Tepotinib in patients with NSCLC harbouring MET exon 14 skipping: Japanese subset analysis from the Phase II VISION study.

BACKGROUND: MET exon 14 skipping is an oncogenic driver occurring in 3-4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib. METHODS: In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned. RESULTS: As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months' follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients' quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively). CONCLUSIONS: Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable.

Correlation of c-MET and CXCR4 proteins and microvessel density with liver metastasis in colorectal cancer / 肿瘤研究与临床

Objective:To explore the correlation of c-MET and CXCR4 proteins and microvessel density (MVD) with liver metastasis in colorectal cancer tissues.Methods:A total of 40 colorectal cancer tissue samples and 10 paracancerous (5 cm from the edge of the tumor) normal colorectal tissue samples were collected from March 2015 to December 2020 in Shanxi Traditional Chinese Medical Hospital. Among 40 patients with colorectal cancer, 15 patients had liver metastasis. Immunohistochemistry was used to detect c-MET protein, CXCR4 protein and CD34-labeled MVD in various tissues, and the relationships between them and liver metastasis and between the three were analyzed.Results:The positive rates of c-MET protein [72.5% (29/40) vs. 30.0% (3/10)], CXCR4 protein [47.5% (19/40) vs. 10.0% (1/10)] and MVD (20.1±5.2 vs. 11.5±4.3) in colorectal cancer tissues were higher than those in paracancerous tissues, and the differences were statistically significant (all P < 0.05). The positive rates of c-MET protein [86.7% (13/15) vs. 64.0% (16/25)] and CXCR4 protein [66.7% (10/15) vs. 36.0% (9/25)] in colorectal cancer liver metastasis group were significantly higher than those in non-liver metastasis group, and the differences were statistically significant (both P < 0.05). MVD in colorectal cancer liver metastasis group was significantly higher than that in non-liver metastasis group (21.5±5.3 vs. 12.4±5.7), and the difference was statistically significant ( P < 0.05). In colorectal cancer tissues, c-MET protein expression was positively correlated with CXCR4 protein expression ( r = 0.568, P < 0.05), and MVD in c-MET-positive patients or CXCR4-positive patients was higher than that in negative ones (both P < 0.05). Conclusions:The c-MET protein, CXCR4 protein and MVD may play important roles in the liver metastasis of colorectal cancer. The three indicators can provide a certain reference for the early diagnosis and prognosis prediction of liver metastasis of colorectal cancer.

Prognostic value of PSMA, c-MET and E-cadherin in salivary duct carcinoma.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.

[Chromophobe renal cell carcinoma-diagnosis and prognosis]. / Chromophobes Nierenzellkarzinom ­ Diagnostik und Prognostik.

Chromophobe renal cell carcinoma is one of four malignant kidney tumor subtypes. Due to its morphological variance in clinical pathological routine diagnostics, this subtype can cause certain difficulties. The tumor can be mistaken for more aggressive or benign tumors. In both cases the consequences of misdiagnosis regarding treatment decisions can be serious. Due to the morphological variance of the tumor, it has not yet been possible to develop a generally accepted, prognostically convincing graduation scheme. The aim is to improve the quality of diagnostics and estimation of prognosis for this subtype of tumor in order to optimize patient care.

Expression of c-Met and c-Src in non-small cell lung cancer and its relationship with prognosis / 中国医师进修杂志

