This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xiao, A. Articles by Van Dyke, T. Search for Related Content PubMed PubMed Citation Articles by Xiao, A. Articles by Van Dyke, T.

Somatic Induction of Pten Loss in a Preclinical Astrocytoma Model Reveals Major Roles in Disease Progression and Avenues for Target Discovery and Validation

Departments of ¹ Biochemistry and Biophysics, and of ² Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ³ Human Genetics Program, Division Population Science, Fox Chase Cancer Center, Cottman Avenue, Philadelphia, Pennsylvania; and ⁴ Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, New York

Requests for reprints: Terry Van Dyke, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: 919-962-2145; Fax: 919-843-3160; E-mail: tvdlab{at}med.unc.edu.

High-grade astrocytomas are invariably deadly and minimally responsive to therapy. Pten is frequently mutated in aggressive astrocytoma but not in low-grade astrocytoma. However, the Pten astrocytoma suppression mechanisms are unknown. Here we introduced conditional null alleles of Pten (Pten^loxp/loxp) into a genetically engineered mouse astrocytoma model [TgG(Z)T₁₂₁] in which the pRb family proteins are inactivated specifically in astrocytes. Pten inactivation was induced by localized somatic retroviral (MSCV)-Cre delivery. Depletion of Pten function in adult astrocytoma cells alleviated the apoptosis evoked by pRb family protein inactivation and also induced tumor cell invasion. In primary astrocytes derived from TgG(Z)T₁₂₁; Pten^loxp/loxp mice, Pten deficiency resulted in a marked increase in cell invasiveness that was suppressed by inhibitors of protein kinase C (PKC) or of PKC-, specifically. Finally, focal induction of Pten deficiency in vivo promoted angiogenesis in affected brains. Thus, we show that Pten deficiency in pRb-deficient astrocytoma cells contributes to tumor progression via multiple mechanisms, including suppression of apoptosis, increased cell invasion, and angiogenesis, all of which are hallmarks of high-grade astrocytoma. These studies not only provide mechanistic insight into the role of Pten in astrocytoma suppression but also describe a valuable animal model for preclinical testing that is coupled with a primary cell-based system for target discovery and drug screening.

This article has been cited by other articles:

				C.-H. Kwon, D. Zhao, J. Chen, S. Alcantara, Y. Li, D. K. Burns, R. P. Mason, E. Y.-H. P. Lee, H. Wu, and L. F. Parada Pten Haploinsufficiency Accelerates Formation of High-Grade Astrocytomas Cancer Res., May 1, 2008; 68(9): 3286 - 3294. [Abstract] [Full Text] [PDF]

				F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]

				D. K. Sandsmark, H. Zhang, B. Hegedus, C. L. Pelletier, J. D. Weber, and D. H. Gutmann Nucleophosmin Mediates Mammalian Target of Rapamycin-Dependent Actin Cytoskeleton Dynamics and Proliferation in Neurofibromin-Deficient Astrocytes Cancer Res., May 15, 2007; 67(10): 4790 - 4799. [Abstract] [Full Text] [PDF]

				Q. Wei, L. Clarke, D. K. Scheidenhelm, B. Qian, A. Tong, N. Sabha, Z. Karim, N. A. Bock, R. Reti, R. Swoboda, et al. High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Res., August 1, 2006; 66(15): 7429 - 7437. [Abstract] [Full Text] [PDF]