Carcinogen-Driven Mouse Models of Oncogenesis, Volume 163 contains a series of protocols written by world-leading experts in the field. Each manuscript provides a detailed methodological description to drive carcinogen-mediated oncogenesis in mice. Chapters in this new release include Chemical carcinogenesis in mice as a model of human cancer: Pros and cons, MPA/DMBA-driven mammary carcinomas, Dimethylbenz(a)anthracene-Induced Mammary Tumorigenesis in mice, Urethane-induced lung carcinogenesis, Methylcholanthrene-induced fibrosarcomas, BBN-driven bladder carcinomas, Oral squamous cell carcinomas driven by 4NQO, Analyzing skin tumor development in mice by the DMBA/TPA model, and much more. Other sections cover DSS/AOM-driven colorectal carcinomas, Diethylnitrosamine-induced liver tumorigenesis in mice, Two-stage 3-methylcholanthrene and butylated hydroxytoluene-induced lung carcinogenesis in mice, Lung carcinomas induced by NNK and LPS, Pristane-induced mammary carcinomas, The 4-NQO mouse model: an update on a well-established in vivo model of oral carcinogenesis, and more. Provides protocols provided by renowned experts in the field Presents detailed descriptions of protocols, hence allowing appropriate reproduction of the models Includes author notes for each protocol, covering useful tips and troubleshooting

Cancer develops as the end product of a multistep process in which cells and/or their microenvironments accumulate alterations, either genetic or epigenetic, which enable uncontrolled growth. During the early steps of this process, altered cells constituting the precursors to cancer are subject to the constraints of natural selection. As such, variations within the population of transformed cells which lead to increased relative fitness are reproductively favored by the various selective pressures of the local microenvironment. Anti-tumor immunity is an important arm of this pre-malignant niche. Consequently, for cancer to develop, at least one of the following four possibilities must occur: 1) the transformed cells progress to cancer without ever becoming immunogenic, 2) the transformed cells are immunogenic, but are able to proliferate faster than they are eliminated, 3) the host immune system becomes compromised or tolerized, or 4) from within the transformed population, new clones evolve adaptations that enable evasion of anti-tumor immunity. This final possibility has been termed “cancer immunoediting” and it includes three distinct stages of cancer-immune interaction: elimination, equilibrium, and escape. As a result of this process, every immunogenic cancer that develops in an immunocompetent host is intrinsically immune-evasive as a result of its past triumphs over anti-tumor immunity. Here, I describe a genetically engineered mouse model developed in order to study this process directly, via in vivo confocal microscopy. This model accurately recapitulates the cancer immunoediting process which occurs as a result of common mutations that drive human carcinomas. Using this model, I identified a previously unknown mechanism of early survival in which transformed cells use an immune-privileged niche as a surrogate for immune evasion. This project also provides a means to further characterize the adaptations that mediate the transitions between the stages of immunoediting. Finally, and perhaps most importantly, this model acts as a prototype for discovery of new biomarkers of human immunoediting as well as a screening tool for therapeutic interventions that could form the basis of rational cancer prevention strategies.

Mice have become the species of choice for modeling the complex interactions between tumor cells and the host environment. Mouse genetics are easily manipulated, and a growing array of technology exists for this purpose. Mouse models allow investigators to better understand causal relationships between specific genetic alterations and tumors, utilize new imaging techniques, and test novel therapies. Recent developments along these lines show great promise for the development of new anti-cancer treatments. Mouse Models of Human Cancer provides researchers and students with a complete resource on the subject, systematically presenting the principles, methodologies, applications, and challenges associated with this exciting field. Offering a survey of the latest research and a description of future areas of interest, this text: Presents real experimental data Describes organ site-specific mouse models Clearly identifies suitable models for further drug testing Critically analyzes current methodologies and their limitations Features numerous recognizable expert contributors Lists key Web sites, reagents, and companies From mouse handling and genetic engineering to preclinical trials, Mouse Models of Human Cancer is a comprehensive guide to using these models and relating them to human disease. Its uniform presentation describes organ-specific models in clinical, imaging, and molecular terms, and lays out the relevant genetics, experimental approaches, histological comparisons with human disease, and conclusions. Combining stellar chapter authors, rich illustrations, and clear, up-to-date coverage, Mouse Models of Human Cancer is an invaluable resource for advanced students and cutting-edge researchers.

Genetically-engineered mouse models for cancer research have become invaluable tools for studying cancer biology and evaluating novel therapeutic approaches. This volume focuses on state-of-the-art methods for generating, analyzing and validating such models for studying aspects of human cancer biology. Additionally, these models are emerging as important pre-clinical systems in which to test cancer prevention and therapeutic strategies in order to select compounds for testing in clinical trials.

Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues. The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.