Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model

Endocrine-Related Cancer

Volumn 23, Issue 4, 2016, Pages 265-280

  Prizant, Hen ^a   Taya, Manisha ^a   Lerman, Irina ^a   Light, Allison ^a   Sen, Aritro ^a   Mitra, Soumya ^a   Foster, Thomas H ^a   Hammes, Stephen R ^a  

^a UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

Author keywords

Estrogen; GPNMB; Lymphangioleiomyomatosis; Metalloproteinase; mTOR; Uterus

Indexed keywords

ESTRADIOL; ESTROGEN; GELATINASE A; GELATINASE B; GLYCOPROTEIN; GLYCOPROTEIN NMB; LETROZOLE; LEUKOCYTE ELASTASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MICROPHTHALMIA ASSOCIATED TRANSCRIPTION FACTOR; PROTEINASE; RAPAMYCIN; S6 KINASE; UNCLASSIFIED DRUG; EYE PROTEIN; GPNMB PROTEIN, HUMAN; GPNMB PROTEIN, MOUSE; MATRIX METALLOPROTEINASE; MEMBRANE PROTEIN; MITF PROTEIN, MOUSE; TUBERIN; TUMOR SUPPRESSOR PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; FEMALE; FLUORESCENCE IMAGING; GENE; GENE OVEREXPRESSION; HUMAN; HUMAN TISSUE; IN VIVO STUDY; LUNG; LYMPH NODE; LYMPHANGIOLEIOMYOMATOSIS; MOUSE; MYOMETRIAL TUMOR; MYOMETRIUM; NONHUMAN; OVARIECTOMY; PROTEIN ANALYSIS; PROTEIN EXPRESSION; RAT; RNA SEQUENCE; TSC2 GENE; TUMOR REGRESSION; UPREGULATION; UTERUS TUMOR; ANIMAL; DISEASE MODEL; DRUG EFFECTS; GENETICS; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; TUMOR CELL LINE; UTERUS; UTERUS CANCER;

ANIMALS; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; ESTRADIOL; ESTROGENS; EYE PROTEINS; FEMALE; HUMANS; LEUKOCYTE ELASTASE; LUNG; LYMPH NODES; LYMPHANGIOLEIOMYOMATOSIS; MATRIX METALLOPROTEINASES; MEMBRANE GLYCOPROTEINS; MICE, KNOCKOUT; MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR; RATS; TUMOR SUPPRESSOR PROTEINS; UTERINE NEOPLASMS; UTERUS;

EID: 84976867030     PISSN: 13510088     EISSN: 14796821     Source Type: Journal    
DOI: 10.1530/ERC-15-0505     Document Type: Article

References (73)

