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Tumor Biology |
Department of Neurosurgery and Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84132
2 Address correspondence and reprint requests to Dan Fults, Department of Neurosurgery, University of Utah Health Sciences Center, Salt Lake City, UT 84132.
Abstract
PTEN/MMAC1 (phosphatase and tensin homolog/mutated in multiple advanced cancers 1) is a tumor suppressor gene, the inactivation of which is an important step in the progression of gliomas to end-stage glioblastoma multiforme. We examined the distribution of PTEN protein in 49 primary human gliomas by immunocytochemistry using polyclonal antibodies that we raised against PTEN-glutathione S-transferase fusion proteins expressed in Escherichia coli. The study group consisted of 6 low-grade astrocytomas, 7 anaplastic astrocytomas, 21 glioblastomas multiforme, 4 low-grade oligodendrogliomas, 6 malignant oligodendrogliomas, and 5 malignant mixed oligoastrocytomas. For each tumor, we determined the percentage of tumor cells showing PTEN immunoreactivity in the most cellular regions of the tumor specimen. In both astrocytomas and oligodendrogliomas, there was an inverse relationship between the percentage of PTEN+ cells and malignancy grade, consistent with a role for PTEN as a tumor suppressor gene, the expression of which declines during glioma progression. In nonneoplastic tissue, PTEN was expressed in human fetal brain at 16, 23, and 27 weeks' gestation, but not in adult brain, indicating that PTEN is developmentally regulated in the CNS. In 21 glioblastomas multiforme, we correlated PTEN protein expression with PTEN gene sequence. Although PTEN-mutant tumors showed significantly diminished PTEN protein expression compared with wild-type cases, suppressed expression of PTEN is more prevalent than predicted from mutation frequencies.
References
Cook, D.L., Gerber, A.N., and Tapscott, S.J. (1998)
Modeling stochastic gene expression: Implications for haploinsufficiency.
Proc. Natl. Acad. Sci. U.S.A.
95,15641
-15646.
Fults, D., and Pedone, C. (1993) Deletion mapping of the long arm of chromosome 10 in glioblastoma multiforme. Genes Chromosomes Cancer 7,173 -177.[ISI][Medline]
Fults, D., Pedone, C.A., Thompson, G.E., Uchiyama, C.M., Gumpper, K.L., Iliev, D., Vinson, V.L., Tavtigian, S.V., and Perry, W.L. (1998) Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS, and MXI1 in human glioblastoma multiforme. Int. J. Oncol. 12,905 -910.[ISI][Medline]
Furnari, F.B., Huang, H.S., and Cavenee, W.K. (1998)
The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1
growth arrest in glioma cells. Cancer Res.
58,5002
-5008.
Haas-Kogan, D., Shalev, N., Wong, M., Mills, G., Yount, G., and Stokoe, D. (1998) Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr. Biol. 21,1195 -1198.
Hsu, S.M., Raine, L., and Fanger, H. (1981) Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unrelated antibody (PAP) procedures. J. Histochem. Cytochem. 29,577 -580.[Abstract]
Kleihues, P., Burger, P.C., and Scheithauer, B.W. (1993) Histological Typing of Tumours of the Central Nervous System. Berlin: Springer-Verlag.
Kleihues, P., and Cavenee, W.K. (Eds.) (1997) Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer.
Li, D.M., and Sun, H. (1997) TEP1, encoded by a
candidate tumor suppressor locus, is a novel protein tyrosine phosphatase
regulated by transforming growth factor ß. Cancer
Res. 57,2124
-2129.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S.I.,
Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S.H., Giovanella,
B.C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler, M.H., and Parsons, R.
(1997) PTEN, a putative protein tyrosine phosphatase
gene mutated in human brain, breast, and prostate cancer.
Science 275,1943
-1947.
