title: Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges.
abstract: Lymphangioleiomyomatosis (LAM), a rare lung disease, is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)-like LAM cells, which lead to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. LAM is a disease predominantly affecting women and is exacerbated by pregnancy; only a lung transplant can save the life of a patient. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 protein complex functions as a negative regulator of the mTOR/S6K1 signaling pathway. These two pivotal observations paved the way for the first rapamycin clinical trial for LAM. The recent discoveries that TSC1/TSC2 complex functions as an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy heightened the interest regarding this rare disease because the elucidation of disease-relevant mechanisms of LAM will promote a better understanding of other metabolic diseases such as diabetes, cancer, and cardiovascular diseases. In this review, we will summarize the progress made in our understanding of TSC1/TSC2 cellular signaling and the molecular mechanisms of LAM; we will also highlight some of the lesser explored directions and challenges in LAM research.
authors.affiliation: Department of Medicine, University of Pennsylvania, Pennsylvania, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goncharova
authors.forename: Vera P
authors.initials: VP
authors.lastname: Krymskaya
mesh_terms: D000328:Adult; D000818:Animals; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics / Q000601:surgery; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics / Q000601:surgery; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D010766:Phosphorylation; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000188:drug therapy / Q000601:surgery; D011499:Protein Processing, Post-Translational; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014402:Tuberous Sclerosis / Q000453:epidemiology / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins; D020123:Sirolimus