1. Ando K, Kurihara M, Kataoka H, Ueyama M, Togo S, Sato T, Doi T, Iwakami S, Takahashi K, Seyama K et al. 2013 Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respiratory Investigation 51 175-183. (doi:10.1016/j. resinv.2013.03.002)
2. Benassayag C, Leroy MJ, Rigourd V, Robert B, Honore JC, Mignot TM, Vacher-Lavenu MC, Chapron C & Ferre F 1999 Estrogen receptors (ERalpha/ERbeta)in normal and pathological growth of the human myometrium: pregnancy and leiomyoma. American Physiological Society 276 E1112-E1118.
3. Berger U, Khaghani A, Pomerance A, Yacoub MH & Coombes RC 1990 Pulmonary lymphangioleiomyomatosis and steroid receptors. An immunocytochemical study. American Journal of Clinical Pathology 93 609-614.
4. Bittmann I, Rolf B, Amann G & Lohrs U 2003 Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis. Human Pathology 34 95-98. (doi:10.1053/hupa.2003.50)
5. Brunelli A, Catalini G & Fianchini A 1996 Pregnancy exacerbating unsuspected mediastinal lymphangioleiomyomatosis and chylothorax. International Journal of Gynecology and Obstetrics 52 289-290. (doi:10.1016/0020-7292(95)02619-3)
6. Carsillo T, Astrinidis A & Henske EP 2000 Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. PNAS 97 6085-6090. (doi:10.1073/pnas.97.11.6085)
7. Chang WY, Cane JL, Blakey JD, Kumaran M, Pointon KS & Johnson SR 2012 Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis. Respiratory Research 13 34. (doi:10.1186/1465-9921-13-34)
8. Chang WY, Cane JL, Kumaran M, Lewis S, Tattersfield AE & Johnson SR 2014 A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. European Respiratory Journal 43 1114-1123. (doi:10.1183/09031936.00167413)
9. Choi YA, Koo JS, Park JS, Park MY, Jeong AL, Oh KS & Yang Y 2014 Estradiol enhances CIP2A expression by the activation of p70 S6 kinase. Endocrine-Related Cancer 21 189-202. (doi:10.1530/ERC-13-0453)
10. Chughtai B & O'Riordan TG 2004 Potential role of inhibitors of neutrophil elastase in treating diseases of the airway. Journal of Aerosol Medicine 17 289-298. (doi:10.1089/jam.2004.17.289)
11. Cockett MI, Murphy G, Birch ML, O'Connell JP, Crabbe T, Millican AT, Hart IR & Docherty AJ 1998 Matrix metalloproteinases and metastatic cancer. Biochemical Society Symposium 63 295-313.
12. El Rayes T, Catena R, Lee S, Stawowczyk M, Joshi N, Fischbach C, Powell CA, Dannenberg AJ, Altorki NK, Gao D et al. 2015 Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1. PNAS 112 16000-16005. (doi:10.1073/pnas.1507294112)
13. Espeillac C, Mitchell C, Celton-Morizur S, Chauvin C, Koka V, Gillet C, Albrecht JH, Desdouets C & Pende M 2011 S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. Journal of Clinical Investigation 121 2821-2832. (doi:10.1172/JCI44203)
14. Fiorentini C, Bodei S, Bedussi F, Fragni M, Bonini SA, Simeone C, Zani D, Berruti A, Missale C, Memo M et al. 2014 GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity. Experimental Cell Research 323 100-111. (doi:10.1016/j.yexcr.2014.02.025)
15. Glassberg MK, Elliot SJ, Fritz J, Catanuto P, Potier M, Donahue R, Stetler- Stevenson W & Karl M 2008 Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness. Journal of Clinical Endocrinology and Metabolism 93 1625-1633. (doi:10.1210/jc.2007-1283)
16. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM et al. 2002 Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). Journal of Biological Chemistry 277 30958-30967. (doi:10.1074/jbc.M202678200)
17. Gu X, Yu JJ, Ilter D, Blenis N, Henske EP & Blenis J 2013 Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. PNAS 110 14960-14965. (doi:10.1073/pnas.1309110110)
18. Haris M, Singh A, Mohammed I, Ittyerah R, Nath K, Nanga RP, Debrosse C, Kogan F, Cai K, Poptani H et al. 2014 In vivo magnetic resonance imaging of tumor protease activity. Science Reports 4 6081. (doi:10.1038/srep06081)
