Am J Respir Cell Mol Biol 36(4): 398-408

Molecular Pathogenesis of Lymphangioleiomyomatosis

Division of Respirology, Department of Medicine, University of Toronto; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Gregory P. Downey, M.D., Executive Vice President Academic Affairs, K701b, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: gro.cjn@gyenwod

Received 2006 Oct 1; Accepted 2006 Oct 16.

Abstract

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.

Keywords: tuberous sclerosis, TSC1, TSC2, mTOR, signal transduction, estrogen

Abstract

CLINICAL RELEVANCE

This review will help clinicians understand the current concepts of the pathogenesis of LAM and apply this knowledge to currently available and experimental treatments for this devastating condition.

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease of uncertain etiology that affects young women. LAM cysts are formed as a result of the proliferation of an abnormal smooth muscle–like cell, the LAM cell. The mechanism by which LAM cells cause this architectural distortion of the lung is unknown. The clinical course of LAM is frequently inexorable, leading to death or lung transplantation in 10 to 15 years, although recent studies indicate that there is much variability in the natural history of the disorder (1, 2). The most common clinical manifestation is the insidious onset of exertional dyspnea; patients may also experience a nonproductive cough. Other common features include spontaneous pneumothorax, which results from cyst rupture, and chylothorax, which results from obstruction of pulmonary lymphatics and hilar lymph nodes by the slowly proliferating LAM cells. Less frequently, hemoptysis or chyloptysis may occur (1, 2).

Most of the current therapies for LAM are supportive in nature. Bronchodilators are offered because many patients have obstructive physiology, often with some degree of reversibility, on pulmonary function testing. Oxygen is provided to patients with significant hypoxia. Current recommendations stipulate pleurodesis for the first pneumothorax, as recurrent pneumothoraces are likely to occur (3). The occurrence of LAM in premenopausal women, and observations that LAM may worsen in pregnancy and with exogenous estrogen therapy, has prompted many clinicians to consider anti-estrogen therapy for this condition. However, whether this approach is effective remains uncertain, as the published studies are retrospective and therefore have the potential for selection bias. Moreover, anti-estrogen therapy may be associated with significant untoward effects. Finally, lung transplantation is a consideration when the forced expiratory volume in one second (FEV₁) approaches 30% of predicted, with rapidly declining lung function associated with a poor quality of life, or when pneumothoraces are recurrent and refractory to pleurodesis.

While LAM occurs spontaneously in otherwise healthy women, it is also observed in as many as 34% of patients (including males) with tuberous sclerosis complex (TSC) (4–6), a congenital disorder associated with multifocal hamartomas, including tumors of the central nervous system, and renal angiomyolipomas (7). The finding that LAM in patients with TSC (TSC-LAM) and sporadic LAM (S-LAM) are histologically indistinguishable has significantly aided research into the cellular and molecular underpinnings of LAM.

In this article, we will describe the current state of knowledge regarding the biology of the abnormal smooth muscle cells observed in LAM lesions, and explore how our evolving understanding of this rare disease has led to novel therapeutic strategies.

Notes

This work was supported by operating grants from the Canadian Institutes of Health Research to G.P.D., and from the National Institutes of Health to F.X.M. (U54 RR019498) and D.J.K. (NS031535).

Originally Published in Press as DOI: 10.1165/rcmb.2006-0372TR on November 10, 2006

Conflict of Interest Statement: D.J.K. is receiving $461,000 in 2006–2008 from Novartis as a research grant for preclinical studies of RAD001 in treatment of TSC mouse models. F.X.M. received Rapamune and $200,000 in trial funding for an upcoming RCT for LAM from Wyeth Pharmaceuticals. G.P.D. and S.C.J. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Notes

This work was supported by operating grants from the Canadian Institutes of Health Research to G.P.D., and from the National Institutes of Health to F.X.M. (U54 RR019498) and D.J.K. (NS031535).

