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St. Jude researchers have found a vulnerable spot in brain tumors they are trying to exploit to improve the treatment of these cancers and prevent tumors from returning. The researchers showed in laboratory studies that brain tumors appear to arise from cancer stem cells (CSCs) that live within microscopic, protective “niches” formed by blood vessels in the brain; and that certain drugs can disrupt these niches, depriving the tumors of their source of cancer cells. CSCs are cells that continually multiply, acting as the source of tumors.
“These niches might also protect CSCs from chemotherapy and radiation therapy,” said Richard Gilbertson, MD, PhD, Developmental Neurobiology. “This could help explain why tumors that rapidly produce new blood vessels are clinically aggressive and how brain tumors reappear following treatment.” Gilbertson is senior author of a report on this work that appears in the January issue of Cancer Cell.
The St. Jude team showed that CSCs are located in vascular niches in four types of brain cancer: medulloblastoma, ependymoma, oligodendroglioma and glioblastoma. The investigators examined thin sections of brain tumors and found about 30 percent of the CSCs in vascular niches were multiplying with abnormal speed, as would be expected for cancer cells.
The team showed in mouse models that CSCs from brain tumors tend to associate more closely with blood vessels than do non-CSC tumor cells. The scientists also demonstrated in test tube experiments that CSCs bind closely to cells isolated from human blood vessels. Further, the investigators found that human blood vessel cells release molecules that trigger brain CSCs to keep their identity as stem cells and continue to multiply rapidly.
“This is strong evidence that the cells making up the vascular niche send signals to CSCs in the brain, causing them to grow and multiply,” Gilbertson said.
The researchers then showed that blood vessel cells do not increase tumor growth by forming new vessels, but by associating with CSCs and stimulating these cells directly to produce tumors. They also showed that drugs that deplete blood vessels from tumors inhibit tumor growth by reducing the number of CSCs. For example, the team depleted blood vessels in tumors with
Avastin® (bevacizumab), an antiangiogenic drug that blocks a protein called VEGF. Anti-angiogenic drugs block the formation of new blood vessels.
“Our data suggest a previously unrecognized way that anti-angiogenic agents inhibit tumor growth,” said Christopher Calabrese, PhD, Developmental Neurobiology, who is first author of the study and completed much of the work.
The St. Jude investigators have now translated these findings into a clinical trial to determine the effectiveness of Avastin® and another drug, Traceva® (erlotinib), in eliminating tumors and preventing their recurrence in children with brain cancers.
Other St. Jude authors of this study include Ildar Bayazitov, PhD, Twala Hogg, Helen Poppleton, PhD, and Stanislav Zakharenko, MD, PhD, all of Developmental Neurobiology; Mehmet Kocak, Biostatistics; Amar Gajjar, MD, Oncology co-chair; Andrew Davidoff, MD, Surgery; David Finkelstein, PhD, Hartwell Center; and former employees Meredith Allen, Adrian Frank, Christine Fuller, Waleed Gaber, Blair Hamner and Eun Oh.