Lymphangioleiomyomatosis (LAM), the pulmonary manifestation of tuberous sclerosis complex (TSC), is a devastating disease affecting women, often leading to end-stage lung disease during or soon after pregnancy. The pathogenesis of LAM is very unusual: LAM cells are histologically benign smooth muscle cells carrying TSC2 mutations that are believed to transfer or metastasize to the lungs, where they cause lung degeneration. The only proven treatment for LAM is lung transplantation, which carries significant 1-year mortality and after which LAM can recur in the transplanted lungs.
The reasons that LAM affects women almost exclusively are not yet clearly defined, and animal models that mimic the metastatic behavior of LAM cells have not been previously developed. Our animal model provides in vivo evidence that estrogen promotes the survival and metastasis of Tsc2-null cells and allows us to investigate the possibility that targeting COX-2 pathways may have a major role in the treatment of TSC and LAM. In addition, this model will allow other novel agents and/or combinations of existing agents to be tested preclinically. This will further facilitate the eventual development of effective therapies for TSC and LAM, which are urgently needed.
|
