Abstract
PTEN/MMAC1/TEP1 (hereafter PTEN) is a tumor suppressor gene (located at 10q23) that is frequently mutated or deleted in sporadic human tumors. PTEN encodes a multifunctional phosphatase, which negatively regulates cell growth, migration and survival via the phosphatidylinositol 3′-kinase/AKT signalling pathway. Accordingly, Pten+/− mice develop various types of tumors including teratocarcinomas and teratomas. We have investigated PTEN expression in 60 bioptic specimens of germ cell tumors (32 seminomas, 22 embryonal carcinomas and six teratomas) and 22 intratubular germ cell neoplasias (ITGCN) adjacent to the tumors for PTEN protein and mRNA expression. In total, 10 testicular biopsies were used as controls. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not an early event in testicular tumor development. The loss of PTEN expression occurs mainly at the RNA level as determined by in situ hybridization of cellular mRNA (17/22) but also it may involve some kind of post-transcriptional mechanisms in the remaining 25% of cases. Analysis of microsatellites D10S551, D10S541 and D10S1765 in GCTs (n=22) showed LOH at the PTEN locus at 10q23 in at least 36% of GCTs (three embryonal carcinoma, three seminoma, two teratoma); one seminoma and one embryonal (9%) carcinoma presented an inactivating mutation in the PTEN gene (2/22). Finally, we demonstrated that the phosphatidylinositol 3′-kinase/AKT pathway, which is regulated by the PTEN phosphatase, is crucial in regulating the proliferation of the NT2/D1 embryonal carcinoma cells, and that the cyclin-dependent kinase inhibitor p27kip1 is a key downstream target of this pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andrews PW . (1984). Dev. Biol., 103, 285–293.
Baldassarre G, Barone MV, Belletti B, Sandomenico C, Bruni P, Spiezia S, Boccia A, Vento MT, Romano A, Pepe S, Fusco A and Viglietto G . (1999). Oncogene, 18, 6241–6251.
Baldassarre G, Boccia A, Bruni P, Sandomenico C, Barone MV, Pepe S, Angrisano T, Belletti B, Motti ML, Fusco A and Viglietto G . (2000). Cell Growth Differ, 11, 517–526.
Baldassarre G, Romano A, Armenante F, Rambaldi M, Paoletti I, Sandomenico C, Pepe S, Staibano S, Salvatore G, De Rosa G, Persico MG and Viglietto G . (1997). Oncogene, 15, 927–936.
Bruni P, Boccia A, Baldassarre G, Trapasso F, Santoro M, Chiappetta G, Fusco A and Viglietto G . (2000). Oncogene, 19, 3146–3155.
Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS and Sidransky D . (1997). Cancer Res., 57, 4997–5000.
Chaganti RSK and Houldsworth J . (2000). Cancer Res., 60, 1475–1482.
Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T and Hay N . (2001). Genes Dev., 15, 2203–2208.
Da-Ming L and Hong S . (1998). Proc. Natl. Acad. Sci. USA, 95, 15406–15411.
Datta SR, Brunet A and Greemberg ME . (1999). Genes Dev., 13, 2905–2927.
Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP . (1998). Nat. Genet., 19, 348–355.
Diehl JA, Cheng M, Roussel MF and Sherr CJ . (1998). Genes Dev., 12, 3499–3511.
Furnari FB, Lin H, Huang HS and Cavenee WK . (1997). Proc. Natl. Acad. Sci. USA, 94, 12479–12484.
Gimm O, Perren A, Weng LP, Marsh DJ, Yeh JJ, Ziebold U, Gil E, Hinze R, Delbridge L, Lees JA, Mutter GL, Robinson BG, Komminoth P, Dralle H and Eng C . (2000). Am. J. Pathol., 156, 1693–1700.
Grimaldi P, Piscitelli D, Albanesi C, Blasi F, Geremia R and Rossi P . (1993). Mol. Endocrinol., 7, 1217–1225.
Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G and Stokoe D . (1998). Curr. Biol., 8, 1195–1198.
Houldsworth J, Reuter V, Bosl GJ and Chaganti RS . (1997). Cell Growth Differ., 8, 293–299.
Iqbal UA . (2000). J. Natl. Cancer Inst., 92, 861–862.
Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, Ikeuchi M, Nagy A, Mak TW and Nakano T . (2003). Development, 130, 1691–1700.
Li DM and Sun H . (1997). Cancer Res., 57, 2124–2129.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R . (1997). Science, 275, 1943–1947.
Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R . (1997). Nat. Genet., 16, 64–67.
Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX, Davies MA, Khan H, Furui T, Mao M, Zinner R, Hung MC, Steck P, Siminovitch K and Mills GB . (1999). Oncogene, 18, 7034–7045.
Luukko K, Ylikorkala A, Tiainen M and Makela TP . (1999). Mech. Dev., 83, 187–190.
