Minireview: Lymphangioleiomyomatosis (LAM): The "Other" Steroid-Sensitive Cancer

Abstract

Lymphangioleiomyomatosis (LAM) is a devastating rare lung disease affecting primarily childbearing age women in which tumors consisting of abnormal smooth-muscle-like cells grow within the lungs and progressively lead to loss of pulmonary function. LAM cells metastasize to the lungs, predominantly through the lymphatics; however, the source of the LAM cell is still unknown. LAM cells contain inactivating mutations in genes encoding tuberous sclerosis 1 or 2, proteins that normally limit cell growth through suppression of mammalian target of rapamycin complex 1. As of today, sirolimus (an mammalian target of rapamycin complex 1 inhibitor) is the only treatment, available for LAM patients that is approved by the Food and Drug Administration; however, this drug and others in its class provide stabilization but not remission of LAM. One of the biggest problems in treating LAM is that both the origin of the LAM cells and the mechanism of the sexual dimorphism in LAM are still not understood. LAM cells express estrogen and progesterone receptors, and lung function declines during periods of high circulating estrogen levels. Moreover, numerous basic research studies find that estrogen is a key driving force in LAM cell proliferation, migration, and metastasis. In this review, we highlight recent insights regarding the role of steroid hormones in LAM and discuss possible explanations for the profound female sexual dimorphism of LAM.

Figure 1.

Lung LAM cell histology. Hematoxylin and eosin staining of lung tissue with thin walled cyst filled with LAM cells (arrow heads, ×4 magnification, left panel) and of a lung LAM nodule (×10 magnification, right panel).

Figure 2.

LAM cell signaling. In LAM tumor cells, the TSC1/TSC2/TBC1D7 complex is nonfunctional, which allows mTORC1 to be activated and leads to up-regulation of S6K activity, translational machinery, melanocytic differentiation markers, and proteases such as MMPs. This ultimately results in increased cell growth, migration, and metastasis. Importantly, loss of TSC-mediated suppression is not sufficient to fully activate mTOR. In addition, a positive signal must be present, such as estrogen or growth factors, which, through EGF receptor-mediated ERK activation, promotes mTOR and S6K activities. Estrogen may be a major positive signal in LAM; thus, antiestrogen therapy would reduce mTOR and S6K signaling, as well as the downstream processes of proliferation, migration, and invasion.