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Relevance of LAM to Common Life-Threatening Diseases
  • LAM provides a unique opportunity for research. Although rare, LAM is well understood at a molecular and cellular level, and lies at the intersection of pathways involved in several more common diseases, including sporadic cancers and diabetes.
  • LAM cells are very similar to cells found in the lungs of patients with a genetic disorder called tuberous sclerosis complex (TSC).1 As many as 39 percent of women with TSC also have LAM.2 In TSC, usually benign tumors grow in the brain, kidneys, heart, eyes, lungs, skin and elsewhere. When it is not accompanied by LAM, TSC is usually treatable; however, it can have serious effects including seizures, developmental delays, and kidney disease.3
  • TSC and LAM seem to be affected by mutations in one of two tumor suppressor genes, TSC1 (which encodes a protein called hamartin) and TSC2 (encoding a protein called tuberin). One of the major functions of the tuberin-hamartin protein complex is to inhibit protein synthesis and limit the growth and proliferation of cells. Growth factors such as insulin activate an enzyme called Akt, which inhibits tuberin-hamartin function and thus increases protein synthesis. The tuberin-hamartin complex is also regulated by another enzyme called AMPK, which inhibits protein synthesis when energy levels in cells drop.4
  • The tuberin-hamartin complex - in combination with Akt, AMPK and a third protein, Rheb - plays a role in a key regulator of cell growth and proliferation, called mTOR.
  • The mTOR pathway regulates cell growth and survival in response to changes in levels of nutrients, energy sources, and growth factors.6 Several clinical trials are investigating inhibition of the mTOR pathway as a potential treatment approach for solid tumors such as those of the breast, prostate, and kidney, as well as certain hematologic malignancies. The mTOR disease pathway has also been implicated in type 1 and 2 diabetes,7 atherosclerosis,8 fibrosis,9 and several neurological disorders beyond TSC including Huntington disease10 and epilepsy.11
  • The mTOR pathway comes in two flavors because the mTOR protein is part of two distinct multiprotein complexes that contain mTOR and different interacting proteins. One complex is defined by the protein raptor and this complex is called mTORC1. mTORC1 is likely to be directly activated by rheb. The second complex is defined by the protein rictor and this complex is called mTORC2. mTORC2 activates the Akt kinase which regulates tuberin-hamartin.12 The potential role of tuberin-hamartin and rheb in regulating mTORC2 is unknown.
  • Despite the evidence that the tuberin-harmartin regulates mTOR there are increasing clues that this complex and rheb have other targets besides mTOR. Certain features of neurons that have lost tuberin-hamartin function are not affected when cells are treated with an mTOR inhibitor.13
  • Recently, scientists have found that mTORC1suppresses signaling by the PI3 Kinase pathway that is the key activator of Akt. Therefore, inhibition of mTORC1 can lead to activation of Akt and activated Akt is thought to promote tumorigenesis. Because loss of tuberin-hamartin (as occurs in LAM) activates mTORC1 it also suppresses Akt.14 Therefore, inhibition or activation of mTORC1 with drugs or genetic mutations will also have effects on Akt signaling. The implications for LAM and TSC of these effects on Akt are currently unknown.
  • Scientists looking for new drugs to inhibit the action of the mTOR pathway are intensely interested in tuberin, hamartin, and Rheb. Compounds that modify the function of those proteins and regulate mTOR activity could be studied as possible treatments for a large array of diseases, many of them life-threatening. It is important to keep in mind that mTOR inhibition is unlikely to affect other potential targets of tuberin-hamartin and rheb that may have a role in pathophysiology of LAM.
  1. Finlay G. The LAM cell: what is it, where does it come from, and why does it grow? Am J Physiol Lung Cell Mol Physiol. 2004 Apr;286(4):L690-3. [PubMed]
  2. McCormack F et al. Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysis. Chest. 2002 Mar;121(3 Suppl):61S [PubMed]
  3. US National Institutes of Health. National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Fact Sheet. Accessed 3 Nov 2005: http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. pdated 13 Oct 2005.
  4. Multi-Disciplinary Tuberous Sclerosis Program. Research Update. Accessed: 17 Jan 2006: http://www.tsclinic.org/research_update.php. No date.
  5. Li Y et al. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci. 2004 Jan;29(1):32-8. [PubMed]
  6. Boulay A et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004;64:252-261. [PubMed]
  7. McDaniel ML et al. Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. Diabetes. 2002 Oct;51(10):2877-85. [PubMed]
  8. Martin KA et al. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 2004 Mar;286(3):C507-17. [PubMed]
  9. Shegogue D. Mammalian target of rapamycin positively regulates collagen type I production via a phosphatidylinositol 3-kinase-independent pathway. J Biol Chem. 2004 May 28;279(22):23166-75. [PubMed]
  10. Ravikumar B et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genetics 2004 Jun;36(6):585-95. [PubMed]
  11. National Institute of Neurological Disorders and Stroke. New Perspectives In Tuberous Sclerosis Complex Conference Summary. September 19-22, 2002. Accessed 16 Nov 2005: http://www.ninds.nih.gov/news_and_events/proceedings/2002_tsc_conference.htm. Updated 9 February 2005.
  12. Tavazoie SF et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. 2005 Dec;8(12):1727-34. [PubMed]
  13. Sarbassov DD et al. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR complex. Science. 2005. 307:1098-1101. [PubMed]
  14. Manning BD et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 2005 Aug 1;19(15):1773-8. [PubMed]
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