Malignant gliomas are brain tumors which remain extremely difficult to treat and ultimately incurable. Recent epidemiologic evidence indicates that they are also increasing the frequency, especially in the elderly. Conventional therapeutic strategies that view cancer cells as foreign aim control disease through selective killing but if cancer is viewed a s a dynamic disorder of growth regulation where tumor cells are closely related to normal ones, then this type of cytoreductive strategy may be counterproductive. Since certain infrequently occurring gliomas are extremely indolent, we propose to induce malignant glioma cells to behave similarly to these tumors by gene manipulation. Because of its association with benign rumor behavior in neuroblastoma, another tumor derived from neural tissues, we examined the effects of incorporating the high affinity nerve growth factor Trka receptor into receptor negative C6 glioma cells. In this model, glioma cells become responsive rather than dependent on nerve growth factor in vitro. Nevertheless, these cells produce much less aggressive tumors when injected into rat brain than those formed by parental C6 cells. Our subsequent studies examining mechanisms underlying this response indicate that this effect is due more to an inability of these cells to invade surrounding brain tissue and an increased rate of apoptosis than to a cessation of proliferation or immune response. The goals of this project are to continue to explore the mechanisms underlying why trkA promotes induction of a less aggressive glioma by assessing: the pathologic correlates of tumor growth; mutations of the trkA phosphorylation sites; NGF modulation of this response; whether benign behavior can be induced after implantation has already taken place; the effect of trkA expression on human glioma cell behavior.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA068426-03
Application #
6300496
Study Section
Project Start
2000-01-01
Project End
2000-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$171,992
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Jang, Taichang; Savarese, Todd; Low, Hoi Pang et al. (2006) Osteopontin expression in intratumoral astrocytes marks tumor progression in gliomas induced by prenatal exposure to N-ethyl-N-nitrosourea. Am J Pathol 168:1676-85
Savarese, Todd M; Jang, Taichang; Low, Hoi Pang et al. (2005) Isolation of immortalized, INK4a/ARF-deficient cells from the subventricular zone after in utero N-ethyl-N-nitrosourea exposure. J Neurosurg 102:98-108
Jang, Taichang; Litofsky, N Scott; Smith, Thomas W et al. (2004) Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Neurobiol Dis 15:544-52
Lachyankar, Mahesh B; Condon, Peter J; Daou, Marie-Claire et al. (2003) Novel functional interactions between Trk kinase and p75 neurotrophin receptor in neuroblastoma cells. J Neurosci Res 71:157-72
Li, Li; Liu, Fenghua; Ross, Alonzo H (2003) PTEN regulation of neural development and CNS stem cells. J Cell Biochem 88:24-8
Quesenberry, P J; Colvin, G A; Abedi, M et al. (2003) The marrow stem cell: the continuum. Bone Marrow Transplant 32 Suppl 1:S19-22
Schonhoff, Christopher M; Daou, Marie-Claire; Jones, Stephen N et al. (2002) Nitric oxide-mediated inhibition of Hdm2-p53 binding. Biochemistry 41:13570-4
Engstrom, Caron M; Demers, Delia; Dooner, Mark et al. (2002) A method for clonal analysis of epidermal growth factor-responsive neural progenitors. J Neurosci Methods 117:111-21
Li, Li; Liu, Fenghua; Salmonsen, Rebecca A et al. (2002) PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol Cell Neurosci 20:21-9
Recht, L D; Salmonsen, R; Rosetti, R et al. (2001) Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol 62:755-63

Showing the most recent 10 out of 21 publications