Monday, January 9th, 2006.

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

Abstract

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.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

mutation

a change; a change in a gene.

epidemiology

(ep-uh-deem-ee-AHL-uh-gee) the study of diseases in populations by collecting and analyzing statistical data. In the field of cancer, epidemiologists look at how many people have cancer; who gets specific types of cancer; and what factors (such as environment, job hazards, family patterns, and personal habits, such as smoking and diet) play a part in the development of cancer.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

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