Repopulating glioma cell lines

Cancer therapies target rapidly dividing cells, which is a problem if tumors contain slow-growing undifferentiated cells that act as stem cell for the malignancy, as accumulating evidence suggests. Now, Toru Kondo, Takao Setoguchi, and Tetsuya Taga (Kumamoto University, Japan, and University of Cambridge, Cambridge, UK) show that this problem may be widespread. They find that several cancer cell lines maintain a small proportion of self-renewing cells.

To search for these potentially dangerous cells, Kondo's team tested several cancer cell lines for the presence of side populations (SP) of cells containing the breast cancer–resistant protein 1 (BCRP1), an ATP-dependent transporter found in many stem cells. Of six lines tested, four had BCRP1-containing SP cells that accounted for between 0.4% and 2.1% of the total population.

The growth of SP cells requires basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). “bFGF seems to be essential for the self-renewal of C6 stem cell but is not enough to induce stem cell proliferation” says Kondo. In the presence of both growth factors, the SP cells proliferate but maintain their stem cell–like qualities.

When the authors isolated SP cells and allowed them to repopulate a culture, they found that the cells produce both SP and non-SP cells. By contrast, non-SP cells cannot be induced to take on SP traits, suggesting that the SP cells are the population's stem cells.

It is these SP cells that seem to be responsible for malignancy. SP cells injected into immunologically compromised mice generate aggressive, invasive cancers, whereas non-SP cells generally give rise only to local tumors. Since both cell types contain the same oncogenic mutations, the difference is probably due to epigenetic differences such as silencing, says Kondo. He and others are already looking for possible stem cell behavior switches, such as Bmi-1, an epigenetic factor recently shown to be concentrated in stem cells. ▪

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