Research Summary

Since everyone has some DNA damage in their cells, an important question is whether we can do anything to prevent cancer progression even after cells are damaged.  Our lab is interested in finding ways to block the development of tumors from these mutated cells that can lie dormant in our bodies for many years.  We have genetically engineered mice that are predisposed to tumor development and, thus, mimic individuals at high risk for developing cancer.  These animals possess two genetic lesions that are commonly found in the majority of human tumors: an activated Ras and high levels of ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines.  Polyamines are essential for normal growth and development of all cells.  We have demonstrated that the expression of just these two proteins, an activated Ras and ODC, is sufficient to transform a normal epithelial cell into a malignant, invasive tumor cell.  A premise of our research efforts is that chemotherapeutic strategies that interfere with signaling events that are downstream from elevated levels of ODC and polyamines will be effective at treating and preventing cancer.  To address this goal, my lab has several distinct but integrated projects, including the study of polyamine-regulated genes that control angiogenesis, chromatin remodeling, the use of chemopreventive agents such as tea polyphenols in cancer prevention, and the formation of a reactive stroma.

1. Currently there is increasing emphasis on identifying naturally occurring dietary substances as chemopreventive agents.  Green tea has been shown to possess cancer chemopreventive effects in a wide range of tissues in both animals and humans.  We are studying the mechanism by which the green tea polyphenol component, EGCG, inhibits the formation of tumors using our ODC/Ras double transgenic mouse model.  We have found that a low dose of EGCG selectively kills skin cells that have high levels of ODC/polyamines but not normal cells.  This is a significant finding since all epithelial tumors, even benign tumors, have high levels of polyamines.  We plan to investigate the mechanism by which EGCG selectively causes an apoptotic death in epithelial cells with elevated levels of polyamines.
2. A tumor has been described as a “wound that never heals.”  Wound healing and tumor formation share many features including increased cellular proliferation, cellular migration, protease activity, and formation of new blood vessels.  We have shown that elevated levels of polyamines that are induced in mouse skin activate both keratinocytes and underlying stromal cells in a manner similar to skin undergoing wound healing.  Raising polyamine levels, as are found in early preneoplastic conditions such as actinic keratoses or intestinal adenomas, stimulates proliferation, differentiation, angiogenesis, and invasiveness.  We are using a transgenic mouse model in which ODC activity and polyamines can be specifically induced de novo in adult skin to study how elevated levels of polyamines affect the cross-talk between epithelial cells and underlying stromal cells to promote angiogenesis and the formation of tumors.
3. Gene expression is altered as normal cells progress to a more malignant phenotype.  Changes in gene expression are regulated in part by changes in the acetylation of histones associated with the chromatin.  We have found that chromatin remodeling is modulated by elevated levels of polyamines.  Tumors and tissues with higher levels of polyamines have intrinsically high histone acetyltransferase (HAT) activity as compared to normal skin.  Using chromatin immunoprecipitation (ChIP) techniques, we plan to identify key polyamine-regulated genes that play a pivotal role in promoting cancer.
4. Cancer is a disease of aging.  We are testing our hypothesis that aging promotes the formation of a reactive stroma in epithelial tissues such as skin, colon, and prostate, and that these changes in the tissue stromal microenvironment facilitate the formation and/or progression of cancer.  Our longterm goal is to identify new targets to which future chemotherapeutic strategies for the treatment of cancer can be directed.

Selected Publications

1. Lan, L., Trempus, C., and Gilmour, S.  (2000).  Inhibition of ornithine decarboxylase decreases tumor vascularization and reverses spontaneous tumors in ODC/Ras transgenic mice. Cancer Res. 60:5696-5703.
2. Gilmour, S.K., Teti, K.A., Wu, K.Q., and Morris, R.J.  (2001). A simple in vivo system for studying epithelialization, hair follicle formation and invasion using primary epidermal cells from wild-type and transgenic ornithine decarboxylase-overexpressing mouse skin.  J. Invest. Dermatology, 117:1674-1676.
3. Hobbs, C., Paul, B., and Gilmour, S.  (2002) Deregulation of polyamine biosynthesis alters intrinsic histone acetytransferase and deacetylase activities in murine skin and tumors.  Cancer Res. 62:67-74.
4. Hobbs, C. Paul, B., and Gilmour, S.  (2003) Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation.  Exp. Cell Res. 290:427-436.
5. Paul B, Hayes CS, Kim A, Athar M, and Gilmour SK. (2005). Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice. Carcinogenesis 26: 119-126.

This work is currently supported by the following grants:

• NIH RO1 CA70739 “Polyamines and Epithelial Tumorigenesis
  
• NIH RO1 CA95592 “Polyamine-Modulated Histone Acetylation in Tumorigenesis
• NIH RO1 CA79909 “Polyamine-Regulated Gene Expression During Cancer Promotion
• NIH RO1 CA97249 “Basal Cell Carcinoma: Molecular Pathogenesis & Prevention

Personnel/Staff

• Candace Sewter, Biomedical Research Assistant II
• Karen DeFeo, Biomedical Research Assistant II