Objective To explore the expressions of c-Met and c-Src in non-small cell lung cancer (NSCLC), and its relationship with clinical pathological characters and prognosis. Methods The c-Met and c-Src expressions were detected by immunohistochemistry in 88 patients with NSCLC from April 2011 to January 2013. The relationship between the expressions of c-Met and c-Src and clinical pathological features and prognosis were analyzed. Results The c-Met and c-Src were all significantly expressed in NSCLC tissues, and no expression showed in interstitial and normal lung tissues. The expressions of c-Met and c-Src in patients with NSCLC were associated with sex, differentiation, pathology type, T staging and TNM staging (P<0.05 or <0.01); and the expression of c-Met was associated with lymph node metastasis (P<0.01). The expressions of c-Met and c-Src in patients with NSCLC were not associated with age, and the expression of c-Src was not associated with lymph node metastasis (P>0.05). Pearson correlation analysis result showed that the expressions of c-Met and c-Src in lung cancer tissues was positive correlation (r=0.662, P<0.01). Kaplan-Meier survival curve analysis result showed that the disease free survival time (DFS) and overall survival time (OS) in c-Met high expression patients (51 cases) were significantly shorter than those in c-Met low expression patients (37 cases): (18.08 ± 1.34) months vs. (23.76 ± 1.79) months and (33.63 ± 1.95) months vs. (42.24 ± 2.68) months, the DFS and OS in c-Src high expression patients (25 cases) were significantly shorter than those in c-Src low expression patients (63 cases): (16.96 ± 2.56) months vs. (21.86 ± 1.15) months and (27.84 ± 2.89) months vs. (40.98 ± 1.81) months, the DFS and OS in both c-Met and c-Src high expression patients (25 cases) were significantly shorter than those in both c-Met and c-Src low expression patients (37 cases): (16.96 ± 2.56) months vs. (23.76 ± 1.79) months and (27.84 ± 2.89) months vs. (42.24 ± 2.68) months, and there were statistical differences (P<0.05). Cox multiplicity result showed that T staging (RR=2.174, 95％CI 1.354 to 3.490, P=0.001) and high expressions of c-Met and c-Src (RR=1.447, 95％CI 1.114 to 1.880, P=0.006) were the independent risk factors of DFS in patients with NSCLC;pathology type (RR=0.610, 95％CI 0.377 to 0.986, P=0.044), T staging (RR=2.215, 95％CI 1.357 to 3.616, P=0.001) and high expressions of c-Met and c-Src (RR=1.979, 95％CI 1.455 to 2.692, P = 0.000) were the independent risk factors of OS in patients with NSCLC. Conclusions The c-Met and c-Src are involved in the development of NSCLC and affect the prognosis of patients with NSCLC.

Correlation between expression of C-met and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in lung adenocarcinoma / 肿瘤研究与临床

Objective To detect C-met protein expression and gene amplification in lung adenocarcinoma, and to analyze their relationship with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance and prognosis. Methods A total of 120 cases of lung adenocarcinoma diagnosed in Shanxi Provincial Cancer Hospital from January 2011 to May 2013 were selected. The expressions of C-met protein and C-met gene amplification were conducted by immunohistochemistry (IHC) method and fluorescence in situ hybridization (FISH), and all patients were followed up. The relationship between the expression of C-met protein and gene amplification with clinicopathological features and EGFR-TKI resistance and prognosis were analyzed. Results The high expression of C-met protein and gene amplification in 120 tissues were 17.5 ％ (21/120), 10.83 ％ (13/120). Of the 80 patients treated with EGFR-TKI, the incidence of C-met protein high expression was 30.43 ％ (14/46) in patients with drug resistance, which was significantly higher than that in patients without drug resistance (11.76 ％, 4/34), the difference was statistically significant (χ2= 3.908, P= 0.048). The rate of C-met gene amplification was 19.57 ％ (9/46) in patients with drug resistance,which was significantly higher than that in patients without drug resistance (2.94 ％, 1/34) the difference was statistically significant (P= 0.038). The expression of C-met protein in 46 patients with drug resistance was positively correlated with gene amplification (r= 0.388, P= 0.008), but in 40 patients without TKI, the expression of C-met protein was not correlated with gene amplification (r=0.279, P=0.081). The high expression of C-met protein was correlated with age, pathological grade and clinical stage (all P<0.05), while C-met gene amplification was related to clinical stage (P=0.036). Cox regression analysis suggested that C-met gene amplification was an independent prognostic factor (P= 0.034). Conclusions C-met protein expression and gene amplification are risk factors for EGFR-TKI resistance. C-met gene amplification suggests poor prognosis, and can be used as an independent factor for prognostic evaluation.

Role of Recepteur D'origine Nantais on Gastric Cancer Development and Progression.

