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Smooth Muscle–like Cells in Pulmonary Lymphangioleiomyomatosis

¹ Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Vera P. Krymskaya, Ph.D., Translational Research Laboratories, Suite 1200, Room 1212, 125 South 31st Street, Philadelphia, PA 19104-3403. E-mail: krymskay{at}mail.med.upenn.edu

ABSTRACT

Proliferation, migration, and differentiation of smooth muscle (SM)–like lymphangioleiomyomatosis (LAM) cells in the lungs are pathologic manifestations of pulmonary LAM, a rare lung disease predominantly afflicting women and exacerbated by pregnancy. LAM cells form nodules throughout the lung without any predominant localization, but can also form small cell clusters dispersed within lung parenchyma. LAM cells have the appearance of "immature" SM-like cells, irregularly distributed within the nodule in contrast to organized SM cell layers in airways and vasculature. Progressive growth of LAM cells leads to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. Pathogenetically, LAM occurs from somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2. The TSC1/TSC2 protein complex is an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy. The observation that the TSC1/TSC2 functions as a negative regulator of the mammalian target of rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling pathway yielded the first rapamycin clinical trial for LAM. Although LAM is a rare lung disease, the elucidation of disease-relevant mechanisms of LAM will provide a better understanding of not only SM-like cell growth, migration, and differentiation in LAM but may also offer insights into other metabolic diseases such as cardiovascular diseases, diabetes, and cancer. In this article, we will summarize the progress made in our understanding of LAM, and we will focus on how dysregulation of TSC1/TSC2 signaling results in abnormal proliferation and migration of SM-like LAM cells.

Key Words: lung cancer • TSC1 • TSC2 • signal transduction • mesenchymal cells

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