Authors: Sarah Jones, Future Science Group
The reason why brain tumors occur more frequently in males and are often more harmful than single tumors in females has been further explained by new research from Washington University School of Medicine in St Louis (MO, USA).
Glioblastomas, which are the most common malignant brain tumors, for example, are diagnosed twice as often in males and result in greater cognitive impairments than when occurring in females; male patients also do not survive as long.
A protein known to reduce cancer risk termed retinoblastoma protein (RB) was demonstrated by the researchers to be significantly less active in male brain cells than in female brain cells.
“This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that’s very exciting,” commented senior author Joshua Rubin, of Washington University School of Medicine. “These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences. Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments.”
RB is the target of drugs currently being evaluated in clinical trials, noted Rubin. It is hoped that the drugs trigger the antitumor effects of the protein, therefore prolonging cancer patient survival.
“In clinical trials, we typically examine data from male and female patients together, and that could be masking positive or negative responses that are limited to one sex,” continued Rubin. “At the very least, we should think about analyzing data for males and females separately in clinical trials.”
Many diseases that either occur at different rates in males and females or which cause different symptoms based on sex have been identified by scientists. The reasons behind this are often linked to sex hormones, which create and maintain many, but not all, of the biological differences between the sexes.
It was known, however, by Rubin and his colleagues that sex hormones could not account for the differences in brain tumor risk.
“Male brain tumor risk remains higher throughout life despite major age-linked shifts in sex hormone production in males and females,” he said. “If the sex hormones were causing this effect, we’d see major changes in the relative rates of brain tumors in males and females at puberty. But they don’t happen then or later in life when menopause changes female sex hormone production.”
A cell model of glioblastoma was used by Rubin to prove it is easier to make male brain cells become tumors. Male brain cells became cancerous faster and more often than female brain cells after a series of genetic alterations and exposure to a growth factor.
Three genes were evaluated by the team to see if they were naturally less active in male brain cells in order to determine the reasons for the differences in the male and female cells. The neurofibromin gene, p53 and RB, which were the genes studied, normally suppress cell division and cell survival, but in many cancers the genes are mutated and disabled.
RB was found to be more likely inactivated in male brain cells than in female brain cells. Both types of cells became equally susceptible to becoming cancerous if the RB protein was disabled in female brain cells.
“There are other types of tumors that occur at different rates based on sex, such as some liver cancers, which occur more often in males,” Rubin said. “Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies and perform more informative clinical trials.”
Sources: Sun T, Warrington NM, Luo J et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J Clin Invest. doi:10.1172/JCI71048 (2014); Washington University in St Louis press release