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase belonging to the subfamily of which c-MET is the prototype. Large epidemiologic studies have confirmed the strong association between RON and gastric cancer development. Constitutive activation of RON signaling directly correlates with tumorigenic phenotypes of gastric cancer and a poor survival rate in advanced gastric cancer patients. In this review, we focus on recent evidence of the aberrant expression and activation of RON in gastric cancer tumors and provide insights into the mechanism of RON signaling associated with gastric cancer progression and metastasis. Current therapeutics against RON in gastric cancer are summarized.

Role of Recepteur D'origine Nantais on Gastric Cancer Development and Progression / 전남의대학술지

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase belonging to the subfamily of which c-MET is the prototype. Large epidemiologic studies have confirmed the strong association between RON and gastric cancer development. Constitutive activation of RON signaling directly correlates with tumorigenic phenotypes of gastric cancer and a poor survival rate in advanced gastric cancer patients. In this review, we focus on recent evidence of the aberrant expression and activation of RON in gastric cancer tumors and provide insights into the mechanism of RON signaling associated with gastric cancer progression and metastasis. Current therapeutics against RON in gastric cancer are summarized.

Expression of bcl-2 and c-Met genes in non-small cell lung cancer cell lines harboring different mutations of epidermal growth factor receptor / 肿瘤研究与临床

Objective To detect the expression of bcl-2 and c-Met genes in lung cancer cell lines with different mutations of epidermal growth factor receptor (EGFR), in order to explore the association between expression of bcl-2 and c-Met genes and drug resistance in non-small cell lung cancer (NSCLC). Methods Direct sequencing was used to detect EGFR mutations status in HCC827 cells, A549 cells and H1975 cells. Immunocytochemistry was conducted to test bcl-2 and c-Met expression. RT-PCR was performed to analyzed bcl-2 gene expression and ARMS was used to detect EGFR mutations status in malignant pleural effusion of NSCLC patients. Results A549 cells, HCC827 cells and H1975 cells were EGFR wild type, EGFR exon 19 deletion (19del), and EGFR exon 21 L858R and exon 20 T790M double mutations. c-Met and bcl-2 protein located in cytoplasm and the intensity of positive expression was highest in HCC827 cells, followed by A549 cells and H1975 cells. The bcl-2 mRNA expression was higher in HCC827 and A549 cells than that in H1975 cells (10.93±1.90 vs. 0.83±0.15, P=0.013; 7.13±1.33 vs. 0.83±0.15, P= 0.000). However bcl-2 mRNA expression was not associated with EGFR mutations (wild type, 19del and L858R) in malignant pleural effusion of NSCLC patients. Conclusion bcl-2 and c-Met gene in HCC827 cells (EGFR 19del) expression is significantly higher than those in H1975 cells (EGFR L858R/T790M), implying EGFR L858R mutations and 19del mutations may be regulated by different signaling pathways.

Research progress of HGF/c-MET signaling pathway inhibitors in anti-pancreatic cancer / 国际肿瘤学杂志

Pancreatic cancer is one of the most malignant tumors.Targeted therapy has become an important part of the treatment of pancreatic cancer.The signaling pathways such as hepatocyte growth factor/c-MET (HGF/c-MET) signaling pathway, inhibition of which may exerts an antitumor effect, play extremely important roles in the occurrence and development of pancreatic cancer.Therefore, the research of HGF/c-MET targeted inhibitors opens up a new avenue for treatment of pancreatic cancer.

Expression of the c-MET, HGF and VEGF biomarkers in intestinal and diffuse gastric cancer in the Brazilian population: a pilot study for the standardization of the quantitative PCR technique

