Introductory comments

The laboratory mouse has been a central player in cancer research for the better part of this century. Particularly over the past two decades, numerous laboratories have used the techniques of transgenesis and gene targeting to create novel mouse strains to study cancer. The analysis of these strains has led to an improved understanding of the genes involved in tumorigenesis in humans, the histopathological progression of cancer, and many other aspects of the disease process that can only be studied in the context of the whole animal. With more genes, more powerful methods of genetic manipulation and greater insight into tumor pro®les on the molecular and cellular levels, the long-standing goal to create genetically and histopathologically accurate models of cancer development in the mouse is beginning to be realized. This special issue of Oncogene features reviews by many leaders of the e€ort to model human cancer in the mouse, and collectively they provide a view of the `state of the art' in this burgeoning ®eld. Historically, transgenic strains carrying activated forms of oncogenes or conventional `knockouts' of tumor suppressor genes have been generated to test the causal relationship between the expression (or lack of expression) of a gene and tumor development. These `®rst generation' models initially validated the importance of particular genes and their mutations in tumorigenesis. Additional e€orts with these models have included the combining of multiple cancerassociated mutations in a single animal, the discovery of cooperating mutations using insertional mutagenesis, and the initial molecular genetic analysis of tumor maintenance and progression. As a better understanding of cancer-associated pathways has emerged from these and other studies, more directed experiments in the mouse have been undertaken, which have sometimes con®rmed or otherwise challenged the importance of a given gene or process in tumor development. The current era of mouse tumor modeling looks very di€erent from the last. Now, at the turn of this millenium, compound mutations are commonplace, constitutive expression systems are being replaced by inducible ones, and conditional gene targeting strategies are quickly becoming feasible and often favored over germline loss-of-function mutations. The study of tumorigenesis in these models has been greatly facilitated by the development of gene expression array technologies, improved tools for genomic analysis, and other powerful methods for the molecular dissection of disease progression. With this new arsenal of strains, tools and expertise, there has been a growing acceptance of the importance of mouse models of human cancer over the past several years. Beyond the technical achievements, this enthusiasm has been fueled by the recognition that cancer is a disease of the organism, not simply of abnormal cells. In order to study accurately the complex host-tumor interactions that occur during tumor development, it is necessary to perform experiments in an in vivo setting in which neoplasms emerge in the appropriate microenvironment. While the achievements in this ®eld are notable, signi®cant challenges remain. Among the unresolved issues is the nature of the species-speci®c phenotypes of germline mutations of cancer-associated genes. In some respects, these di€erences represent limitations of the mouse as a model; however, the elucidation of these di€erences may also provide insight into the molecular basis for tissue speci®city of cancer predisposition in humans. For instance, malignant progression, especially to metastasis, is less common in mouse tumors compared to humans. Given the clinical importance of these end stages of human cancer, this di€erence must also be resolved for mouse models to realize their full utility. Mouse cancer models have been useful in screening some potential chemotherapeutic and chemopreventative agents, but there remains considerable skepticism from drug development circles about the value of such models. In large part, this concern re ̄ects a long and unsatisfying history with xenograft models, in which highly malignant human tumor cells are grafted under the skin or elsewhere in an immunocompromised mouse. Until the modern mouse modeling community delivers additional evidence that the new strains can be used to predict the ecacy of a potential human therapeutic, such skepticism will remain. Finally, to reach their full potential, current and future mouse tumor models must be viewed as a source of discovery for new therapeutic leads, not simply as vehicles to con®rm information gained from human studies. Such initiatives should include expanding the e€ort to discover natural, variant alleles that modify cancer phenotypes and forward genetic screens that will create new alleles of genes that can enhance or suppress tumor development. With the recent commitments from the NIH and NCI to improve genomic tools for the mouse and to accelerate the sequencing of the mouse genome, the timing is right to scale-up true cancer genetics in the mouse. As exempli®ed by the reviews that follow, the ®eld of cancer modeling in the mouse has come a long way since the earliest oncogene transgenic strains, and the pace of change is accelerating. With time, all major human tumor types should have one or more associated mouse models that accurately re ̄ect the genetic and histopathological progression of the disease. Until then we anticipate a journey of great discovery, during which the mouse will be teaching us how cancer arises, how it is sustained, and how it can be subdued. *Correspondence: T Jacks Oncogene (1999) 18, 5248 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $15.00