C-met is usually overexpressed in prostate cancer (Chau CM, etal, AACR98, Abs. 1444:211)

C-met is overexpressed in a lesser degree in breast cancer and may lead to invasiveness (Chau CM, etal, AACR98, Abs. 1444:211).

Germline missense mutations in the c-MET receptor are implicated in hereditary papillary renal cell carcinoma (RCC).

Scientists at Nagasaki University School of Medicine and Nagasaki Hospital, in Japan, investigated the role of 2 phosphorylation tyrosine sites on c-Met in tumor progression of renal cell carcinoma (RCC). In the RCC cell line ACHN, phosphorylation at Y1234/Y1235 was maximal at 30 minutes upon hepatocyte growth factor (HGF) stimulation followed by rapid inactivation, whereas phosphorylation at Y1349 was detected at 120 minutes post-stimulation. Median rates (range) of cancer cells immunopositive for pY1234/pY1235 HGFr/c-Met and pY1349 HGFr/c-Met in the tumor sections were 0% (0-5.2%) and 14.3% (0-64.3%), respectively. Phosphorylation at Y1349 was associated with high pathologic tumor stage, metastasis, and high grade carcinoma. Phosphorylation at Y1349 was an independent predictor of cause-specific survival in multivariate Cox analysis. These results suggest c-Met is important in RCC progression, and phosphorylation at Y1349 may be predictive of metastasis and survival in patients with RCC (Miyata Y, etal, Clinical Cancer Research, 15 August 2006; 12:4876-81).

Scientists at University of Chicago investigated the contribution of c-Met activation to reactive oxygen species generation and motility of small cell lung cancer (sclc) cells. When c-Met overexpressing sclc cell line H69 was stimulated with hepatocyte growth factor (HGF), reactive oxygen species increased, whereas c-Met nonexpressing cell line H446 showed no response. Reactive oxygen species production was higher in cell lines harboring juxtamembrane-mutated variants, R988C and T1010I, compared to those with wildtype (wt) c-Met. Pyrrolidine dithiocarbamate and c-Met inhibitor, SU11274, inhibited the reactive oxygen species response and abrogated HGF-induced proliferation and motility in a cooperative manner. Hydrogen peroxide induced phosphorylation of c-Met and downstream phosphorylation of Akt, ERK1/2, and paxillin in sclc cell lines. These results suggest that c-Met and downstream pathways leading to reactive oxygen species production may provide therapeutic intervention strategies (Jagadeeswaran R, etal, Am J Physiol Lung Cell Mol Physiol 2007;292:L1488-94).

Investigators at Merck Research Laboratories (Boston, MA) evaluated non-small cell lung cancer (nsclc) cell lines for c-Met gene amplification, receptor expression, pathway activation, and sensitivity to c-Met specific shRNA. The c-Met gene was amplified in 2 cell lines, EBC-1 and H1993, with the receptor overexpressed and constitutively phosphorylated. Gene amplification and receptor overexpression was not detected in 7 other cell lines in which c-Met was phosphorylated only upon stimulation by hepatocyte growth factor (HGF). The phosphorylation of beta-catenin and p120-catenin were strongly upregulated in EBC-1 and H1993 cells. C-Met knockdown by shRNA inhibited cell growth, induced G1-S arrest and apoptosis in these cells. C-Met specific shRNA did not affect the other 7 cell lines. These results suggest the subset of nsclc with c-Met amplification may respond to c-Met targeted therapies (Lutterbach B, etal, Cancer Research, 1 March 2007;67:2081-8).

Investigators at Genentech (South San Francisco, CA) identified a c-Met deletion that plays a role in ligand-dependent activation in lung cancer. This deletion led to loss of Cbl E3-ligase binding site in the juxtamembrane domain via somatic intronic mutations that result in an alternatively spliced transcript. Ubiquitinylation of the mutant receptor was decreased and receptor downregulation was delayed resulting in elevated c-Met expression in primary tumors. Phosphorylation of c-Met and downstream MAPK activation was therefore sustained upon stimulation by hepatocyte growth factor (HGF). The deletion mutant also led to higher HGF-mediated cell proliferation and in vivo tumor growth. An HGF-competitive c-Met antagonist inhibited mutant c-Met activation and tumor cell proliferation. These results indicate a role of c-Met in lung cancer and identified its deletion mutant as a novel mechanism in the modulation of receptor expression (Kong-Beltran M, etal, Cancer Res, 1 January 2006;66:283-9).

