Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges

J Cell Biochem. 2008 Feb 1;103(2):369-82. doi: 10.1002/jcb.21419.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Animals
  • Combined Modality Therapy
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / epidemiology
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / surgery
  • Lymphangioleiomyomatosis* / drug therapy
  • Lymphangioleiomyomatosis* / epidemiology
  • Lymphangioleiomyomatosis* / genetics
  • Lymphangioleiomyomatosis* / surgery
  • Male
  • Mice
  • Mice, Mutant Strains
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / genetics
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neoplastic Syndromes, Hereditary / genetics
  • Phosphorylation
  • Pregnancy
  • Pregnancy Complications, Neoplastic / drug therapy
  • Pregnancy Complications, Neoplastic / surgery
  • Protein Processing, Post-Translational
  • Rats
  • Signal Transduction / physiology
  • Sirolimus / therapeutic use
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Tuberous Sclerosis / epidemiology
  • Tuberous Sclerosis / genetics
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / metabolism

Substances

  • CRTC1 protein, human
  • CRTC2 protein, human
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Neoplasm Proteins
  • TSC1 protein, human
  • TSC2 protein, human
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tsc1 protein, rat
  • Tsc2 protein, mouse
  • Tsc2 protein, rat
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • rho GTP-Binding Proteins
  • Sirolimus