1. ¹Department of Pathology, Columbia University College of Physicians & Surgeons, New York, NY, USA
2. ²Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA

Correspondence: Dr CA Powell, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, 630 West 168th Street, Box 91, New York, NY 10032, USA. E-mail: cap6@columbia.edu

³Current address: IV Divisione Oncologia e Dermatologia Oncologica, IDI IRCCS, Roma, Italy.

Received 15 December 2005; Revised 8 May 2006; Accepted 6 June 2006; Published online 24 July 2006.

Abstract

Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin–proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin–proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.