Self-renewing cancer stem cells (CSCs) comprise only a tiny fraction of most brain tumors, but eliminating them is likely to have a profound impact on the ability of a tumor to survive and grow. However, CSCs might resist traditional therapies that target the great bulk of the cells in cancers. Now, new research published in the January 2007 issue of the journal Cancer Cell, published by Cell Press, reveals that small blood vessels associated with brain tumors orchestrate a distinct microenvironment that is critical for maintaining CSCs. Importantly, antiangiogenic drugs that disrupt this microenvironment reduce the CSC population and arrest tumor growth.
Dr. Richard J. Gilbertson and colleagues from the St. Jude Children's Research Hospital established that CSCs in human brain tumors are associated with blood vessels and that vascular cells physically interact with and maintain brain CSCs in culture. A similar interaction was not observed for the bulk of non-CSC tumor cells. To examine whether the vessel-derived factors promote maintenance of CSCs and tumor propagation in vivo, the researchers transplanted human brain tumors into mice with or without vascular cells. The mice with extra vascular cells exhibited an increase in CSCs as well as enhanced initiation and proliferation of tumors. The authors also found that when antiangiogenic therapies were used to diminish tumor blood vessels, CSCs were reduced and tumor growth was arrested, further supporting the importance of the vascular microenvironment to CSCs.
"Our data identify a possible role for niche microenvironments in the maintenance of CSCs and identify a mechanism by which antiangiogenic drugs inhibit brain tumor growth," concludes Dr. Gilbertson. "If the notion that niches protect CSCs proves correct, then targeting these microenvironments could prove highly effective treatments of cancer." Further research and clinical trials are needed to investigate this important new mechanism associated with antiangiogenic cancer therapies. It seems likely that effective cancer treatments must target both the bulk of rapidly proliferating tumor cells and the smaller population of self-renewing CSCs.
The researchers include Christopher Calabrese, Helen Poppleton, Mehmet Kocak, Twala L. Hogg, Christine Fuller, Blair Hamner, Eun Young Oh, M. Waleed Gaber, David Finklestein, Meredith Allen, Adrian Frank, Ildar T. Bayazitov and Stanislav S. Zakharenko, Amar Gajjar, Andrew Davidoff and Richard J. Gilbertson of St. Jude Children's Research Hospital in Memphis, TN.
This work was supported by the Sontag Foundation (R.J.G.), NCI grant CA096832 (R.J.G.), the V-Foundation for Cancer Research (R.J.G.), and the American Lebanese Syrian Associated Charities (ALSAC).
Calabrese et al.: "A Perivascular Niche for Brain Tumor Stem Cells." Publishing in Cancer Cell 11, 69-82, January 2007. DOI 10.1016/j.ccr.2006.11.020 http://www.