Malignant mesothelioma (MM) is a very aggressive tumor that causes approximately 2,500 deaths per year in the U.S. MM is incurable unless detected in its earlier stages. The incidence of MM has increased more than that of any other cancer in the past 50 years (from about none in the early 1900s to the current 2-3000 cases/year in the US). This increase is mostly related to the use of asbestos in the shipping and construction industries in the US and Europe until the late 1960s-1970s (asbestos continues to be used in other parts of the world). Because asbestos is difficult and expensive to remove, exposure continues globally to these days. It has been estimated that about 25 million Americans have been exposed to asbestos and are at high risk of developing mesothelioma.
The mechanism of asbestos carcinogenesis is still unclear. In tissue culture, asbestos does not induce transformation of primary human mesothelial cells (HM); instead asbestos is very cytotoxic to HM, causing extensive cell death. This raised an apparent paradox: how can asbestos cause MM if HM exposed to asbestos die? The goal of my research is to identify the mechanisms responsible for asbestos carcinogenesis to develop novel specific approaches for early detection and treatment.
We have found that asbestos induces the secretion of TNF-alpha and the expression of TNF-alpha receptor I in HM. TNF-alpha activates NF-kB and that NF-kB activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data shows a critical role for TNF-alpha and NF-kB signaling in mediating HM responses to asbestos. TNF-alpha allows HM with asbestos-induced DNA damage to divide rather than die. If sufficient genetic damage accumulates, this could eventually develop into a MM. Our results also indicate that blocking TNF-alpha or NF-kB pathway may lead to novel preventive strategies for MM.
In the mean time, we are also performing early detection studies of MM by using two promising biomarkers. The results of these studies are likely to benefit millions people exposed to asbestos and to other carcinogenic mineral fibers in the US and worldwide.
Selected
Publications
Yang H, Pass H and Carbone M. Pathogenesis of mesothelioma. In: Mesothelioma from Bench Side to Clinic. Baldi A. (ed.), (Nova Biomedical, Now York) pp 105-116. 2008.
Beck AK, Pass HI, Carbone M and Yang H. Overview of ranpirnase as a potential anti-tumor ribonuclease treatment for mesothelioma and other malignancies. Future Oncology, 4: 341-349, 2008.
Carbone M, Strianese O, Theos K and Yang H. Mesothelioma. Hawai’i Medical Journal, 66: 48-50, 2007.
Kroczynska B, Cutrone R, Bocchetta M, Yang H, Elmishad AG, Vacek P, Ramos-Nino M, Mossman BT, Pass HI, Carbone M. Crocidolite asbestos and SV40 are co-carcinogens in human mesothelial cells and in causing mesothelioma in hamsters. Proc Natl Acad Sci USA, 103(38): 14128-14133, 2006.
Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G, Carbone M. TNF-a inhibits asbestos induced cytotoxicity via a NF-kB dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci USA, 103(27): 10397-10402, 2006.