Originally Published in Press as DOI: 10.1165/rcmb.2006-0372TR on November 10, 2006

References

1. Glassberg MKLymphangioleiomyomatosis. Clin Chest Med 2004;25:573–582. (vii.). [[PubMed][Google Scholar]
2. Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, et al. The NHLBI Lymphangioleiomyomatosis Registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006;173:105–111.
3. Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ, Maurer J, McCormack FX, Sahn SAManagement of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129:1274–1281. [[PubMed][Google Scholar]
4. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FXMutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001;164:661–668. [[PubMed][Google Scholar]
5. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, Hedin CJ, Hunsberger S, Kristof ASPrevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669–671. [[PubMed][Google Scholar]
6. Costello LC, Hartman TE, Ryu JHHigh frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000;75:591–594. [[PubMed][Google Scholar]
7. Sparagana SP, Roach ESTuberous sclerosis complex. Curr Opin Neurol 2000;13:115–119. [[PubMed][Google Scholar]
8. Cornog JL Jr, Enterline HTLymphangiomyoma, a benign lesion of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 1966;19:1909–1930. [[PubMed][Google Scholar]
9. Basset F, Soler P, Marsac J, Corrin BPulmonary lymphangiomyomatosis: three new cases studied with electron microscopy. Cancer 1976;38:2357–2366. [[PubMed][Google Scholar]
10. Capron F, Ameille J, Leclerc P, Mornet P, Barbagellata M, Reynes M, Rochemaure JPulmonary lymphangioleiomyomatosis and Bourneville's tuberous sclerosis with pulmonary involvement: the same disease? Cancer 1983;52:851–855. [[PubMed][Google Scholar]
11. Yockey CC, Riepe RE, Ryan KPulmonary lymphangioleiomyomatosis complicated by pregnancy. Kans Med 1986;87:277–278, 293. [[PubMed][Google Scholar]
12. Tomasian A, Greenberg MS, Rumerman HTamoxifen for lymphangioleiomyomatosis. N Engl J Med 1982;306:745–746. [[PubMed][Google Scholar]
13. Winter JAOophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 1981;305:1416–1417. [[PubMed][Google Scholar]
14. Banner AS, Carrington CB, Emory WB, Kittle F, Leonard G, Ringus J, Taylor P, Addington WWEfficacy of oophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 1981;305:204–209. [[PubMed][Google Scholar]
15. Eliasson AH, Phillips YY, Tenholder MFTreatment of lymphangioleiomyomatosis: a meta-analysis. Chest 1989;96:1352–1355. [[PubMed][Google Scholar]
16. Berger U, Khaghani A, Pomerance A, Yacoub MH, Coombes RCPulmonary lymphangioleiomyomatosis and steroid receptors: an immunocytochemical study. Am J Clin Pathol 1990;93:609–614. [[PubMed][Google Scholar]
17. Colley MH, Geppert E, Franklin WAImmunohistochemical detection of steroid receptors in a case of pulmonary lymphangioleiomyomatosis. Am J Surg Pathol 1989;13:803–807. [[PubMed][Google Scholar]
18. Brentani MM, Carvalho CR, Saldiva PH, Pacheco MM, Oshima CTSteroid receptors in pulmonary lymphangiomyomatosis. Chest 1984;85:96–99. [[PubMed][Google Scholar]
19. Matthews TJ, Hornall D, Sheppard MNComparison of the use of antibodies to alpha smooth muscle actin and desmin in pulmonary lymphangioleiomyomatosis. J Clin Pathol 1993;46:479–480. [Google Scholar]
20. Bonetti F, Pea M, Martignoni G, Zamboni G, Iuzzolino PCellular heterogeneity in lymphangiomyomatosis of the lung. Hum Pathol 1991;22:727–728. [[PubMed][Google Scholar]
21. Bonetti F, Chiodera PL, Pea M, Martignoni G, Bosi F, Zamboni G, Mariuzzi GM. Transbronchial biopsy in lymphangiomyomatosis of the lung. HMB45 for diagnosis. Am J Surg Pathol 1993;17:1092–1102. [[PubMed]
22. Hoon V, Thung SN, Kaneko M, Unger PDHMB-45 reactivity in renal angiomyolipoma and lymphangioleiomyomatosis. Arch Pathol Lab Med 1994;118:732–734. [[PubMed][Google Scholar]
23. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, Moss JMarkers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 1999;21:327–336. [[PubMed][Google Scholar]
24. Finlay GThe LAM cell: what is it, where does it come from, and why does it grow? Am J Physiol Lung Cell Mol Physiol 2004;286:L690–L693. [[PubMed][Google Scholar]
25. Kwiatkowski DJTuberous sclerosis: from tubers to mTOR. Ann Hum Genet 2003;67:87–96. [[PubMed][Google Scholar]
26. Sampson JR, Scahill SJ, Stephenson JB, Mann L, Connor JMGenetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet 1989;26:28–31. [Google Scholar]