According to investigators at the University of Chicago Medical Center (Chicago, IL), Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School (Boston, MA), BioSource International (Camarillo, CA), and Pfizer (San Diego, CA), c-Met is overexpressed, activated, and/or mutated in non-small cell lung cancer (nsclc) cell lines and tumor tissues. All of 23 nsclc tumor tissues and 8 out of 9 cell lines expressed c-Met. Overexpression was detected in 61% of tumors with adenocarcinoma being the most prevalent at 67%. Phosphorylation of c-Met at Y1003 and Y1230/1234/1235 was detected preferentially in the tumor’s invasive fronts. Mutations of c-Met at E168D, L299F, S323G, and N375S were localized in the semaphoring domain, and R988C, R988C/T1010I, and S1058P were in the juxtamembrane domain. Alternative splice variants omitting the entire juxtamembrane domain were also found in nsclc cell lines and adenocarcinoma tissues. Downregulation of c-Met expression by siRNA to 50-60% inhibited phosphorylation of c-Met and Akt, and reduced cell viability to 57.1 ± 7.2% in cell lines. SU11274, a c-Met inhibitor, similarly inhibited viability in these cells. It also abrogated hepatocyte growth factor (HGF)-induced phosphorylation of c-Met and downstream signaling. These results suggest c-Met inhibition as a potential therapeutic strategy for nsclc (Ma PC, etal, Cancer Res, 15 February 2005;65:1479-88).

Because c-met is frequently overexpressed in lung cancer and there is a strong correlation between c-met overexpression and decreased patient survival, the HGF/c-met signaling pathway is a potential target for tumor control. The c-met protein was down regulated by 40-60% in two lung cancer cell lines, 201-T and 128-88T (Stabile LA, etal, AACR03, Abs. R774).

Phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells (Ma PC, etal, Cancer Metastasis Rev, Dec 2003;22(4):309-25).

C-met protein was overexpressed in 63 of 95 (66%) serous and 19 of 24 (79%) mucinous human ovarian carcinomas. Overexpression of c-met protein significantly correlated with poor prognosis using either all serous carcinomas, or Stage III serous carcinomas. Both c-met mRNA and protein were upregulated in 13 of 20 (65%) human ovarian carcinoma cell lines as compared to 0 of 8 normal human ovarian surface epithelial (HOSE) cell cultures. Levels of activated c-met protein were increased in the majority of these ovarian carcinoma cell lines and were significantly correlated to the total c-met expression (r = 0.81). Based on these findings total c-met is overexpressed in the majority of malignant ovarian epithelial cells both in vivo and in vitro, and the level of activated c-met protein is significantly correlated to the level of total c-met protein in vitro (Koon EC, etal, AACR03, Abs. R1357).

Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas. Experimental data suggest a putative roleof c-met in melanomagenesis and progression of cutaneous malignant melanoma. C-met expression was evaluted in a cohort of 62 primary cutaneous malignant melanoma patients diagnosed and primarily treated at the same institution. Membranous and cytoplasmic pattern of c-met expression was significantly associated with presence of vertical growth phase, thick tumors, ulceration, high mitotic index, lymphatic and vascular invasion, and nodal and combined (nodal and/or visceral) metastases, and also proved to be a significant prognostic factor for overall survival in univariate analysis (Cruz J, etal, Oncology 2003;65(1):72-82).

Expression levels of HGF/SF and c-Met were examined in a panel of 10 cell lines to assess their role in regulating the invasiveness of pancreatic cancer cells. Expression of HGF/SF was absent in all cell lines and c-Met was overexpressed at varying levels in 9 of the 10 cell lines. These results suggest that pancreatic cancer cells respond to HGF/SF through a paracrine signaling pathway. To test the responsiveness of these cells lines to HGF/SF, transwell migration assays were performed using CFPAC-1 (c-Met positive) and MiaPaCa-2 (c-Met negative) cells. Media containing HGF/SF had greater than a three-fold effect on CFPAC-1 migration, while MiaPaCa-2 was not significantly affected. Analysis of the gene expression profiles of HGF/SF-treated CFPAC-1 and MiaPaCa-2 cells produced 22 genes specifically upregulated in CFPAC-1 (c-Met positive) cells. These genes represent potential mediators of HGF/SF signaling and include K-ras, ROCK1, Lyn, TRAF5 and ARNO all of which have been shown to play roles in cell motility and migration. In addition, HGF/SF treated CFPAC-1 cells showed significant downregulation of 42 genes. Interestingly, several of the downregulated genes are known negative regulators of cell migration such as APC and the tight junction protein, ZO-1. These data provide important new insight into the cell response downstream of HGF/SF and c-Met and may provide new targets for drug development in pancreatic and other tumors (Warner SL, etal, AACR02, Abs. LB42).

