Functional Analysis of c-Met/Hepatocyte Growth Factor Pathway in Malignant Pleural Mesothelioma

Cancer Research. 66, 352-361, January 1, 2006]. [Link]

Ramasamy Jagadeeswaran1, Patrick C. Ma1, Tanguy Y. Seiwert1, Sujatha Jagadeeswaran1, Osvaldo Zumba1, Vidya Nallasura1, Salman Ahmed1, Rosangela Filiberti2, Michela Paganuzzi2, Riccardo Puntoni2, Robert A. Kratzke3, Gavin J. Gordon4, David J. Sugarbaker4, Raphael Bueno4, Varalakshmi Janamanchi1, Vytas P. Bindokas1, Hedy L. Kindler1 and Ravi Salgia1

1 Section of Hematology/Oncology, Department of Medicine, University of Chicago Cancer Research Center, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois; 2 Environmental Epidemiology and Biostatistics, National Cancer Research Institute, Largo Rosanna Benzi, Genoa, Italy; 3 Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of Minnesota Medical School, Minneapolis, Minnesota; and 4 Department of Surgery, Division of Thoracic Surgery, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts


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-5A (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.