Background: Gastric carcinoma (GC) is the third leading cause of death among malignant tumors worldwide, causing approximately 900,000 deaths/year. Changes in oncogenes that encode tyrosine kinase receptors play an important role in the pathogenesis of GC. MET gene is a proto-oncogene that encodes a tyrosine kinase receptor c-MET and it is required for embryonic development and tissue repair. The hepatocyte growth factor (HGF) is the only known ligand for c-Met receptor. The MET oncogene activation suppresses apoptosis and promotes the survival, proliferation, migration, differentiation and angiogenesis of cells. Among the angiogenic factors, VEGF is the main regulator. Its biological function includes the promotion of endothelial cells mitosis to stimulate cells proliferation. These biomarkers expression in GC is relatively recent and population-based studies are required to define the expression pattern. The aim of this study was to determine qPCR technical standardization to evaluate quantitatively, in paraffin tissue samples, the presence of gene 23 expression of the MET, HGF and VEGF in diffuse and intestinal GC types. Methods: Twenty GC patients were studied, 10 patients were intestinal-type GC (average age 72.1 years) and 10 diffuse-type (average age 50.1 years). In all patients, tissue samples were analyzed from the tumor and distant areas of the tumor tissue. The relative expressions of the tumor markers c-Met, HGF and VEGF were performed by qPCR technique by comparing tumor and non-tumoral samples and they were normalized with the GAPDH constitutive gene. Statistical analysis was performed through T-test. Results: For c-Met, 18/20 (90%) patients expressed the marker and 9/20 (45%) overexpressed this gene, in which three were intestinal-type GC and six were diffuse-type GC. For HGF, only 7/20 (35%) patients expressed this gene and it was overexpressed in 4/20 (20%), in which two were intestinal-type GC and two were diffuse-type GC. For VEGF, 20/20 (100%) patients expressed this marker and in 12/20 (60%) were observed overexpression, in which eight patients had diffuse-type GC and four had intestinal-type GC. Conclusions: qPCR technique was standardized and suitable for expression analysis of the three biomarkers using paraffin embedded tissue samples. Further studies should be carried out to characterize the expression pattern of these biomarkers in GC in the Brazilian population (AU)

Role of Recepteur D'origine Nantais on Gastric Cancer Development and Progression / 전남의대학술지

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase belonging to the subfamily of which c-MET is the prototype. Large epidemiologic studies have confirmed the strong association between RON and gastric cancer development. Constitutive activation of RON signaling directly correlates with tumorigenic phenotypes of gastric cancer and a poor survival rate in advanced gastric cancer patients. In this review, we focus on recent evidence of the aberrant expression and activation of RON in gastric cancer tumors and provide insights into the mechanism of RON signaling associated with gastric cancer progression and metastasis. Current therapeutics against RON in gastric cancer are summarized.

Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: a Danish cohort study.

PURPOSE: We aimed to investigate the prevalence and prognostic impact of tumor mesenchymal epithelial transition factor (MET) expression in stage IV gastric cancers in a real-world clinical setting because existing evidence is sparse. METHODS: The study included archived cancer specimens from 103 stage IV gastric cancer patients (2003-2010). We analyzed MET-protein expression by immunohistochemistry (MET-positive if ≥25% of tumor cells showed MET expression). We calculated overall survival using the Kaplan-Meier method and hazard ratios comparing mortality among MET-positive and MET-negative patients using Cox regression adjusted for age, gender, and comorbidity. RESULTS: We found that 62.1% (95% confidence interval, 52.0-71.5) of patients had MET-positive tumors. Median survival was lower among patients with MET-positive tumors (3.5 months) than among patients with MET-negative tumors (9.6 months), corresponding to an adjusted hazard ratio of 2.2 (95% confidence interval, 1.3-3.7). CONCLUSIONS: Tumor MET expression is prevalent and has substantial prognostic impact in stage IV gastric cancer patients.

Metastasis-associated in colon cancer 1 and its role in cancer / 国际肿瘤学杂志

The protein product of metastasis-associated in colon cancer 1 (MACC1) gene induces the activation of hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) signaling pathway through transcriptionally activating c-Met gene and upregulating its expression to further promote tumor invasion and metastasis.High level expression of MACC1 is associated with the occurrence and metastasis of a wide variety of human tumors, such as colon cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer etc.In addition, the overexpression of MACC1 is also closely associated with clinical TNM stages and distant metastasis.Thus, MACC1 can serve as an independent indicator of tumor metastasis and prognosis, and become a new target for gene therapy.

