Now researchers at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute, using mouse and human cells, have defined a subset of neural stem cells that have this tumor-tracking potential. They also have identified a biochemical mechanism that appears to govern the homing behavior. Their results appear in the May/June issue of the journal Neoplasia.
The prognosis for patients with malignant brain tumors called gliomas is extremely poor. Those with glioblastoma multiforme, the most aggressive of the gliomas, usually have a life expectancy of only months from the time of diagnosis. Survival for two years is extremely rare, even with aggressive treatment. Chemotherapy and radiation therapy have only minimal impact, and because gliomas have poorly defined borders, with glioma cells intermingling with healthy brain tissue, complete surgical removal is nearly impossible. Furthermore, cancer cells migrate away from the main tumor to form satellites that often escape treatment and lead to recurrence.
"We have previously demonstrated the uncanny ability of neural stem cells to seek out and destroy satellites of tumor cells in the brain. Now we know at least one component of tumor cells that is attracting neural stem cells toward them. With this knowledge, we hope to expedite the translation of this powerful and novel strategy for the clinical benefit of patients with brain tumors," said John S. Yu, senior author of the study and co-director of the Comprehensive Brain Tumor Program at Cedars-Sinai.
"Given the very poor prognosis associated with high-grade gliomas, there is an urgent need to develop novel therapies that can be translated into clinical practice. The use of neural stem cells as therapeutic delivery vehicles has offered encouraging results in pre-clinical models," said Keith L. Black, MD, director of the Institute and of Cedars-Sinai's Division of Neurosurgery and the Comprehensive Brain Tumor Program. "It is exciting to begin to identify and describe the mechanisms that govern this tracking behavior. This obviously is fundamental to advancing our earlier observations toward successful treatment."
Within the past several years, Cedars-Sinai researchers have published animal and laboratory studies showing that neural stem cells - "immature" cells that have the potential to differentiate into any of several types of central nervous system cells - have the ability to track glioma cells as they migrate. In recently published work, the researchers genetically engineered tumor-tracking stem cells to secrete interleukin 12, which elicited a local immune response that attacked cancer cells at the tumor site and in the satellites. They also engineered neural stem cells to deliver a protein that causes the death of cancer cells without harming normal cells.
While these and similar studies suggest that cancer-killing immune system components can be piggybacked with neural stem cells to track and attack glioma cells even as they migrate, the mechanisms responsible for this tracking ability have remained a mystery.
Although many of the stem cells transplanted into tumors have demonstrated robust migratory activity and tumor tracking capabilities, a significant number have remained at the injection site. The injections have consisted of stem cells at various levels of differentiation - some still "uncommitted" as to the type of cells they would eventually become, some developing into neurons, and some becoming glial cells.
"We hypothesized that the tumor-tracking capacity was likely exhibited by a specific subpopulation of progenitor cells at a particular stage of differentiation," said Dr. Yu. "Our findings clearly point to astrocytic progenitors as the candidate cells exhibiting tumor-tracking capacity within transplanted neural stem cells."
Specifically, he said, the candidate cells appear to be at an advanced stage of differentiation but are not yet mature astrocytes, a subcategory of glial cells. Astrocytes are comparatively large, star-shaped cells that influence the activity of neurons and provide structure for the cells of the brain.
The researchers also found that these astrocytic precursors expressed significant levels of a "chemokine receptor" called CXCR4. Chemokines are proteins that are produced and released by a variety of types of cells. Like chemical magnets, in a sense, they attract cells that have compatible receptors on their surfaces. When the proteins bind at the receptors, they activate internal signaling pathways that cause a cell to behave in a certain way.
CXCR4 is known to govern cellular migration and homing in a variety of cell types, including neuronal and glial precursors in the developing brain. The only known chemokine that binds with CXCR4 is stromal-cell derived factor-1 (SDF-1). High-grade gliomas have recently been found to secrete significant levels of SDF-1.
The authors conclude that SDF-1 secreted by glioma cells migrating away from a tumor attracts CXCR4 and the neural stem cells upon which these receptors reside. In fact, when these receptors were blocked from interacting with SDF-1 in the laboratory, neural stem cell migration toward glioma cells was inhibited, confirming the importance of the CXCR4/SDF-1 pathway.
"The identification of CXCR4 as a key element governing the process of neural precursor migration toward glioma cells may allow for more efficient isolation of potential tumor-tracking cells, which may hasten the therapeutic testing of glioma-tracking neural precursors in the clinical setting," said Dr. Black, who holds the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai.
This study was supported in part by National Institutes of Health grant NS02232 to Dr. Yu.
Cedars-Sinai is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthroughs in biomedical research and superlative medical education. The Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.