Lymphangioleiomyomatosis — a wolf in sheep’s clothing
Elizabeth P. Henske, Francis X. McCormack
Elizabeth P. Henske, Francis X. McCormack
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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 3

Hypothesis for LAM progression.

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Hypothesis for LAM progression. LAM cells have smooth muscle cell featur...
LAM cells have smooth muscle cell features and originate from an unknown source; renal angiomyolipomas and uterine lesions have been proposed as potential primaries. These cells proliferate and drive a lymphangiogenic program that results in demarcation of tissue by chaotic lymphatic channels and the formation of LAM cell islands surrounded by lymphatic endothelium, which then bud into the lumen of the lymphatic system (i). These LAM cell clusters ascend the lymphatic tree by serial cycles of implantation and shedding (ii) and are transported by lymphatic flow to the venous circulation (iii) and ultimately impact in the pulmonary microvasculature (iv). Modified from ref. 28.