27. The European Chromosome 16 Tuberous Sclerosis ConsortiumIdentification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75:1305–1315. [[PubMed][Google Scholar]
28. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805–808. [[PubMed]
29. Knudson AG JrMutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–823. [Google Scholar]
30. Carbonara C, Longa L, Grosso E, Borrone C, Garre MG, Brisigotti M, Migone N9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum Mol Genet 1994;3:1829–1832. [[PubMed][Google Scholar]
31. Green AJ, Johnson PH, Yates JRThe tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum Mol Genet 1994;3:1833–1834. [[PubMed][Google Scholar]
32. Henske EP, Neumann HP, Scheithauer BW, Herbst EW, Short MP, Kwiatkowski DJLoss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer 1995;13:295–298. [[PubMed][Google Scholar]
33. Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, Lewin-Kowalik J, Kotulska K, Kwiatkowski DJPathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004;63:1236–1242. [[PubMed][Google Scholar]
34. Astrinidis A, Khare L, Carsillo T, Smolarek T, Au KS, Northrup H, Henske EPMutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis. J Med Genet 2000;37:55–57. [Google Scholar]
35. Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJMolecular genetic advances in tuberous sclerosis. Hum Genet 2000;107:97–114. [[PubMed][Google Scholar]
36. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS, Reeve MP, Thiele E, Egelhoff JC, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64–80.
37. Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JPComprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 1999;64:1305–1315. [Google Scholar]
38. Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, Zonnenberg B, Verhoef S, Halley D, van den Ouweland AMutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet 2005;13:731–741. [[PubMed][Google Scholar]
39. Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EPEvidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet 1998;62:810–815. [Google Scholar]
40. Carsillo T, Astrinidis A, Henske EPMutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97:6085–6090. [Google Scholar]
41. Sato T, Seyama K, Fujii H, Maruyama H, Setoguchi Y, Iwakami S, Fukuchi Y, Hino OMutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. J Hum Genet 2002;47:20–28. [[PubMed][Google Scholar]
42. Plank TL, Yeung RS, Henske EPHamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 1998;58:4766–4770. [[PubMed][Google Scholar]
43. Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RSMulticompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin. Arch Biochem Biophys 2002;404:210–217. [[PubMed][Google Scholar]
44. Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs PCharacterization of the cytosolic tuberin-hamartin complex: tuberin is a cytosolic chaperone for hamartin. J Biol Chem 1999;274:35647–35652. [[PubMed][Google Scholar]
45. Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, Hall AThe TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2000;2:281–287. [[PubMed][Google Scholar]
46. Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, Ramesh VThe TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton. J Biol Chem 2002;277:44180–44186. [[PubMed][Google Scholar]
47. Plank TL, Logginidou H, Klein-Szanto A, Henske EPThe expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas. Mod Pathol 1999;12:539–545. [[PubMed][Google Scholar]
48. van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs PInteraction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998;7:1053–1057. [[PubMed][Google Scholar]
49. Maheshwar MM, Sandford R, Nellist M, Cheadle JP, Sgotto B, Vaudin M, Sampson JRComparative analysis and genomic structure of the tuberous sclerosis 2 (TSC2) gene in human and pufferfish. Hum Mol Genet 1996;5:131–137. [[PubMed][Google Scholar]
50. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LCIdentification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002;10:151–162. [[PubMed][Google Scholar]
51. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002;277:35364–35370. [[PubMed]
52. Inoki K, Li Y, Zhu T, Wu J, Guan KLTSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648–657. [[PubMed][Google Scholar]
53. Liu MY, Cai S, Espejo A, Bedford MT, Walker CL14–3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s). Cancer Res 2002;62:6475–6480. [[PubMed][Google Scholar]
