Tuesday, June 27th, 2006.

Proceedings of the National Academy of Sciences. 2006 Jun 23; [Epub ahead of print] [Link]

Haining Yang ^a, Maurizio Bocchetta ^a, Barbara Kroczynska ^a, Amira G. Elmishad ^a, Yuanbin Chen ^a, Zemin Liu ^b, Concetta Bubici ^c, Brooke T. Mossman ^d, Harvey I. Pass ^e, Joseph R. Testa ^b, Guido Franzoso ^c, and Michele Carbone ^a

^aThoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153;
^bHuman Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111;
^cThe Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637;
^dDepartment of Pathology, College of Medicine, University of Vermont, Burlington, VT 05404; and
^eDivision of Thoracic Surgery, New York University, New York, NY 10016

Abstract

Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-α and other cytokines that contribute to carcinogenesis through unknown mechanisms. In vitro, asbestos does not induce transformation of primary human mesothelial cells (HM); instead, asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can asbestos cause MM if HM exposed to asbestos die? We found that asbestos induced the secretion of TNF-α and the expression of TNF-α receptor I in HM. Treatment of HM with TNF-α significantly reduced asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and small interfering RNA strategies, we demonstrate that, in HM, TNF-α activates NF-κB and that NF-κB activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data show a critical role for TNF-α and NF-κB signaling in mediating HM responses to asbestos. TNF-α signaling through NF-κB-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both TNF-α and asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of asbestos to transform HM in vitro, elucidate and underscore the role of TNF-α in asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and therapy.

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.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

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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