Liaw, D., Marsh, D.J., Li, J., Dahia, P.L.M., Wang, S.I., Zheng, Z., Bose, S., Call, K.M., Tsou, H.C., Peacocke, M., Eng, C., and Parsons, R. (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16,64 -67.[CrossRef][ISI][Medline]
Liu, W., James, C.D., Frederick, L., Aldrete, B.E., and Jenkins,
R.B. (1997) PTEN/MMAC1 mutations and EGFR
amplification in glioblastomas. Cancer Res.
57,5254
-5257.
Maehama, T., and Dixon, J.I. (1998) The tumor
suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger,
phosphatidylinositol 3,4,5–trisphosphate. J. Biol.
Chem. 273,13375
-13378.
Mrzijak, L., Uylings, H.B.M., Kostovic, I., and Van Eden, C.G. (1988) Prenatal development of neurons in the human prefrontal cortex: A qualitative Golgi study. J. Comp. Neurol. 271,355 -386.[CrossRef][ISI][Medline]
Myers, M.P., Stolarov, J.P., Eng, C., Li, J., Wang, S.I., Wigler,
M.H., Parsons, R., and Tonks, N.K. (1997) P-TEN, the tumor
suppressor from human chromosome 10q23, is a dual-specificity phosphatase.
Proc. Natl. Acad. Sci. U.S.A.
94,9052
-9057.
Noble, M. (1996) Steps toward a cellular biological analysis of human gliomas. In: Raffel, C., and Harsh. G.R. (Eds.), The Molecular Basis of Neurosurgical Disease. Baltimore: Williams and Wilkins. Vol. 8, pp.87 -97.
Ohlsson, R., Tycko, B., and Sapienza, C. (1998) Monoallelic expression: "There can only be one." Trends Genet. 14,435 -438.[CrossRef][ISI][Medline]
Rasheed, B.K.A., Stenzel, T.T., McLendon, R.E., Parsons, R.,
Friedman, A.H., Friedman, H.S., Bigner, D.D., and Bigner, S.H.
(1997) PTEN gene mutations are seen in high-grade but
not in low-grade gliomas. Cancer Res.
57,4187
-4190.
Sano, T., Lin, H., Chen, X., Langford, L.A., Koul, D., Bondy, M.L.,
Hess, K.R., Myers, J.N., Hong, Y.K., Yung, W.K.A., and Steck, P.A.
(1999) Differential expression of MMAC/PTEN in
glioblastoma multiforme: Relationship to localization and prognosis.
Cancer Res. 59,1820
-1824.
Steck, P.A., Pershouse, M.A., Jasser, S.A., Yung, W.K.A., Lin, H., Ligon, A.H., Langford, L.A., Baumgard, M.L., Hattier, T., Davis, T., Frye, C., Hu, R., Swedlund, B., Teng, D.H.F., and Tavtigian, S.V. (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15,356 -362.[CrossRef][ISI][Medline]
Suzuki, A., de la Pompa, J.L., Stambolic, V., Elia, A.J., Sasaki, T., Barrantes, I.B., Ho, A., Wakeham, A., Itie, A., Khoo, W., Fukumoto, M., and Mak, T.W. (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 21,1169 -1178.
Tamura, M., Gu, J., Matsumoto, K., Aota, S., Parsons, R., and
Yamada, K.M. (1998) Inhibition of cell migration, spreading, and
focal adhesions by tumor suppressor PTEN. Science
280,1614
-1617.
Wang, S.I., Puc, J., Li, J., Bruce, J.N., Cairns, P., Sidransky,
D., and Parsons, R. (1997) Somatic mutations of PTEN in
glioblastoma multiforme. Cancer Res.
57,4183
-4186.
Whang, Y.E., Wu, X., Suzuki, H., Reiter, R.E., Tran, C., Vessella,
R.L., Said, J.W., Isaacs, W.B., and Sawyers, C.L. (1998)
Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate
cancer through loss of expression. Proc. Natl. Acad. Sci.
U.S.A. 95,5246
-5250.
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