphology and formation of branched tube-like structures [12,13]. HGF induces random movement/scattering in epithelial cells as well as dissociation, migration, and invasion of cells through the extracellular matrixin vivo[14,15]. HGF actions are mediated through binding to its specific cell surface receptor, Met. Activation of Met by HGF initiates various intracellular signal transduction cascades [16,17]. Met gene, located on chromosome 7q31, encodes a receptor protein tyrosine kinase (RPTK). Native Met protein is proteolytically processed to a heterodimer composed of a 50 kDa subunit and a 145 kDa subunit, linked together by disulfide bonds [18]. In addition to the intracellular tyrosine kinase domain, Met also has several other.