19. Hayashi AA & Proud CG 2007 The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. American Journal of Physiology: Endocrinology and Metabolism 292 E1647-E1655. (doi:10.1152/ajpendo.00674.2006)
20. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J, Ferrans VJ & Travis WD 1997 Immunohistochemical study of matrix metalloproteinases (MMPs)and their tissue inhibitors (TIMPs)in pulmonary lymphangioleiomyomatosis (LAM). Human Pathology 28 1071-1078. (doi:10.1016/S0046-8177(97)90061-7)
21. Hayashi T, Kumasaka T, Mitani K, Terao Y, Watanabe M, Oide T, Nakatani Y, Hebisawa A, Konno R, Takahashi K et al. 2011 Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. American Journal of Surgical Pathology 35 1776-1785. (doi:10.1097/PAS.0b013e318235edbd)
22. Hoashi T, Sato S, Yamaguchi Y, Passeron T, Tamaki K & Hearing VJ 2010 Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein. FASEB Journal 24 1616-1629. (doi:10.1096/fj.09-151019)
23. Howe SR, Gottardis MM, Everitt JI, Goldsworthy TL, Wolf DC & Walker C 1995 Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines. American Journal of Pathology 146 1568-1579.
24. Jimi S, Shono T, Ono M, Kuwano M, Tanaka M, Lopezotin C & Kono A 1997 Expression of matrix metalloproteinases 1 and 2 genes in a possible association with metastatic abilities of human pancreatic cancer cells. International Journal of Oncology 10 623-628. (doi:10.3892/ijo.10.3.623)
25. Karbowniczek M, Astrinidis A, Balsara BR, Testa JR, Lium JH, Colby TV, McCormack FX & Henske EP 2003 Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. American Journal of Respiratory and Critical Care Medicine 167 976-982. (doi:10.1164/rccm.200208-969OC)
26. Kelly J & Moss J 2001 Lymphangioleiomyomatosis. American Journal of the Medical Sciences 321 17-25. (doi:10.1097/00000441-200101000-00004)
27. Kenerson H, Dundon TA & Yeung RS 2005 Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatric Research 57 67-75. (doi:10.1203/01.PDR.0000147727.78571.07)
28. Kinoshita M, Yokoyama T, Higuchi E, Yano H, Watanabe H, Rikimaru T, Ichikawa Y & Oizumi K 1995 Hormone receptors in pulmonary lymphangiomyomatosis. Kurume Medical Journal 42 141-144. (doi:10.2739/kurumemedj.42.141)
29. Klarquist J, Barfuss A, Kandala S, Reust MJ, Braun RK, Hu J, Dilling DF, McKee MD, Boissy RE, Love RB et al. 2009 Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells. American Journal of Pathology 175 2463-2472. (doi:10.2353/ajpath.2009.090525)
30. Kristof AS 2010 mTOR signaling in lymphangioleiomyomatosis. Lymphatic Research and Biology 8 33-42. (doi:10.1089/lrb.2009.0019)
31. Kuhnen C, Preisler K & Muller KM 2001 Pulmonary lymphangioleiomyomatosis. Morphologic and immunohistochemical findings. Der Pathologe 22 197-204. (doi:10.1007/s002920100462)
32. Lee L, Sudentas P, Donohue B, Asrican K, Worku A, Walker V, Sun Y, Schmidt K, Albert MS, El-Hashemite N et al. 2005 Efficacy of a rapamycin analog (CCI-779)and IFN-gamma in tuberous sclerosis mouse models. Genes, Chromosomes and Cancer 42 213-227. (doi:10.1002/gcc.20118)
33. Lesma E, Chiaramonte E, Ancona S, Orpianesi E, Di Giulio AM & Gorio A 2015 Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis. BioMed Research International 2015 315240. (doi:10.1155/2015/315240)
34. Li C, Zhou X, Sun Y, Zhang E, Mancini JD, Parkhitko A, Morrison TA, Silverman EK, Henske EP & Yu JJ 2013 Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. American Journal of Respiratory Cell and Molecular Biology 49 135-142. (doi:10.1165/rcmb.2012- 0476OC)
35. Li C, Lee PS, Sun Y, Gu X, Zhang E, Guo Y, Wu CL, Auricchio N, Priolo C, Li J et al. 2014 Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2- deficient LAM cells. Journal of Experimental Medicine 211 15-28. (doi:10.1084/jem.20131080)
36. Light A & Hammes SR 2015 LH-induced steroidogenesis in the mouse ovary, but not testis, requires matrix metalloproteinase 2- and 9-mediated cleavage of upregulated EGF receptor ligands. Biology of Reproduction 93 65. (doi:10.1095/biolreprod.115.130971)