Pharmacodynamic screening of anticancer agents used as c-Met inhibitor in vitro and in vivo / 天津医药

Objective To screen 8 series of LY compounds, c-Met tyrosine kinase inhibitors, and evaluate their anti-tumor effects in vitro and in vivo. Methods Preliminary screening was carried out by detecting the c-Met kinase phosphor?ylation inhibition activity of the compounds. CCK-8 assay was adopted for secondary anti-tumor screen of the selected com?pounds using MKN-45, U87MG, Caki-1 and PC-3 cell lines in vitro. The transplanted tumor model of U87MG cells in nude mice was established to evaluate the antitumor activity in vivo. Results Four compounds (LY22, LY25, LY28 and LY32) with better activities were selected by HTRF method, in which LY28 had better inhibitory effect on c-Met than that of Crizo?tinib. The above active compounds showed different degrees of inhibition on the four kinds of target cells (MKN-45, U87MG, Caki-1 and PC-3) detected by CCK-8 method, and the inhibitory effect of LY28 showed the most obvious. Antitumor activi?ty in vivo showed that LY28 can significantly inhibited tumor growth in a dose-dependent manner. The tumor inhibitory rate in high-dose of LY28 was 78.13%. Conclusion The compound LY28 has good antitumor activity in vitro and in vivo, which will be a new tyrosine kinase inhibitor.

Expression of c-MET in Invasive Meningioma.

BACKGROUND: Meningiomas show high recurrence rates even after curative tumor removal. The invasiveness of meningiomas may contribute to their high recurrence rates. Recently, c-MET and hepatocyte growth factor (HGF) have been reported to be involved in cancer invasion. METHODS: We examined the immunohistochemical expression of c-MET and HGF in 100 cases of patients with meningiomas who have undergone complete tumor removal. RESULTS: c-MET(-High) and HGFHigh were found in 17% and 13% of meningiomas, respectively. Brain invasion was observed in 17.6% of c-MET(-High) meningiomas, but in only 2.4% of c-MET(-Low) meningiomas (p=.033). Bone/soft tissue invasion was observed in 23.5% of c-MET(-High) meningiomas and in 9.6% of c-MET(-Low) meningiomas (p=.119). HGF(-High) did not show statistical association with brain invasion or bone/soft tissue invasion. c-MET(-High) demonstrated shorter recurrence-free survival (RFS, 93.5±8.2 months vs 96.1±1.9 months); however, this difference was not statistically significant (p=.139). There was no association of HGF(-High) with RFS. CONCLUSIONS: This study demonstrates that c- MET(-High) is associated with brain invasion of meningiomas, and that c-MET expression may be a useful predictive marker for meningioma recurrence. Patients with invasive meningiomas with high expressions of c-MET may be good candidates for targeted therapy using c-MET inhibitors.

Research progress in c-Met and hepatocellular carcinoma / 临床肝胆病杂志

c-Met plays a pivotal role in the development and progression of hepatocellular carcinoma (HCC), which can lead to proliferation, survival, cytoskeleton reorganization, separation and diffusion, and angiogenesis of tumor cells. Moreover, c-Met is an important prognostic factor for HCC. In HCC, c-Met acts as an activator of a series of signaling pathways, including PI3K/AKT/mTOR, ERK/MAPK, and Rac-Pak. In recent years, it has been reported that small-molecule kinase inhibitors can abolish phosphorylation at the intracellular carboxyl terminal of c-Met, and then inhibit the recruitment of signal convertors and downstream signaling pathways, which finally achieve anti-tumor activities. Based on the carcinogenic activity of c-Met in HCC, this paper points out that selective inhibitors of c-Met hold promise for targeted therapies for HCC.