Maehama T and Dixon JE . (1998). J. Biol. Chem., 273, 13375–13378.
Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ and Eng C . (1997). Nat. Genet., 16, 333–334.
Marte BM and Downward J . (1997). Trends Biochem. Sci., 22, 355–358.
Matsui Y . (1998). Acta. Pathol. Microbiol. Immunol. Scand., 106, 142–148.
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M and Sellers WR . (1999). Cancer Res., 59, 4291–4296.
Meistrich ML . (1977). Methods Cell Biol., 15, 15–54.
Mertens F, Johansson B, Hoglund M and Mitelman F . (1997). Cancer Res., 57, 2765–2780.
Moe-Behrens GH, Klinger FG, Eskild W, Grotmol T, Haugen TB and De Felici M . (2003). Mol. Endocrinol. Dec., 17, 2630–2638.
Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP and Eng CJ . (2000). Natl. Cancer Inst., 92, 924–930.
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP and Tonks NK . (1997). Proc. Natl. Acad. Sci. USA, 94, 9052–9057.
Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW and Kremer H . (1997). Mol. Genet., 6, 1383–1387.
Okahara F, Ikawa H, Kanaho Y and Maehama T . (2004). J. Biol. Chem., 279, 45300–45303.
Perren A, Komminoth P, Saremasiani P, Matter C, Feurer S, Lees JA, Heitz PU and Eng C . (2000). Am. J. Pathol., 157, 1097–1103.
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE and Parsons R . (1999). Proc. Natl. Acad. Sci. USA, 96, 1563–1568.
Rasheed BK, Stenzel TT, McLendon RE, Parsons R, Friedman AH, Friedman HS, Bigner DD and Bigner SH . (1997). Cancer Res., 57, 4187–4190.
Risinger JI, Hayes AK, Berchuck A and Barrett JC . (1997). Cancer Res., 57, 4736–4738.
Rossi P, Dolci S, Albanesi C, Grimaldi P, Ricca R and Geremia R . (1993). Dev. Biol., 155, 68–74.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B and Velculescu VE . (2004). Science, 304, 554–558.
Scala S, Bruni P, Lo Muzio L, Mignogna M, Viglietto G and Fusco A . (1998). Int. J. Oncol., 13, 665–668.
Sette C, Bevilacqua A, Bianchini A, Mangia F, Geremia R and Rossi P . (1997). Development, 124, 2267–2274.
Skotheim RI and Lothe RA . (2003). APMIS, 111, 136–150.
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW . (1998). Cell, 95, 29–39.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH and Tavtigian SV . (1997). Nat. Genet., 15, 356–362.
Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M and Mak TW . (1998). Curr. Biol., 8, 1169–1178.
Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R and Ellenson LH . (1997). Cancer Res., 57, 3935–3940.
Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Yung WK, Fujii G, Berson A and Steck PA . (1997). Cancer Res., 57, 5221–5225.
Torres J and Pulido R . (2001). J. Biol. Chem., 276, 993–998.
Ulbright TM . (1993). Am. J. Surg. Pathol., 17, 1075–1091.
Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A and Santoro M . (2002). Nat. Med., 8, 1136–1144.
Viglietto G, Romano A, Maglione D, Rambaldi M, Paoletti I, Lago C, Califano D, Monaco C, Mineo A, Santelli G, Manzo G, Botti G, Chiappetta G and Persico MG . (1996). Oncogene, 13, 577–587.
Vos A, Oosterhuis JW, de Jong B, Buist J and Schraffordt Koops H . (1990). Cancer Genet. Cytogenet., 46, 75–81.
Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D and Parsons R . (1997). Cancer Res., 57, 4183–4186.
Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE and Ghio AJ . (2003). J. Biol. Chem., 278, 28258–28263.
Wu Y, Dowbenko D, Pisabarro MT, Dillard-Telm L, Koeppen H and Lasky LA . (2001). J. Biol. Chem., 276, 21745–21753.
Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ and Eng V . (2000). Am. J. Pathol., 157, 1123–1128.
Acknowledgements
This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) to GV. We are indebted to Jean Ann Gilder for revising and editing the text.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Di Vizio, D., Cito, L., Boccia, A. et al. Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene 24, 1882–1894 (2005). https://doi.org/10.1038/sj.onc.1208368
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208368
Keywords
This article is cited by
-
Testicular cancer in mice: interplay between stem cells and endocrine insults
Stem Cell Research & Therapy (2022)
-
Testicular germ cell tumor: a comprehensive review
Cellular and Molecular Life Sciences (2019)
-
Molecular Mechanisms of Cisplatin Chemoresistance and Its Circumventing in Testicular Germ Cell Tumors
Current Oncology Reports (2018)
-
Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
Cell Death & Disease (2017)
-
Hypermethylation of genes in testicular embryonal carcinomas
British Journal of Cancer (2016)