Lymphangioleiomyomatosis — a wolf in sheep’s clothing
Elizabeth P. Henske, Francis X. McCormack
Elizabeth P. Henske, Francis X. McCormack
Published November 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3807-3816. https://doi.org/10.1172/JCI58709.
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Science in Medicine

Lymphangioleiomyomatosis — a wolf in sheep’s clothing

Abstract

Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease of women. LAM is caused by mutations in the tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network. Over the past 11 years, there has been remarkable progress in the understanding of LAM and rapid translation of this knowledge to an effective therapy. LAM pathogenic mechanisms mirror those of many forms of human cancer, including mutation, metabolic reprogramming, inappropriate growth and survival, metastasis via blood and lymphatic circulation, infiltration/invasion, sex steroid sensitivity, and local and remote tissue destruction. However, the smooth muscle cell that metastasizes, infiltrates, and destroys the lung in LAM arises from an unknown source and has an innocent histological appearance, with little evidence of proliferation. Thus, LAM is as an elegant, monogenic model of neoplasia, defying categorization as either benign or malignant.

Authors

Elizabeth P. Henske, Francis X. McCormack

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Figure 5

Future directions in therapy for LAM.

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Future directions in therapy for LAM. (A) Potential cell-autonomous ther...
(A) Potential cell-autonomous therapeutic approaches in LAM include TORC1 inhibitors that may more effectively inhibit TORC1 (including kinase domain inhibitors) and/or have favorable toxicity and/or pharmacokinetic features; autophagy inhibitors; inhibitors of the putative “noncanonical” functions of TSC and Rheb, including Notch activation and Rho activation; direct inhibitors of Rheb’s activity (such as farnesyl transferase inhibitors). (B) Potential non-cell-autonomous therapeutic targets in LAM include inhibition of the lymphatic recruitment and vascular remodeling via inhibition of VEGF or VEGFR; inhibition of MMPs, cathepsin K, and other proteases that contribute to alveolar destruction; inhibition of LAM cells utilizing melanocyte or neural crest antigens as targets; and estrogen antagonism.