Astrocytomas are the most common primary supratentorial cerebral neoplasms in adults, with an average annual incidence of 5.3 per 100,000. These tumors are diffusely infiltrative and uniformly rapidly fatal. Despite scientific and therapeutic advances, the clinical behavior of these tumors has not been significantly altered, with current median survival 12-14 months. The motile invading cells from these tumors are responsible for recurrence following resection, and also these cells that, by unknown mechanisms, lead to progressive neurologic dysfunction without evidence of mass effects or recurrence of bulk disease. Surprisingly, little effort has been made to investigate the cellular and molecular biology of invading astrocytoma cells. Preliminary Results from the PI's laboratory indicate that invading astrocytoma cells: invade along white matter tracts, without forming secondary tumors can be reestablished in culture, and produce tumors when reimplanted into naive rats motility increases with increasing serum, exposure to taxol or EGF, and with increasing tumor grade motility decreases with exposure to cytochalasin B, PDGFbb, bFGF, and NGF blocking mitosis does not alter motility subpopulations of cells that are more motile can be isolated in humans with glioblastoma, histologically normal brain, -4cm from bulk tumor, contains tumor cells that can be grown in culture.
The Specific Aims addressed by this project will extend these preliminary results and open avenues critical to the isolation and biological characterization of invasive astrocytoma cells, thus providing a fundamental first step toward the development of therapies specifically designed to target these cells. Furthermore, the specific properties to be studied, such as motility, which are intrinsic to normal glia, and retained and amplified in neoplastic glia, may help provide an understanding of the basic biology of normal glia. Hypothesis #1: Invading astrocytoma cells comprise a biologically distinct cell subpopulation. A. Invading astrocytoma cells are biologically unique and more motile than cells which comprise the bulk tumor. B. Invading astrocytoma cells respond to inhibitors and promoters of motility differently than cells from the bulk tumor. Hypothesis #2: Astrocytoma resection alters the movement of the remaining tumor cells. A. Chemoattractants, such as cytokines, released during tumor resection promote movement of invasive tumor cells back towards the resection cavity. B. Blockade of cytokine receptors with antireceptor antibodies affect the movement of the astrocytoma cells that have invaded beyond the resection margins. Hypothesis #3: Chemotherapeutic intervention alters the movement of invading astrocytoma cells. A. Specific drugs alter tumor invasion when given after tumor implantation, but without tumor resection. B. Specific drugs alter tumor invasion when given after tumor implantation, and after surgical tumor resection.
| Mesiwala, Ali H; Farrell, Lindi; Santiago, Paul et al. (2003) The effects of hydrogen peroxide on brain and brain tumors. Surg Neurol 59:398-407; discussion 407 |
| Mesiwala, Ali H; Farrell, Lindi; Wenzel, H Jurgen et al. (2002) High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo. Ultrasound Med Biol 28:389-400 |
