mTOR Signaling in Lymphangioleiomyomatosis

Abstract

The protein mammalian target of rapamycin (mTOR) plays a central role in cell growth and proliferation. Excessive mTOR activity is a prominent feature of many neoplasms and hamartoma syndromes, including lymphangioleiomyomatosis (LAM), a destructive lung disease that causes progressive respiratory failure in women. Although pharmacological inhibitors of mTOR should directly target the pathogenesis of these disorders, their clinical efficacy has been suboptimal. Recent scientific findings reviewed here have greatly improved our understanding of mTOR signaling mechanisms, provided new insights into the control of cell growth and proliferation, and facilitated the development of new therapeutic approaches in LAM, as well as other neoplastic disorders that exhibit excessive mTOR activity.

Paradoxical Effects of Rapamycin on Experimental House Dust Mite-Induced Asthma

“…mTOR complex 1 (mTORC1) controls nutrient-sensitive protein synthesis and cell growth primarily via the initiation of translation and ribosomal biogenesis, whereas mTORC2 controls cytokinesis and cell survival via distinct effector kinases [20], [21]. Novel adaptor proteins define the functions of these mTOR complexes.…”

Regulation of Karyopherin α1 and Nuclear Import by Mammalian Target of Rapamycin

“…FoxO3A, NF-B, and p53) is likely to represent an important step in the elaboration of their target transcriptional programs, as well as a potential therapeutic target (40). This may be especially relevant in diseases of excessive mTOR activity, such as lymphangioleiomyomatosis or tuberous sclerosis complex (41). Our studies, and those of others, indicate that the nuclear content of latent STAT1 can be regulated by mTOR, PP2Ac, and KPNA1 and can determine the inducibility of genes involved in innate immunity, immune modulation, and oncogenesis (11,16,29,32,41,42).…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease that is etiologically associated with excessive proliferation of LECs (lymphangio) and smooth muscle cells (leiomyoma) throughout the lungs including bronchioles, alveolar septa, perivascular spaces, and parenchyma (Hohman et al 2008;Darling et al 2010;Kristof 2010;Kwiatkowski 2010;Seyama et al 2010). The abnormal proliferation of these two types of cells (LECs and SMCs) in LAM results in both obstruction of airways and tissue fluid drainage, causing pulmonary cyst formation, pneumothorax, and chylous pleural effusion with respiratory failure, needing lung transplantation.…”

“…Importantly, LAM patients express a high level of the potent lymphangiogenic factor VEGF-D in their blood serums, which may partly explain the excessive LEC proliferation in their lungs. Because mutations in TSC1/2 lead to abnormal activation of the downstream effector mTOR, rapamycin, a chemical inhibitor for mTOR, was found to be beneficial to some LAM patients (Darling et al 2010;Kristof 2010). Kaposi's sarcoma (KS) is an endothelial cell tumor and the most common neoplasm among HIV-positive individuals .…”