The controversy surrounding human embryonic stem cells has captured headlines in the mainstream media in the last few years; meanwhile, the pages of the scientific literature have recently revealed some groundbreaking findings with adult stem cells. Scientists have shown that certain adult stem cells neural, mesenchymal, and endothelial stem cellshave an uncanny ability to home to cancer cells and tumors, even moving through large areas of the body. Researchers hope to exploit this "attraction" to kill cancer by using the cells as Trojan horses to attach and deliver deadly payloads to cancer cells as an adjunct to other treatments.
Stem cells play a key role in development and repair, and like cancer cells, they are self-renewing. "That stem cells and brain tumor cells behave very, very similarly gave rise to two areas of investigation," said Evan Snyder, M.D., Ph.D., director of stem cell research at the Burnham Institute in San Diego. "First, it made us ask whether the tumors had stem cells in them, and second, if they migrate to cancer cells, could we use them to treat tumors?"
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Snyder's laboratory got the beginnings of an answer to whether stem cells could be used to treat tumors when they demonstrated in 2000 that they could implant neural stem cells into the brains of animals with gliomas and the cells would quickly migrate to the tumor and infiltrate tumor cells, even when implanted at distant sites within the brain. Since then, other researchers have shown that neural stem cells and other types of stem cells migrate to sites of injury, and they have identified some of the factors responsible for the attraction.
Stem Cells in Brain Cancer
Brain cancer is particularly difficult to treat, as those cancers are characterized not only by tumor masses but also by spider-like infiltrations and small tumor areas detached from the main tumor body. "What enables brain cancer to escape the best surgery, chemotherapy, and radiationits ability to infiltrate deep into the brainis precisely what makes stem cells so attractive as a treatment," said Snyder.
Unlike asking stem cells to repair a brain injured by stroke or Parkinson disease, which would require forming new complex neural connections, using stem cells to find and kill brain cancer cells is much simpler, he said. "We're not asking a lot of stem cells in this situation: just find a pathway to the cancer cells, deliver a payload, and don't cause mischief."
At last October's Society for Neuroscience meeting, Snyder discussed using fetal neural stem cells engineered with adenoviruses to secrete tumor necrosis factor apoptosisinducing ligand (TRAIL) to induce apoptosis of human glioblastoma cells in culture. When implanted into adult nude mice with brain tumors, the cells distributed extensively throughout the tumor and migrated to infiltrating tumor satellites, resulting in a reduction in tumor volume.
Snyder envisions that neural stem cells could ultimately be developed into a treatment that would be used as an adjunct to surgery, chemotherapy, and radiation to improve the outcomes of these therapies, especially for refractive and invasive brain tumors. So far, cancer-killing viruses, genes encoding antitumor cytokines such as interleukin 12 (IL-12) and interferon beta, and prodrug converting enzymes have been engineered into engraftable neural stem cells, and Snyder said he thinks these could be tested in the near future in adults with glioblastoma and in children with medulloblastoma and brainstem gliomas.
John Yu, M.D., co-director of the Comprehensive Brain Tumor Program at Cedars-Sinai Medical Center in Los Angeles, estimates that he could begin testing autologous bone marrow derived neural stem cells in patients with refractory glioma within 18 months. He is considering using neural stem cells engineered with TRAIL for its proapoptotic effects or IL-12 for its antiangiogenic effects, having recently tested both approaches in animal models.
"Brain cancer appears to be a stem cell disease, making stem cells particularly appropriate to treat it," said Yu. "Because the brain is such an eloquent structure, and the cancer usually so disseminated, it is impossible to remove [all of the tumor] without disturbing important structures." The cancer stem cells are resilient, chemotherapy resistant, and ultimately cause regrowth of the cancer. "Using [neural stem cells] to track cancer is like a brother finding a brother in a disasterin the brain," said Yu. He is working to find a way to multiply neural stem cells so there are more available for implantation by exploiting the Wnt growth pathway and differentiating cells into astrocytes that express the CXCR4 receptor.
Mesenchymal Stem Cells
Michael Andreeff, M.D., Ph.D., first thought to use mesenchymal stem cells to track and kill tumor cells more than 20 years ago after he read an article describing tumors as "never-healing wounds." Bone marrowderived mesenchymal stem cells help form stroma, or connective tissue (including bone, fat, muscle, cartilage, and tendons) during development and normally migrate to sites of injury in the body to help facilitate healing. Like wounds, tumors send out signals and factors such as vascular endothelial growth factor (VEGF) to recruit mesenchymal stem cells to form stroma for support, and recruit pericytes to form blood vessels for nourishment.
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This local delivery of interferon beta with mesenchymal stem cells is desirable because interferon beta has a very short half-life and is toxic if given systemically at high doses. In November 2004 in the Journal of the National Cancer Institute (see Vol. 96, No. 21, p. 1593), Andreeff described the administration of interferon betaexpressing mesenchymal stem cells to mice with human breast cancer and pulmonary metastases, and also to mice with melanoma. Treatment with the engineered stem cells prolonged survival in mice compared with treatment with interferon beta.
Andreeff said that he is currently developing a protocol for a clinical trial at M. D. Anderson in metastatic cancer that will use mesenchymal stem cells, an adenoviral vector, and a marker so that the movement of the stem cells through the body can be tracked. Ovarian cancer would be treated via peritoneal stem cell administration, and brain cancer with carotid artery administration. Andreeff cautioned that patients receiving mesenchymal stem cell treatment could not have had recent surgery, pneumonia, catheters, or any wounds, because the cells could migrate to those sites.
Jeffrey Bartlett, Ph.D., assistant professor of pediatrics at Ohio State University in Columbus, is testing mesenchymal stem cells engineered with adeno-associated viral vectors and adenoviral vectors with TRAIL, IL-2, IL-12, and interferons in animals to determine which combination might be best to treat pediatric soft tissue sarcomas. "We have found that mesenchymal stem cells engineered with certain cytokines engraft into tumor stroma and kill neighboring tumor cells, whereas TRAIL seems to affect the tumor itself," Bartlett said. He is trying to determine what combination of vector, gene, and method of administration is best for these pediatric tumors.
Endothelial Progenitor Cells
Bone marrowderived endothelial progenitor cells share the cancer-homing attributes of mesenchymal and neural stem cells due to chemoattractants such as VEGF, said Howard Fine, M.D., chief of the Neuro-Oncology Branch of the National Cancer Institute and of the National Institute of Neurologic Disorders and Stroke.
In a recent study, Fine labeled these endothelial progenitor cells with supermagnetic iron oxide nanoparticles and infused them into mice. He and his colleagues then imaged the brain with MRI during tumor growth to see if the stem cells incorporated into the new blood vessels that fed tumors in a mouse model of glioma. He found that the stem cells did indeed home to areas of ongoing angiogenesis and differentiated into endothelial-like cells in tumor vasculature after intravenous infusion, but they did not incorporate into quiescent vasculature.
"This technique could be used to identify neovasculature in vivo and to facilitate gene therapy by noninvasively monitoring these cells as gene delivery vectors," he and his colleagues wrote in Blood in January. Other researchers are investigating endothelial cellbased gene transfer approaches to deliver immune-activating cytokines and other secreted proteins to brain and breast tumors.
In the next few years, it is likely that one or more adult stem cell types could begin human testing for cancer treatment. What type of cell, route of administration, and cancer-killing substance works best in different tumors will take time to determine.
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