54. Potter CJ, Pedraza LG, Xu TAkt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002;4:658–665. [[PubMed][Google Scholar]
55. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PPPhosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005;121:179–193. [[PubMed][Google Scholar]
56. Li Y, Inoki K, Vacratsis P, Guan KLThe p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14–3-3. J Biol Chem 2003;278:13663–13671. [[PubMed][Google Scholar]
57. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis JTumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004;101:13489–13494. [Google Scholar]
58. Johnson MW, Emelin JK, Park SH, Vinters HVCo-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain Pathol 1999;9:45–54. [[PubMed][Google Scholar]
59. Fukuda T, Kobayashi T, Momose S, Yasui H, Hino ODistribution of Tsc1 protein detected by immunohistochemistry in various normal rat tissues and the renal carcinomas of Eker rat: detection of limited colocalization with Tsc1 and Tsc2 gene products in vivo. Lab Invest 2000;80:1347–1359. [[PubMed][Google Scholar]
60. Murthy V, Haddad LA, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh VSimilarities and differences in the subcellular localization of hamartin and tuberin in the kidney. Am J Physiol Renal Physiol 2000;278:F737–F746. [[PubMed][Google Scholar]
61. Mizuguchi M, Ikeda K, Takashima SSimultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta Neuropathol (Berl) 2000;99:503–510. [[PubMed][Google Scholar]
62. Murthy V, Stemmer-Rachamimov AO, Haddad LA, Roy JE, Cutone AN, Beauchamp RL, Smith N, Louis DN, Ramesh VDevelopmental expression of the tuberous sclerosis proteins tuberin and hamartin. Acta Neuropathol (Berl) 2001;101:202–210. [[PubMed][Google Scholar]
63. Johnson MW, Kerfoot C, Bushnell T, Li M, Vinters HVHamartin and tuberin expression in human tissues. Mod Pathol 2001;14:202–210. [[PubMed][Google Scholar]
64. Catania MG, Johnson MW, Liau LM, Kremen TJ, deVellis JS, Vinters HVHamartin expression and interaction with tuberin in tumor cell lines and primary cultures. J Neurosci Res 2001;63:276–283. [[PubMed][Google Scholar]
65. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IKThe Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001;105:345–355. [[PubMed][Google Scholar]
66. Potter CJ, Huang H, Xu TDrosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001;105:357–368. [[PubMed][Google Scholar]
67. Gao X, Pan DTSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 2001;15:1383–1392. [Google Scholar]
68. Astrinidis A, Henske EPTuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene 2005;24:7475–7481. [[PubMed][Google Scholar]
69. Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda HA mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 2002;11:525–534. [[PubMed][Google Scholar]
70. Kenerson HL, Aicher LD, True LD, Yeung RSActivated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 2002;62:5645–5650. [[PubMed][Google Scholar]
71. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002;277:30958–30967. [[PubMed]
72. Jaeschke A, Hartkamp J, Saitoh M, Roworth W, Nobukuni T, Hodges A, Sampson J, Thomas G, Lamb RTuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 2002;159:217–224. [Google Scholar]
73. Krymskaya VPTumour suppressors hamartin and tuberin: intracellular signalling. Cell Signal 2003;15:729–739. [[PubMed][Google Scholar]
74. Fingar DC, Blenis JTarget of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004;23:3151–3171. [[PubMed][Google Scholar]
75. Nobukini T, Thomas GThe mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Found Symp 2004;262:148–154; discussion 154–159, 265–268. [[PubMed][Google Scholar]
76. Dufner A, Thomas GRibosomal S6 kinase signaling and the control of translation. Exp Cell Res 1999;253:100–109. [[PubMed][Google Scholar]
77. Sehgal SNRapamune (Sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 1995;17:660–665. [[PubMed][Google Scholar]
78. Schmelzle T, Hall MNTOR, a central controller of cell growth. Cell 2000;103:253–262. [[PubMed][Google Scholar]
79. Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MNTOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 1996;7:25–42. [Google Scholar]
80. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B, Pan DTsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002;4:699–704. [[PubMed][Google Scholar]
81. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas GInsulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003;11:1457–1466. [[PubMed][Google Scholar]
82. Inoki K, Li Y, Xu T, Guan KLRheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003;17:1829–1834. [Google Scholar]
83. Castro AF, Rebhun JF, Clark GJ, Quilliam LARheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem 2003;278:32493–32496. [[PubMed][Google Scholar]
84. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BARheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 2003;5:566–571. [[PubMed][Google Scholar]
85. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen ERheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003;5:559–565. [[PubMed][Google Scholar]
86. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis JTuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003;13:1259–1268. [[PubMed][Google Scholar]
87. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan DRheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003;5:578–581. [[PubMed][Google Scholar]
88. Li Y, Inoki K, Guan KLBiochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol 2004;24:7965–7975. [Google Scholar]
89. Nellist M, Sancak O, Goedbloed MA, Rohe C, van Netten D, Mayer K, Tucker-Williams A, van den Ouweland AM, Halley DJDistinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet 2005;13:59–68. [[PubMed][Google Scholar]
90. Blume-Jensen P, Hunter TOncogenic kinase signalling. Nature 2001;411:355–365. [[PubMed][Google Scholar]
91. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJLoss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 2003;112:1223–1233. [Google Scholar]
92. Shah OJ, Wang Z, Hunter TInappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004;14:1650–1656. [[PubMed][Google Scholar]
93. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004;166:213–223.
94. Inoki K, Zhu T, Guan KLTSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577–590. [[PubMed][Google Scholar]
95. El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJPerturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment. Cancer Res 2004;64:3436–3443. [[PubMed][Google Scholar]
96. El-Hashemite N, Kwiatkowski DJInterferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target. Am J Respir Cell Mol Biol 2005;33:227–230. [Google Scholar]
97. Lee L, Sudentas P, Dabora SLCombination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Genes Chromosomes Cancer 2006;45:933–944. [[PubMed][Google Scholar]
98. Lee L, Sudentas P, Donohue B, Asrican K, Worku A, Walker V, Sun Y, Schmidt K, Albert MS, El-Hashemite N, et al. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 2005;42:213–227. [[PubMed]
99. El-Hashemite N, Walker V, Kwiatkowski DJEstrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. Cancer Res 2005;65:2474–2481. [[PubMed][Google Scholar]
100. Finlay GA, York B, Karas RH, Fanburg BL, Zhang H, Kwiatkowski DJ, Noonan DJEstrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2. J Biol Chem 2004;279:23114–23122. [[PubMed][Google Scholar]
101. Finlay GA, Thannickal VJ, Fanburg BL, Kwiatkowski DJPlatelet-derived growth factor-induced p42/44 mitogen-activated protein kinase activation and cellular growth is mediated by reactive oxygen species in the absence of TSC2/tuberin. Cancer Res 2005;65:10881–10890. [[PubMed][Google Scholar]
102. Noonan DJ, Lou D, Griffith N, Vanaman TCA calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis. Arch Biochem Biophys 2002;398:132–140. [[PubMed][Google Scholar]
103. Yu J, Astrinidis A, Howard S, Henske EPEstradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 2004;286:L694–L700. [[PubMed][Google Scholar]
104. York B, Lou D, Panettieri RA Jr, Krymskaya VP, Vanaman TC, Noonan DJCross-talk between tuberin, calmodulin, and estrogen signaling pathways. FASEB J 2005;19:1202–1204. [[PubMed][Google Scholar]
105. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JKInteraction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407:538–541. [Google Scholar]
106. Flores-Delgado G, Anderson KD, Warburton DNongenomic estrogen action regulates tyrosine phosphatase activity and tuberin stability. Mol Cell Endocrinol 2003;199:143–151. [[PubMed][Google Scholar]
107. Astrinidis A, Cash TP, Hunter DS, Walker CL, Chernoff J, Henske EPTuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene 2002;21:8470–8476. [[PubMed][Google Scholar]
108. Goncharova E, Goncharov D, Noonan D, Krymskaya VPTSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. J Cell Biol 2004;167:1171–1182. [Google Scholar]
109. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MNMammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:1122–1128. [[PubMed][Google Scholar]
110. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DMRictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296–1302. [[PubMed][Google Scholar]
111. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DMGbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11:895–904. [[PubMed][Google Scholar]
112. Crawford HC, Matrisian LMTumor and stromal expression of matrix metalloproteinases and their role in tumor progression. Invasion Metastasis 1994;14:234–245. [[PubMed][Google Scholar]
113. Yu J, Astrinidis A, Henske EPChromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Respir Crit Care Med 2001;164:1537–1540. [[PubMed][Google Scholar]
114. Matsui K, Takeda K, Yu ZX, Valencia J, Travis WD, Moss J, Ferrans VJDownregulation of estrogen and progesterone receptors in the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy: an immunohistochemical study. Am J Respir Crit Care Med 2000;161:1002–1009. [[PubMed][Google Scholar]
115. Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, Ferrans VJRole for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med 2000;124:267–275. [[PubMed][Google Scholar]
116. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J, Ferrans VJ, Travis WDImmunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol 1997;28:1071–1078. [[PubMed][Google Scholar]
117. Rajah R, Nunn SE, Herrick DJ, Grunstein MM, Cohen PLeukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells. Am J Physiol 1996;271:L1014–L1022. [[PubMed][Google Scholar]
118. Schneider BS, Maimon J, Golub LM, Ramamurthy NS, Greenwald RATetracyclines inhibit intracellular muscle proteolysis in vitro. Biochem Biophys Res Commun 1992;188:767–772. [[PubMed][Google Scholar]
119. Ginns LC, Roberts DH, Mark EJ, Brusch JL, Marler JJPulmonary capillary hemangiomatosis with atypical endotheliomatosis: successful antiangiogenic therapy with doxycycline. Chest 2003;124:2017–2022. [[PubMed][Google Scholar]
120. Moses MA, Harper J, Folkman JDoxycycline treatment for lymphangioleiomyomatosis with urinary monitoring for MMPs. N Engl J Med 2006;354:2621–2622. [[PubMed][Google Scholar]
121. Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, Hayashi S, Minami M, Uekusa T, Fukuchi Y, et al. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol 2004;28:1007–1016. [[PubMed]
122. Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol 2005;29:1356–1366. [[PubMed]
123. Travis WD, Usuki J, Horiba K, Ferrans VJHistopathologic studies on lymphangioleiomyomatosis. In J. Moss, editor. LAM and other diseases characterized by smooth muscle proliferation. New York: Marcel Dekker, Inc.; 1999. pp. 171–217.
124. Dauwerse JG, Bouman K, van Essen AJ, van Der Hout AH, Kolsters G, Breuning MH, Peters DJAcrofacial dysostosis in a patient with the TSC2-PKD1 contiguous gene syndrome. J Med Genet 2002;39:136–141. [Google Scholar]
125. Henske EPTuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol 2005;20:854–857. [[PubMed][Google Scholar]
126. Mendel DB, Laird AD, Smolich BD, Blake RA, Liang C, Hannah AL, Shaheen RM, Ellis LM, Weitman S, Shawver LK, et al. Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drug Des 2000;15:29–41. [[PubMed]
127. Mross K, Drevs J, Muller M, Medinger M, Marme D, Hennig J, Morgan B, Lebwohl D, Masson E, Ho YY, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 2005;41:1291–1299. [[PubMed]
128. Jones-Bolin S, Zhao H, Hunter K, Klein-Szanto A, Ruggeri BThe effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. Mol Cancer Ther 2006;5:1744–1753. [[PubMed][Google Scholar]
129. Fritz G, Kaina BRho GTPases: promising cellular targets for novel anticancer drugs. Curr Cancer Drug Targets 2006;6:1–14. [[PubMed][Google Scholar]
130. Gau CL, Kato-Stankiewicz J, Jiang C, Miyamoto S, Guo L, Tamanoi FFarnesyltransferase inhibitors reverse altered growth and distribution of actin filaments in Tsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways. Mol Cancer Ther 2005;4:918–926. [[PubMed][Google Scholar]
131. Inoki K, Corradetti MN, Guan KLDysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005;37:19–24. [[PubMed][Google Scholar]
132. Manning BDBalancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004;167:399–403. [Google Scholar]