Studying cancer in the mouse.

Abstract

The mouse has been long studied by cancer researchers. The fact that mice can and do get cancer, coupled with the long and extensive experience with the mouse as an experimental organism, has fostered the important role of the mouse in cancer research. An enormous amount of this research over the past 20 years has involved the xenografting of human cancers into immunologically compromised mice. The limitations of this arti®cial experimental set-up, even with modi®cations such as orthotopic implantation, have become abundantly clear. While much information has been gleaned and some questions answered by the study of xenografts, critical conceptual and technical advances in cancer and experimental biology have allowed us to look beyond the era of xenografts to a new, modern era of mouse cancer research. There are major limitations of xenografts: (1) they do not allow us to examine the development of cancer; and (2) they largely treat cancer as a disease that can be understood by studying the cancer cells themselves and not as a complex interaction between the cancer and the host. The modern era of mouse cancer rests on at least two critical conceptual and two critical technical advances. Few conceptual advances can equal that of the unifying picture of cancer as a genetic disease whose behavior re ects the complex pattern of genetic and epigenetic changes that alters the information content of the developing cancer cell. The successful hunt for cancer genes, a relatively limited subset of all genes whose altered expression and/or function are central to the development of di€erent cancers, has totally altered our understanding of cancer. Decoding the meaning of these critically changed genes by identifying the cellular pathways in which they function is the central and increasingly successful e€ort in cancer biology. The second profound conceptual advance in biology is the truly unexpected level of conservation of genes, biologic molecules and cellular function across even the greatest evolutionary distances. That the structure and function of mismatch repair gene products which explain the human hereditary cancer syndrome, HNPCC, are conserved from bacteria to man illustrates this profound fact of conservation across species. Compared to the total span of evolution, the lineage that gave rise to mouse and man diverged relatively recently. While subtle details di€er, the essential function of most genes, in general, and most, if not all, genes identi®ed as important in human cancer, are likely to be very similar between mouse and man. It is this fact of the conservation of gene function between mouse and man, coupled with the genetic nature of cancer that conceptually underpins the new era of mouse cancer research. At the same time, major technical advances have allowed us to identify and assess the molecular changes associated with cancer and cancer development. There has been an explosive growth of accessible genetic databases and available collections of genomic and expressed gene reagents and rapidly evolving tools for detecting genomic alterations and gene expression patterns. Finally, we have entirely new capabilities for manipulating gene expression and gene function in the mouse. All of these technological and informational advances enable new approaches to the mouse and to the study of mouse cancer.