TY - JOUR
T1 - Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma
AU - Jagadeeswaran, Ramasamy
AU - Ma, Patrick C.
AU - Seiwert, Tanguy Y.
AU - Jagadeeswaran, Sujatha
AU - Zumba, Osvaldo
AU - Nallasura, Vidya
AU - Ahmed, Salman
AU - Filiberti, Rosangela
AU - Paganuzzi, Michela
AU - Puntoni, Riccardo
AU - Kratzke, Robert A.
AU - Gordon, Gavin J.
AU - Sugarbaker, David J.
AU - Bueno, Raphael
AU - Janamanchi, Varalakshmi
AU - Bindokas, Vytas P.
AU - Kindler, Hedy L.
AU - Salgia, Ravi
PY - 2006/1/1
Y1 - 2006/1/1
N2 - c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 μmol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-SA (IC50 >10 μmol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM.
AB - c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 μmol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-SA (IC50 >10 μmol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM.
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U2 - 10.1158/0008-5472.CAN-04-4567
DO - 10.1158/0008-5472.CAN-04-4567
M3 - Article
C2 - 16397249
AN - SCOPUS:31544482729
SN - 0008-5472
VL - 66
SP - 352
EP - 361
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -