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Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis

Christine E. Eyler, Jeremy N. Rich

From the Departments of Pharmacology and Cancer Biology, Medicine, and Surgery, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham NC

Corresponding author: Jeremy N. Rich, MD, Duke University Medical Center, PO Box 2900, Durham, NC 27710; e-mail: rich0001{at}mc.duke.edu

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

Supported 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 Grant (J.N.R.), and National Institutes of Health Grants No. NS047409, NS054276, and CA116659 (J.N.R.). J.N.R. is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Foundation for Cancer Research Scholar. C.E.E. receives Medical Scientist Training Program support from the National Institute of General Medical Sciences (Grant No. 2T32GM007171).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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