37. Lin TS, Chiou SH, Wang LS, Huang HH, Chiang SF, Shih AY, Chen YL, Chen CY, Hsu CP, Hsu NY et al. 2004 Expression spectra of matrix metalloproteinases in metastatic non-small cell lung cancer. Oncology Reports 12 717-723. (doi:10.3892/or.12.4.717)
38. Lin P, Lan X, Chen F, Yang Y, Jin Y & Wang A 2013 Reference gene selection for real-time quantitative PCR analysis of the mouse uterus in the peri-implantation period. PLoS One 8 e62462. (doi:10.1371/journal.pone.006246)
39. Loftus SK, Antonellis A, Matera I, Renaud G, Baxter LL, Reid D, Wolfsberg TG, Chen Y, Wang C, Program NCS et al. 2009 Gpnmb is a melanoblast-expressed, MITF-dependent gene. Pigment Cell & Melanoma Research 22 99-110. (doi:10.1111/j.1755-148X.2008.00518.x)
40. Maric G, Rose AA, Annis MG & Siegel PM 2013 Glycoprotein non-metastatic b (GPNMB): a metastatic mediator and emerging therapeutic target in cancer. OncoTargets and Therapy 6 839-852. (doi:10.2147/ott.s44906)
41. Maruo T, Ohara N, Wang J & Matsuo H 2004 Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Human Reproduction Update 10 207-220. (doi:10.1093/humupd/dmh019)
42. Matsui K, Takeda K, Yu ZX, Travis WD, Moss J & Ferrans VJ 2000 Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. Archives of Pathology & Laboratory Medicine 124 267-275.
43. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM et al.2011 Efficacy and safety of sirolimus in lymphangioleiomyomatosis.New England Journal of Medicine 364 1595-1606.(doi:10.1056/NEJMoa1100391)
44. Moraes TJ, Zurawska JH & Downey GP 2006 Neutrophil granule contents in the pathogenesis of lung injury.Current Opinion in Hematology 13 21-27.(doi:10.1097/01.moh.0000190113.31027.d5)
45. Odajima N, Betsuyaku T, Nasuhara Y, Inoue H, Seyama K & Nishimura M 2009 Matrix metalloproteinases in blood from patients with LAM.Respiratory Medicine 103 124-129.(doi:10.1016/j.rmed.2008.07.017)
46. Pacheco-Rodriguez G & Moss J 2010 The role of chemokines in migration of metastatic-like lymphangioleiomyomatosis cells.Critical Reviews in Immunology 30 387-394.(doi:10.1615/critrevimmunol.v30.i4.40)
47. Pimenta SP, Baldi BG, Acencio MM, Kairalla RA & Carvalho CR 2011 Doxycycline use in patients with lymphangioleiomyomatosis: safety and efficacy in metalloproteinase blockade.Jornal Brasileiro de Pneumologia 37 424-430.(doi:10.1590/S1806-37132011000400003)
48. Prizant H, Sen A, Light A, Cho SN, DeMayo FJ, Lydon JP & Hammes SR 2013 Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs.Molecular Endocrinology 27 1403-1414.(doi:10.1210/me.2013-1059)
49. Qian X, Mills E, Torgov M, LaRochelle WJ & Jeffers M 2008 Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate.Molecular Oncology 2 81-93.(doi:10.1016/j.molonc.2008.02.002)
50. Ripoll VM, Irvine KM, Ravasi T, Sweet MJ & Hume DA 2007 Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses.Journal of Immunology 178 6557-6566.(doi:10.4049/jimmunol.178.10.6557)
51. Rose AA, Annis MG, Dong Z, Pepin F, Hallett M, Park M & Siegel PM 2010a ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties.PLoS One 5 e12093.(doi:10.1371/journal.pone.0012093)
52. Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, St-Pierre Y, Simantov R, Hallett M, Park M et al.2010b Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer.Clinical Cancer Research 16 2147-2156.(doi:10.1158/1078-0432.CCR-09- 1611)
53. Ruiz de Garibay G, Herranz C, Llorente A, Boni J, Serra-Musach J, Mateo F, Aguilar H, Gomez-Baldo L, Petit A, Vidal A et al.2015 Lymphangioleiomyomatosis biomarkers linked to lung metastatic potential and cell stemness.PLoS One 10 e0132546.(doi:10.1371/journal.pone.0132546)
54. Sehgal SN 1998 Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.Clinical Biochemistry 31 335-340.(doi:10.1016/S0009- 9120(98)00045-9)
55. Shen A, Iseman MD, Waldron JA & King TE 1987 Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens.Chest 91 782-785.(doi:10.1378/chest.91.5.782)
