The survival of patients with primary brain tumors has seen little change in recent years despite the many advances in the understanding and treatment of cancer. Some tumors have been found to exhibit an autocrine or paracrine growth factor loop to support continued tumor growth and proliferation. The transforming growth factors beta (TGFbeta) are a group of multifunctional factors that have been shown to play a vital role in normal cellular functions, including cell proliferation and differentiation, extracellular matrix deposition, and cell adhesion and migration. In the majority of tissue types studied, TGFbeta has been shown to be growth suppressive likely due to the increased expression or activities of several cyclin-dependent kinase inhibitors. The role of TGFbeta in cancer is quite complex -- it may act as a tumor suppressor in the early stages of tumorigenesis, but later as a tumor stimulator by increasing the invasiveness and survival of tumors due to TGFbeta's effects on local immunosuppression. TGFbeta is postulated to exert an inhibitory effect on the growth of normal astrocytes, however, many gliomas secrete TGFbeta and this activity has been shown to be associated with a higher-grade tumor phenotype. TGFbeta thus appears to play a number of roles in the development and continued growth of gliomas, though the precise biological mechanisms of TGFbeta involved in those processes remain poorly understood. The hypothesis of the proposed project, therefore, is that the altered response to TGFbeta in gliomas is, in part, responsible for its malignant behavior. We intend to elucidate the mechanism underlying the inhibitory role of TGFbeta on the growth of both normal, primary astrocytes as well as TGFbeta-sensitive gliomas most likely representing the early stage of tumor growth. We will then determine the mechanism by which many high-grade gliomas become resistant to the TGFbeta growth- inhibitory signal then attempt to correct the defect. Furthermore, we will investigate the mechanism by which TGFbeta plays a stimulatory role in promoting glioma invasiveness as well as the effect on peritumoral edema.
| Rich, Jeremy N (2003) The role of transforming growth factor-beta in primary brain tumors. Front Biosci 8:e245-60 |
| Rich, Jeremy N; Shi, Qing; Hjelmeland, Mark et al. (2003) Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem 278:15951-7 |
| Rich, J N; Guo, C; McLendon, R E et al. (2001) A genetically tractable model of human glioma formation. Cancer Res 61:3556-60 |
