Christopher Kemp

Environmental and genetic control of cancer cell evolution

The goal of our research is to understand how environmental exposure to carcinogens interacting with the genetic susceptibility of the host leads to cancer. As a basic research laboratory, we study multistage carcinogenesis in the mouse in order to model the entire natural history of neoplastic development from the initiated cell to clonal evolution to a fully malignant tumor. This has the following benefits: the study of a real biological endpoint in vivo; the influence of the host genetic background (e.g., susceptibility and resistance loci or modifier genes) can be studied; the role of particular genes can be studied using transgenic and knockout mice; somatic genetic changes (e.g., mutations in oncogenes and tumor suppressor genes) driving clonal neoplastic evolution and their phenotypic consequences can be studied in detail; and finally the specific effects of different carcinogen treatments on tumor development can be studied.

As a hallmark of the cancerous cell is loss of genetic fidelity, we are focusing on mutations in genes which control the cell cycle and/or the faithful segregation of genetic material as likely rate limiting steps. The p53 tumor suppressor gene is one such gene. It is mutated in the majority of human cancers and plays a critical role in maintaining genetic fidelity. p53 is normally induced in response to DNA damage leading to cell cycle arrest or apoptosis both of which protect the organism from the propagation of cells which have potentially neoplastic mutations. This pathway may also be important in the success or failure of chemo- or radio-therapy for cancer. We are addressing the following questions regarding p53 function: (1) What is the nature of the signal leading from DNA damage to increased levels of p53 protein to cellular response? We have discovered marked tissue specificity in the p53 response, even between tumor types and we are examining the role of DNAPK and ATM in this tissue specific response. (2) What is the role of p19/Arf as a tumor suppressor and in regulation of p53? We recently published a paper showing that Arf does indeed regulate p53 during skin tumor progression in vivo and, moreover that loss of Arf led to increased metastic spread of these tumors. We are now pursuing the mechanism by which loss of Arf increases metastasis (3)What is the role of p53 in the response of tumors to chemotherapy?

We have discovered that the cell cycle inhibitor p27/kip1 is a tumor suppressor gene in multiple epithelial tissues in mice. Expression of p27/kip1 is also an important prognostic marker in virtually all human neoplasias examined. We are following up on these observations by: (1) Testing for genetic interaction between p27 loss and other oncogenes such as ras and tumor suppressor genes such as p53 and apc. We have shown strong synergy between loss of p27 and alteration in these genes indicating that p27 acts a tumor suppressor in multiple tissues and on multiple genetic pathways. (2) Pursuing the biological mechanism by which p27 suppresses tumor formation. (3) We have also discovered that p27 is mislocalized in tumor cells, with much higher levels in cytoplasmic vs. nuclear fractions. We actively investigating the mechanism of mislocalization as well as the consequences for tumorigenesis. We spectulate that cytoplasmic p27 may play in role in tumor cell invasion.

We are also involved in a large multicenter grant, the goal of which is to enhance the early detection of cancer using serum proteomics. We are using ten different mouse models of cancer as a model system to identify serum peptides that are correlate with tumor burden and that can be used for early detection.