Non-melanoma skin cancer is the most common form of human malignancy. It is widely believed that cytokines produced by the skin play a fundamental role in controlling the development of this type of malignancy and that genetic polymorphisms that control cytokine production are important determinants in individual susceptibility to skin cancer. In spite of this, relatively little is known about the mechanisms by which cytokines influence skin cancer development and essentially no experimental studies have examined their influence on the cutaneous carcinogenesis pathway prior to the time that tumor s have developed. Based on our preliminary data in mice that suggests that cytokines inhibit the development of skin cancer at a very early stage in its evolution, we propose to examine in detail the role that TNF-alpha and other cytokines play in chemically-induced skin cancer in C3H/HeJ mice. These two stains of mice differ only at the Lps locus, a gene which controls synthesis and release of tumor necrosis factor-alpha and other cytokines such as IL-1 and IL-6. Initial studies will examine whether the administration of TNF-alpha antibodies in vivo to C3H/HeN mice augments dimethylbenz(a-anthracene (DMBA)-induced cutaneous tumorigenesis. In order to determine whether TNF-alpha inhibits the tumor initiation stage of carcinogenesis, anti-TNF-alpha antibodies will be administered to C3H/HeN mice to determine whether 3H-DMBA binding to DNA is increased and recombinant TNF-alpha will be given to C3H/H3J mice in an attempt to decrease 3H-DMBA binding to epidermal DNA. Once the studies with TNF-alpha have been completed, we will examine other multifunctional cytokines which are known to be produced in response to Lps in C3H/HeN mice, but are not produced by C3H/HeJ mice fore the same effects. Included among these are IL-1 alpha, IL-1 beta, and IL-6. In other experiments, the in vitro cytotoxic and growth inhibitory activity of TNF-alpha and other cytokines on cell lines derived from epidermal tissue at various stages in the DMBA-induced cutaneous carcinogenesis pathway will be examined. Localization of cytokine mRNAs and protein in skin following DMBA treatment will be determined by in situ hybridization and immunohistochemistry. Finally, the effect of DMBA on TNF-alpha gene transcription and mRNA translation by the skin will be investigated. Knowledge obtained from these studies may help to define the role that polymorphic genetic factors that control cytokine biosynthesis play in the development of skin cancer. The results may offer new approaches for the prevention and therapy of skin cancer.
Showing the most recent 10 out of 12 publications