Investigators at Academic Medical Center (Amsterdam, the Netherlands) examined c-Met expression and signaling in the pathogenesis of B-cell malignancies. They had previously shown that c-Met signaling controlled survival and proliferation in multiple myeloma. In a panel of 110 B-cell malignancies, c-Met expression was largely confined to diffuse large B-cell lymphoma (30%) and multiple myeloma (48%). The c-Met gene was not amplified in diffuse large B-cell lymphoma. Mutation R1166Q in tyrosine kinase domain was detected in 1 patient sample whereas mutation R988C in the juxtamembrane domain was detected in 4 patient samples. R988C mutation enhanced tumorigenesis. Hepatocyte growth factor (HGF) induced MEK-dependent activation of ERK, and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a, and alpha4/beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. In the tumor microenvironment, diffuse large B-cell lymphoma cells produced serine protease HGF activator, that in turn autocatalyzed the activation of HGF that was secreted by macrophages. These results suggest that c-Met signaling and secretion of serine protease HGF activator by diffuse large B-cell lymphoma may contribute to lymphomagenesis (Tjin EPM, etal, Blood, 15 January 2006;107(2):760-8).

In a panel of 110 B-cell malignancies, c-Met expression was present in 48% of multiple myeloma cases (Tjin EPM, etal, Blood, 15 January 2006;107(2):760-8).

Investigators at University of Chicago Medical Center (Chicago, IL), National Cancer Research Institute (Genoa, Italy), University of Minnesota Medical School (Minneapolis, MN), and Dana-Farber Cancer Institute, Harvard Medical School (Boston, MA) studied the role of c-Met in malignant pleural mesothelioma. C-Met was overexpressed and activated in most mesothelioma cell lines tested. Its expression in malignant pleural mesothelioma was 82% higher than that in normal tissues. Circulating hepatocyte growth factor (HGF) was 2-fold higher in serum of patients with mesothelioma than in healthy controls. In various mesothelioma cell lines, HGF stimulated cell growth and activation of Akt and ERK1/2 differentially. SU11274, a c-Met inhibitor, inhibited cell growth in these cell lines except H2052, H2452, and nonmalignant MeT-5A. SU11274 and c-Met specific siRNA inhibited migration of H28 cells that strongly expressed c-Met. Abrogation of HGF induced c-Met and downstream signaling was detected in mesothelioma cells. Mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and exon 10 deletion in c-Met, were detected in some of the 43 malignant pleural mesothelioma tissues and 7 cell lines tested. Relative to H28 cells with wild type (wt) c-Met and nonmalignant MeT-5A cells, SU11274 reduced cell growth most robustly in H513 and H2596 cell lines with T1010I mutation. These results suggest c-Met is an important target for therapy against malignant pleural mesothelioma (Jagadeeswaran R, etal, Cancer Research, 1 January, 2006; 66:352-61).

Investigators at Memorial Sloan-Kettering Cancer Center (New York, NY), Dana-Farber Cancer Institute (Boston, MA), and Johns Hopkins Hospital (Baltimore, MD) examined if c-Met is a transcriptional target of ASPS-TFE3. TFE3 is a basic helix-loop-helix leucine zipper transcriptional factor. Expression of oncogenic TFE3 fusion proteins defines a subset of pediatric renal adenocarcinoma. In alveolar soft part sarcoma (ASPS), the expression of fusion protein ASPS-TFE3 is common. C-Met is over-expressed in ASPS relative to other types of primitive sarcoma. ASPS-TFE3 bound to and activated c-Met promoter. Two other TFE3 proteins fused with pre-mRNA splicing factors, PSF-TFE3 and NonO-TFE3, also bound to c-Met promoter. ASPS-TFE3 induced c-Met expression, resulting in c-Met autophosphorylation and downstream signaling in response to hepatocyte growth factor (HGF). In cancer cell lines expressing TFE3-fusion proteins, c-Met specific RNAi and c-Met inhibitor, PHA665752, abolished HGF-dependent c-Met activation, decreased cell growth, and induced loss of HGF-dependent phenotypes. These results suggest when oncogenic TFE3 fusion proteins upregulated c-Met transcription, cancer cells became dependent on c-Met signaling. Both c-Met and signaling pathways upregulated by oncogenic fusion proteins may represent potential therapeutic targets for ASPS (Tsuda M, etal, Cancer Research, 1 February, 2007;67:919-29).

According to investigators at the University of Chicago Medical Center, c-Met was expressed in 6 of 7 melanoma cell lines by immunoblotting. Also, a new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88% of melanoma samples and 15% of nevi, and that c-Met (pY1003) was activated in 21% of cases of human melanoma (Puri N, etal, Clin Cancer Res, 1 Apr 2007;13(7):2246-53; rsalgia@medicine.bsd.uchicago.edu).