Of note, mesenchymal stem cells (MSC) produce HGF, which activates and expands the myeloid-derived suppressor cells (MDSC) in a STAT3-dependent manner (68). almost 60,000 patients were diagnosed with a malignancy of the oral cavity, pharynx or larynx in the United States (2). Although 95% of HNC are squamous cell carcinomas (HNSCC), previous and ongoing genetic profiling underscores the distinct heterogeneity of this entity (3, 4). However, one common observation in up to 90% of the HNSCCs is the overexpression of EGFR (5). Major risk factors for the development of HNSCC include tobacco Rabbit Polyclonal to MAP3K4 use, excessive alcohol consumption, and human papillomavirus (HPV) infection. Impaired oral hygiene and genetic alterations resulting in susceptibility to malignancies such as Fanconi anemia have also been implicated as risk factors. Depending on site and tumor stage, therapeutic options include surgery, irradiation, and chemotherapy. Cetuximab, an FDA-approved CP-96486 mAb targeting EGFR, is the only targeted therapy for HNSCC (6, 7). However, cetuximab treatment results in modest survival benefit in combination with radiation (29.3 vs. 49 months) or chemotherapy (7.4 vs. 10.1 months; refs. 6, 7). Activation of alternative signaling pathways, such as the HGF/Met signaling axis, has been implicated to mediate cetuximab resistance (8). HGF/Met Pathway The mesenchymal epithelial transition (Met) factor receptor is a receptor tyrosine kinase (RTK) that is encoded by the protooncogene (9). Briefly, the Met receptor consists of a 45 kDa extracellular -chain, linked to a 145-kDa transmembrane -chain via disulphide bonds (10). Upon binding to its ligand HGF, two Met receptors dimerize leading to autophosphorylation of three tyrosine residues (Y1230, CP-96486 Y1234, Y1235; refs. 11, 12; Fig. 1). Following this initial phosphorylation cascade, phosphorylation of two other tyrosine residues (Y1349,Y1356) occurs and these residues serve as docking sites for downstream signaling molecules that mediate Ras/Raf, PI3K/Akt/mTOR, and/or STAT3 pathways (13C15). Met activation has been extensively shown to drive proliferation, migration, invasion, and angiogenesis in HNSCC and other tumor types (16) and HGF/Met activation is a known mechanism of resistance to anti-EGFR therapy (17). Open in a separate window Figure 1. The HGF/Met pathway. The hepatocyte growth factor (HGF) is mainly produced and secreted by the tumor-associated fibroblast (TAF) as an inactive precursor pro-HGF (Step 1 1; ref. 26). Cleavage of pro-HGF to active HGF is facilitated, among others, by the membrane-anchored enzyme matriptase on the cancer cell surface (Step 2 2; ref. 34). HGF binding to Met results in a dimerization of two Met receptor molecules (3). Upon dimerization, activation of both receptors is promoted by transphosphorylation at several binding sites (Y1230, Y1234, Y1235; refs. 11, 12). Further tyrosine residues on the C-terminal end (Y1349, Y1356) become phosphorylated, serving as docking sites for downstream adaptor molecules, such as Grb2-associated binding protein 1 (GAB1; Step 4 4; ref. 16). Importantly, Gab1 as major adaptor molecule for downstream of HGF/Met signaling can bind to Met indirectly via Grb2 (89). Common HGF/Met downstream signaling is mediated by PI3K/Akt/mTOR, Ras/Raf (MAPK signaling pathway) and STAT3 (Step 5; ref. 16). Activation of these downstream pathways drive transcriptomic changes (Step 6), that mediate a plethora of cancer cell phenotypes (Step 7; refs. 26, 35, 42, CP-96486 43). The mechanism by which cancer cells engage TAFs to produce pro-HGF is not fully understood (Step 8). Targeting approaches to the HGF/Met signaling axis is mostly comprised of mAbs (directed against Met or HGF), tyrosine kinase inhibitors (TKI), and/or a NK4 decoy, which is a HGF antagonist (18). Most preclinical studies and clinical trials have focused on the mAbs (e.g., ficlatuzumab, rilotumumab, onartuzumab) or TKIs (e.g., foretinib, crizotinib, tivantinib), leading to phase III studies for tivantinib and crizotinib in lung cancer ( and , respectively) or rilotumumab in gastric cancer (). Importantly, only crizotinib and cabozantinib have received FDA approval for lung adenocarcinoma (19, 20) and RET-positive medullary thyroid carcinoma (21), respectively. Moreover, cabozantinib has shown activity in renal cell carcinoma (22) and was recently FDA approved for this disease. HGF/Met in HNSCC Genomic and proteomic data More than 20% of HNSCC harbor either a copy number gain or amplification of (23, 24) and more than 80% show Met protein overexpression (ref. 25; Fig. 2). The Met ligand, HGF, which is secreted by cells in the surrounding tumor microenvironment in a paracrine manner (26) is overexpressed.Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Introduction The annual incidence of head and neck cancer (HNC) worldwide is about 650,000 cases (1). In 2015, almost 60,000 individuals were diagnosed with a malignancy of the oral cavity, pharynx or larynx in the United States (2). Although 95% of HNC are squamous cell carcinomas (HNSCC), earlier and ongoing genetic profiling underscores the unique heterogeneity of this entity (3, 4). However, one common observation in up to 90% of the HNSCCs is the overexpression of EGFR (5). Major risk factors for the development of HNSCC include tobacco use, excessive alcohol usage, and human being papillomavirus CP-96486 (HPV) illness. Impaired oral hygiene and genetic alterations resulting in susceptibility to malignancies such as Fanconi anemia have also been implicated as risk factors. Depending on site and tumor stage, restorative options include surgery treatment, irradiation, and chemotherapy. Cetuximab, an FDA-approved mAb focusing on EGFR, is the only targeted therapy for HNSCC (6, 7). However, cetuximab treatment results in modest survival benefit in combination with radiation (29.3 vs. 49 weeks) or chemotherapy (7.4 vs. 10.1 months; refs. 6, 7). Activation of alternate signaling pathways, such as the HGF/Met signaling axis, has been implicated to mediate cetuximab resistance (8). HGF/Met Pathway The mesenchymal epithelial transition (Met) element receptor is definitely a receptor tyrosine kinase (RTK) that is encoded from the protooncogene (9). Briefly, the Met receptor consists of a 45 kDa extracellular -chain, linked to a 145-kDa transmembrane -chain via disulphide bonds (10). Upon binding to its ligand HGF, two Met receptors dimerize leading to autophosphorylation of three tyrosine residues (Y1230, Y1234, Y1235; refs. 11, 12; Fig. 1). Following this initial phosphorylation cascade, phosphorylation of two additional tyrosine residues (Y1349,Y1356) happens and these residues serve as docking sites for downstream signaling molecules that mediate Ras/Raf, PI3K/Akt/mTOR, and/or STAT3 pathways (13C15). Met activation has been extensively shown to travel proliferation, migration, invasion, and angiogenesis in HNSCC and additional tumor types (16) and HGF/Met activation is definitely a known mechanism of resistance to anti-EGFR therapy (17). Open in a separate window Number 1. The HGF/Met pathway. The hepatocyte growth factor (HGF) is mainly produced and secreted from the tumor-associated fibroblast (TAF) as an inactive precursor pro-HGF (Step 1 1; ref. 26). Cleavage of pro-HGF to active HGF is definitely facilitated, among others, from the membrane-anchored enzyme matriptase within the malignancy cell surface (Step 2 2; ref. 34). HGF binding to Met results in a dimerization of two Met receptor molecules (3). Upon dimerization, activation of both receptors is definitely advertised by transphosphorylation at several binding sites (Y1230, Y1234, Y1235; refs. 11, 12). Further tyrosine residues within the C-terminal end (Y1349, Y1356) become phosphorylated, providing as docking sites for downstream adaptor molecules, such as Grb2-connected binding protein 1 (GAB1; Step 4 4; ref. 16). Importantly, Gab1 as major adaptor molecule for downstream of HGF/Met signaling can bind to Met indirectly via Grb2 (89). Common HGF/Met downstream signaling is definitely mediated by PI3K/Akt/mTOR, Ras/Raf (MAPK signaling pathway) and STAT3 (Step 5; ref. 16). Activation of these downstream pathways travel transcriptomic changes (Step 6), that mediate a plethora of tumor cell phenotypes (Step 7; refs. 26, 35, 42, 43). The mechanism by which tumor cells participate TAFs to produce pro-HGF is not fully recognized (Step 8). Targeting approaches to the HGF/Met signaling axis is mostly comprised of mAbs (directed against Met or HGF), tyrosine kinase inhibitors (TKI), and/or a NK4 decoy, which is a HGF antagonist (18). Most preclinical studies and clinical tests have focused on the mAbs (e.g., ficlatuzumab, rilotumumab, onartuzumab) or TKIs (e.g., foretinib, crizotinib, tivantinib), leading to phase III studies for tivantinib and crizotinib in lung malignancy ( and , respectively) or rilotumumab in gastric malignancy (). Importantly, only crizotinib and cabozantinib have received FDA authorization for lung adenocarcinoma (19, 20) and RET-positive medullary thyroid carcinoma (21), respectively. Moreover, cabozantinib has shown activity in renal cell carcinoma (22) and was recently FDA approved for this disease. HGF/Met in HNSCC Genomic and proteomic data More than 20% of HNSCC harbor either a copy quantity gain or amplification of (23, 24) and more than 80% display.