Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males
Tao Sun, … , Rajarshi Sengupta, Joshua B. Rubin
Tao Sun, … , Rajarshi Sengupta, Joshua B. Rubin
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):4123-4133. https://doi.org/10.1172/JCI71048.
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Research Article Oncology

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Abstract

The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1–/–) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.

Authors

Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin

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Figure 4

Sex differences in induction of a stem-like cell subpopulation in Nf1–/– DNp53 astrocytes.

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Sex differences in induction of a stem-like cell subpopulation in Nf1–/–...
(A) Frequency of clonogenic (stem-like) cells was measured by ELDA in Nf1–/– DNp53 cells (3,000, 600, 120, 24, 5, and 1 cell per well; 10–12 replicates per dilution), with 3 independent astrocyte preparations. Shown is a representative ELDA analysis from one of the three cell preparations. CSC, clonogenic (stem-like) cell. (B) Male Nf1–/– DNp53 cells have a significantly higher stem-like cell frequency (12.2% ± 3.4%) than female (2.77% ± 0.6%) counterparts, as derived from the ELDA analysis (*P = 0.03, t test). (C) Sex differences in expression of stem cell markers CD133 and Sox2 (*P = 0.018 and **P = 0.03 for CD133 and Sox2 respectively, 2-tailed t test). (D) Representative images of neurospheres from male and female Nf1–/– DNp53 cells (3,000 cells per well) 1 week after plating. Scale bar: 500 microns. (E) The frequency of clonogenic stem-like cells, as determined by ELDA, was equal in male (2.49% ± 1.1%) and female (1.73% ± 0.63) Nf1–/– NSCs. (F) The frequency of clonogenic stem-like cells, as determined by ELDA, was equally low (0.2%) in both male and female Nf1–/– astrocytes.