by Simone Alves

Regulation is controlled by PTEN, PI3K/Akt and drug-effluxing ABCG2

Some chemotherapeutics used to target gliomas may actually increase the cancer stem cell population and make tumours more aggressive.

Working in mice genetically engineered to have gliomas, Eric Holland and his team at the Memorial Sloan-Kettering Cancer Center in New York showed that a previously identified population of brain cells known as the side population is more tumorigenic than other cells in the brain. The proportion of cells belonging to the side population (SP) was also several-fold larger in glioma-susceptible mice compared to normal mice, and this population increased in the absence of the tumour suppressor gene PTEN. SP cells from gliomas were able to generate neurospheres in vitro, suggesting that this population can harbour brain cancer stem cells.

 SP cells make high levels of the protein ATP binding cassette transporter (ABCG2), a molecular pump that actively shuttles drugs out of cells, protecting them from toxic effects. These cells also efflux fluorescent dye, allowing researchers to track the cells.


Although ABCG2 does not seem responsible for starting cancer, it does seem important for sustaining the cells in the SP, which are more likely to be cancer stem cells. Blocking ABCG2 with small molecules dramatically lowered the number of SP cells and also made them more susceptible to the cancer drug mitoxantrone.

ABCG2, in turn, is regulated by other proteins. Holland found that blocking the PI3K/Akt pathway ablates ABCG2's ability to efflux mitoxantrone. Exactly how this happens is unclear, but Holland's results indicate that it is the activity rather than the expression of the protein that is regulated.

Treatment for glioma often relies on temozolomide, a drug which, although not a substrate of ABCG2, seems to select for SP cells and drives cells to become more stem like, allowing cancer to recur. Holland believes that better characterization of the SP might facilitate combination therapies that target both these cells and the bulk of the tumour. "You can't ignore this subset of cells like the SP cells, because they do behave differently to the rest of the tumour."

"This paper really pulls together a number of observations regarding the side population, PTEN and Akt that have been made before and turns them into a cohesive story," says Jeremy Rich, chair of stem cell biology at the Cleveland Clinic in Ohio. "What is interesting for general stem cell biology is how the side population phenotype in normal stem cells is regulated by PTEN and Akt, a pathway which is vital in all cells. And what is the role of the ABCG2 transporter?"


Source: Nature

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