The Molecular Biology and Biological Strategies of Cancer Genes
Cancer development involves alterations in both protooncogenes and tumor suppressor genes. In vitro systems have provided molecular details for the pathways potentially disrupted in this multi-step process. Yet, understanding tumorigenesis of diverse cell types clearly requires the use of in vivo systems such as genetically engineered mouse models. We have established several tumor models using transgenic (Tg) and knock-out strategies which have facilitated analysis of the tumor suppressors, p53 and pRb, including their contribution to normal growth control and the consequences of their inactivation to multi-step tumorigenesis. In two model systems, thymic lymphoma and brain carcinoma, in depth studies have shown that these tumor suppressors each have distinct roles depending upon the cell type. For example, inactivation of pRb causes tumor initiation in the brain system, although it has no measurable effect in T cells. Inactivation of p53, a gene that is altered in about 50 % of human cancers, contributes to tumorigenesis in both cell types, but in different ways. In T cells p53-deficiency predisposes to, or initiates, tumorigenesis, whereas in the brain tumor system p53 inactivation contributes only to tumor progression after initiation by other mechanisms. In this latter case p53 provides the cellular defense to oncogenic events causing abnormal cells to die by apoptosis.
We have utilized genetic, molecular, and cell biological approaches to explore the molecular pathways utilized by these tumor suppressors. These studies have identified some components of the pathway(s) and have shown which of them may or may not act as tumor suppressors, and why. This type of analysis provides validation of mechanisms suggested by in vitro studies, and in addition can reveal previously unknown possibilities. Also under study are the genes and mechanisms involved in tumor progression in each model. Genetic studies of predictable tumor stages form the basis for these projects. For example, in the brain model loss of the normal p53 allele occurs predictably in all in animals of a p53+/- background. Subsequent to p53 loss, these tumors rapidly progress to highly aggressive states, including extensive angiogenesis and invasiveness. This enables a detailed examination of the molecular and cellular events in developing tumors, a study not possible in human cancers. Studies are underway to characterize the chromosomal and gene expression aberrations that characterize these events. Furthermore, factors involved in angiogenesis and invasiveness are under study.
Finally, using combined transgenic and gene-targeting technologies we are developing preclinical models of glioma, mammary and prostate cancer. Tissue-specific technology is being applied to the systematic analysis of tumor-specific functions. The aim is to both understand the genetic and cellular changes that contribute to cancer in each case, to understand the cell-specificity of these mechanisms and to establish animal models for preclinical testing and development of therapeutic agents. For example, collaborative studies are underway with the Samulski lab at UNC to test and develop genetic therapy strategies for the delivery of anti-angiogenesis factors.
Room 5072, Genetic Medicine Bldg., CB 7264
Chapel Hill, NC 27599-7295
Office: (919) 962-2145
Lab: (919) 962-2148
Fax: (919) 843-3160
Email: Terry Van Dyke, Ph.D.