Expressions of MACC1 and c-Met genes in prostate cancer tissues / 天津医药

Objective This study is to investigate the expressions of MACC1 and c-Met genes in prostate cancer tis?sues and to explore the relationship between these gene expressions with the development, invasion and metastasis of pros?tate cancer. Methods The expressions of MACC1 and c-Met genes were examined in 30 cases of benign prostatic hyperpla?sia and 67 cases of prostate cancer using citron acid-microwave-SP immunohistochemical method and analysed with their clinical pathological features. Results Expressions of MACC1 and c-Met in prostate tissues show statistical difference ac?cording to Gleason score, PSA level, pathological stages and whether bone metastasis occurs after radical surgery ( P<0.05 or P < 0.01), but their expressions in prostate tissue show no significant difference among different sex, age and whether smoking or not. Expression of MACC1 in prostate tissue of stageⅢandⅣcancer is significantly higher than that in benign prostatic hyperplasia (BPH) tissues (P<0.05) while the expression of c-Met only shows statistical difference in prostate tis?sue of stage Ⅳcancer compared with that in BPH (P < 0.05). There is a positive correlation between the expression of MACC1 with expression of c-Met in prostate cancer tissues (P<0.01). Kaplan-Meier curves revealed that the survival rates was lower and survival time of bone-free metastasis were shorter in patients with high MACC1 and c-Met expressions in prostate tissue than those with low expressions of MACC1 and c-Met in prostate tissue. Conclusion Expression of MACC1 and c-Met is closely related to the development, invasion and metastasis of prostate cancer, so MACC 1 and c-Met may be used as promising diagnostic and prognostic markers for prostate tumor, and as new therapeutic targets for prostate cancer.

Expression of c-MET in Invasive Meningioma

BACKGROUND: Meningiomas show high recurrence rates even after curative tumor removal. The invasiveness of meningiomas may contribute to their high recurrence rates. Recently, c-MET and hepatocyte growth factor (HGF) have been reported to be involved in cancer invasion. METHODS: We examined the immunohistochemical expression of c-MET and HGF in 100 cases of patients with meningiomas who have undergone complete tumor removal. RESULTS: c-MET(-High) and HGF(-High) were found in 17% and 13% of meningiomas, respectively. Brain invasion was observed in 17.6% of c-MET(-High) meningiomas, but in only 2.4% of c-MET(-Low) meningiomas (p=.033). Bone/soft tissue invasion was observed in 23.5% of c-MET(-High) meningiomas and in 9.6% of c-MET(-Low) meningiomas (p=.119). HGF(-High) did not show statistical association with brain invasion or bone/soft tissue invasion. c-MET(-High) demonstrated shorter recurrence-free survival (RFS, 93.5+/-8.2 months vs 96.1+/-1.9 months); however, this difference was not statistically significant (p=.139). There was no association of HGF(-High) with RFS. CONCLUSIONS: This study demonstrates that c-MET(-High) is associated with brain invasion of meningiomas, and that c-MET expression may be a useful predictive marker for meningioma recurrence. Patients with invasive meningiomas with high expressions of c-MET may be good candidates for targeted therapy using c-MET inhibitors.

Development and characteristics of preclinical experimental models for the research of rare neuroendocrine bladder cancer.

PURPOSE: For rare cancers such as neuroendocrine bladder cancer treatment options are limited due partly to the lack of preclinical models. Techniques to amplify rare primary neuroendocrine bladder cancer cells could provide novel tools for the discovery of drug and diagnostic targets. We developed preclinical experimental models for neuroendocrine bladder cancer. MATERIALS AND METHODS: Fresh tumor tissue from 2 patients with neuroendocrine bladder cancer was used to establish in vitro and in vivo models. We analyzed additional archived tissues in the National Center of Tumor Diseases tissue bank from patients with neuroendocrine bladder cancer. Primary tumor samples were collected during radical cystectomy. PHA-665752 was used to inhibit MET in animal models and cell cultures. The expression of markers and drug targets in neuroendocrine bladder cancer was determined by flow cytometry. The growth of neuroendocrine bladder cancer in vitro was determined by counting live cells. Tumor growth in mice was assessed by measuring tumor volume. Groups were compared using the nonparametric Kruskal-Wallis test. RESULTS: Xenograft models and serum-free cultures of neuroendocrine bladder cancer cells allowed screening for cell surface markers and drug targets. We found expression of the HGF receptor MET in neuroendocrine bladder cancer cultures, xenograft models and primary patient sections. The growth of neuroendocrine bladder cancer spheroids in vitro depended critically on HGF. Treatment of neuroendocrine bladder cancer bearing mice with a MET inhibitor significantly decreased tumor growth compared to that in control treated mice. CONCLUSIONS: Neuroendocrine bladder cancer xenografts and serum-free cultures provided suitable models in which to identify diagnostic markers and therapeutic targets. Using the models, we noted HGF dependent growth of human neuroendocrine bladder cancer and identified MET as a new treatment target for neuroendocrine bladder cancer.