56. Shen Y, Li Y, Ye F, Wang F, Lu W & Xie X 2010 Identification of suitable reference genes for measurement of gene expression in human cervical tissues.Analytical Biochemistry 405 224-229.(doi:10.1016/j.ab.2010.06.029)
57. Shim B, Pacheco-Rodriguez G, Kato J, Darling TN, Vaughan M & Moss J 2013 Sex-specific lung diseases: effect of oestrogen on cultured cells and in animal models.European Respiratory Review 22 302-311.(doi:10.1183/09059180.00002813)
58. Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG & Henske EP 1998 Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis.American Journal of Human Genetics 62 810-815.(doi:10.1086/301804)
59. Sun Y, Gu X, Zhang E, Park MA, Pereira AM, Wang S, Morrison T, Li C, Blenis J, Gerbaudo VH et al.2014 Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells.Cell Death & Disease 5 e1231.(doi:10.1038/cddis.2014.204)
60. Tanaka H, Imada A, Morikawa T, Shibusa T, Satoh M, Sekine K & Abe S 1995 Diagnosis of pulmonary lymphangioleiomyomatosis by HMB45 in surgically treated spontaneous pneumothorax.European Respiratory Journal 8 1879-1882.(doi:10.1183/09031936.95.08111879)
61. Taveira-DaSilva AM, Hathaway O, Stylianou M & Moss J 2011 Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus.Annals of Internal Medicine 154 797-805.(doi:10.7326/0003-4819-154-12- 201106210-00007)
62. Tomihari M, Hwang SH, Chung JS, Cruz PD Jr & Ariizumi K 2009 Gpnmb is a melanosome-associated glycoprotein that contributes to melanocyte/keratinocyte adhesion in a RGD-dependent fashion.Experimental Dermatology 18 586-595.(doi:10.1111/exd.2009.18.issue-7)
63. Torres C, Linares A, Alejandre MJ, Palomino-Morales R, Martin M, Delgado JR, Martinez J & Perales S 2015 The potential role of the glycoprotein osteoactivin/glycoprotein nonmetastatic melanoma protein B in pancreatic cancer.Pancreas 44 302-310.(doi:10.1097/MPA.0000000000000250)
64. Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, Hackett CS, Shenoy SG, Kuang B, Boldog FL et al.2006 CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.Clinical Cancer Research 12 1373-1382.(doi:10.1158/1078-0432.CCR-05-2018)
65. Urban T, Lazor R, Lacronique J, Murris M, Labrune S, Valeyre D & Cordier JF 1999 Pulmonary lymphangioleiomyomatosis.A study of 69 patients.Medicine 78 321-337.(doi:10.1097/00005792- 199909000-00004)
66. Vinals F, Chambard JC & Pouyssegur J 1999 p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation.Journal of Biological Chemistry 274 26776-26782.(doi:10.1074/jbc.274.38.26776)
67. Woessner JF Jr 1991 Matrix metalloproteinases and their inhibitors in connective tissue remodeling.FASEB Journal 5 2145-2154.
68. Yano S 2002 Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous oestrogen used for infertility treatment.Thorax 57 1085-1086.(doi:10.1136/thorax.57.12.1085)
69. Yoo B, Sheth VR, Howison CM, Douglas MJ, Pineda CT, Maine EA, Baker AF & Pagel MD 2014 Detection of in vivo enzyme activity with CatalyCEST MRI.Magnetic Resonance in Medicine 71 1221-1230.(doi:10.1002/mrm.v71.3)
70. Yu J, Astrinidis A, Howard S & Henske EP 2004 Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic |signaling pathways.American Journal of Physiology: Lung Cellular and Molecular Physiology 286 L694-L700.(doi:10.1152/ajplung.00204.2003)
71. Yu JJ, Robb VA, Morrison TA, Ariazi EA, Karbowniczek M, Astrinidis A, Wang C, Hernandez-Cuebas L, Seeholzer LF, Nicolas E et al.2009 Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells.PNAS 106 2635-2640.(doi:10.1073/pnas.0810790106)
72. Zhe X & Schuger L 2004 Combined smooth muscle and melanocytic differentiation in lymphangioleiomyomatosis.Journal of Histochemistry and Cytochemistry 52 1537-1542.(doi:10.1002/ijc.v136.1)
73. Zoncu R, Efeyan A & Sabatini DM 2011 mTOR: from growth signal integration to cancer, diabetes and ageing.Nature Reviews Molecular Cell Biology 12 21-35.(doi:10.1038/nrm3025)