Brain
tumors called glioblastomas are among the most difficult to treat and lethal
cancers. New understanding of the role of cancer stem cells in their development,
however, might provide attractive targets for treatments.
Jeremy Rich, MD, Chair of the Department of Stem Cell Biology and Regenerative Medicine, has identified a gene that plays an essential role in the cancer stem cells responsible for renewing tumor cells.
Standard cancer treatments focus on eliminating as much tumor tissue as possible through chemotherapy, radiation and surgery. Glioblastomas present a significant challenge, though, because they lack distinct “borders” and often weave throughout brain and spinal cord tissues – making total surgical removal nearly impossible. Brain tumor stem cells also are highly resistant to chemotherapy and radiation.
As a result, brain tumor stem cells remain following treatment, renew cancer cells, propagate into new tumors, and invade other tissues. Each year, 8.2 of every 100,000 people in the United States are diagnosed with primary malignant brain tumors, or about 2% of all cancers diagnosed. About 13,000 Americans die of malignant brain tumors every year.
“Brain tumor stem cells make glioblastomas particularly aggressive and lethal. But they could be targets for new therapeutic interventions,” Dr. Rich said.
Tumors lack a natural source of oxygen and nutrients, so they require new blood vessels to form, a process known as angiogenesis. This lack of oxygen to tissues is called hypoxia, and it is a well-recognized condition of tumors.
Dr. Rich's team found that a family of genes called hypoxia-inducible factors (HIFs) is expressed by glioblastoma stem cells. In particular, glioblastoma stem cells express the gene HIF2alpha during angiogenesis – if the gene isn't expressed, angiogenesis is decreased. The presence of HIF2alpha correlates to poor survival rates among glioblastoma patients.
“HIFs are essential to cancer stem cell maintenance and angiogenesis,” Dr. Rich said. “If we find a way to stop the expression of HIF2alpha, we could stop the development of new blood vessels that deliver oxygen and nutrients to brain tumors. Slowing or stopping tumor angiogenesis could make existing tumors more susceptible to treatment. Or it could keep any cancer stem cells that remain after treatment from propagating into new tumors.
“What's especially intriguing about HIF2alpha is that it is expressed by brain tumor stem cells, but not other stem cells responsible for brain and nervous system cells. So stopping its expression would not adversely affect the stem cells required for maintaining other essential neural cells,” he said.
Dr. Rich's research team included Shideng Bao, PhD, Qiulian Wu, Justin Lathia, PhD, and Anita B. Hjelmeland, PhD, of the Institute's Department of Stem Cell Biology and Regenerative Medicine; and Zhizhong Li, PhD, Hui Wang, Christine Eyler, Sith Sathornsumetee, MD, Qing Shi, Yiting Cao, MD, PhD, and Roger E. McLendon, MD, of the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center. The findings appeared recently in Cancer Cell ( www.cell.com/cancer-cell/ , 2009 Jun 2;15:501-13 ). Financial support was provided by the Childhood Brain Tumor Foundation, the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, Alexander and Margaret Stewart Trust, Brain Tumor Society, Goldhirsh Foundation, Duke Comprehensive Cancer Center Stem Cell Initiative, and the National Institutes of Health.