• Lung Cancer
• Wnt Signalling Pathway
• Bronchioalveolar Carcinoma
• Cancer Stem Cells
• Esophageal Cancer
• Mesothelioma
• Expression Profiling
• Lung Cancer System Genetics
• KRas Pathway
• Other Cancers
• Diagnostics Development

Mesotheliomas are tumors of the lining (pleural) cells of the thoracic cavity, pericardium, and peritoneum and are most commonly associated with prolonged asbestos exposure. Mesothelioma is a relatively uncommon but inexorably fatal carcinoma affecting about 3,000 new patients in the United States annually. Diffuse malignant mesothelioma (MM) comprises about 75% of mesotheliomas diagnosed. Despite advances in cancer treatment, the median survival rate remains low, and most patients die within 10-17 months of their first symptoms. The pathogenesis of the disease remains poorly understood, and the molecular mechanisms by which mesothelial cells undergo neoplastic transformation are largely unknown. The majority of studies on the pathogenesis of MM have focused on asbestos as the primary causative agent.

Although the pathogenesis of asbestos-induced malignancy is not well understood, current evidence suggests that the physicochemical properties of asbestos fibers play an important role in the initiation of an inflammatory response that in turn promotes epithelial cancers by providing growth and survival factors to initiated cells and contributes to tissue remodeling and angiogenesis. Thus, mesothelioma provides yet another platform to study the correlation between inflammation and cancer. Although there is a strong correlation between mesothelioma and asbestos exposure, up to one third of cases have no known association with asbestos-making predictions about the future prevalence of the disease difficult. Interestingly, simian virus-40 (SV40) antigens have been indicated as potential co-carcinogens or alternative carcinogens in MM, which may account for an increased susceptibility among patients with mesothelioma or perhaps a portion of cases with no known asbestos exposure. We are part of a nine-laboratory multicenter investigation into the correlation of mesothelioma with SV40.

Data from our lab have shown that the Wnt signaling pathway is activated in MM as evidenced by increased expression of cytosolic/nuclear beta-catenin and c-Myc, two downstream target genes in the activated pathway. Moreover, we have shown that sFRPs, potential endogenous inhibitors of Wnt, are down-regulated in MMs, and that Dvls, key mediators of the pathway, are overexpressed-both observations hitherto unseen in MM. In addition to illuminating the molecular mechanisms of Wnt signaling in MM, we are also developing molecular therapies to treat this malignancy.

We have demonstrated that WIF-1 expression is down-regulated in both MM cell lines and primary tissue when compared to normal mesothelial cell lines and adjacent pleura, respectively. Our data also suggest that WIF-1 silencing is an important mechanism underlying the constitutively activated Wnt signaling in mesothelioma, and therapies targeting inhibition of the Wnt pathway through WIF-1 might be promising for future treatment of MM.

Furthermore, our lab has discovered that up-regulation of Wnt2 protein is a common event in MM, and we have shown that inhibition of Wnt2 induces apoptosis in the diseased cells. We were able to achieve substantial inhibition of Wnt2 in mesothelioma cell lines using a combination of Wnt2 antibody and Alimta, one of the current standard MM treatments. We thus propose that inhibition of Wnt2 is of therapeutic interest in the development of more effective treatments for MM. In another effort to stymie MM oncogenesis, we were able to down-regulate the expression of Dvl using a reformed type of small interfering RNA (siRNA), stealth RNAi. Dvl stealth RNAi down-regulated the expression of Dvl in mesothelioma cells and induced cell cycle aberration causing suppression of cell growth. Moreover, Dvl stealth RNAi in combination with the chemotherapeutic agent cisplatin suppressed cell growth synergistically. Our group has, additionally, discovered a small molecule inhibitor of Dvl, which inhibits Wnt signaling in lung cancer, and we are currently testing its efficacy in the treatment of mesothelioma.

Despite environmental restrictions on asbestos use and exposure, the 30-40 year latency of this highly lethal disease will not result in a decline in incidence for several more decades. In the mean time, study into its pathogenesis and treatment are vital to improving the lives of patients and elucidating mechanisms of cancer in general.