Mouse models of inherited cancer syndromes (original) (raw)
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Handbook of Experimental Pharmacology, 2007
be reconstituted by selectively restoring MMP9 expression in haematopoietic cells, showing that inflammatory cells, recruited by the tumour, can provide MMP-9 to stimulate tumour growth.
Genetically engineered mouse models have significantly contributed to our understanding of cancer biology. They have proven to be useful in validating gene functions, identifying novel cancer genes and tumor biomarkers, gaining insight into the molecular and cellular mechanisms underlying tumor initiation and multistage processes of tumorigenesis, and providing better clinical models in which to test novel therapeutic strategies. However, mice still have significant limitations in modeling human cancer, including species-specific differences and inaccurate re-capitulation of de novo human tumor development. Future challenges in mouse modeling include the generation of clinically relevant mouse models that recapitulate the molecular, cellular, and genomic events of human cancers and clinical response as well as the development of technologies that allow for efficient in vivo imaging and high-throughput screening in mice.
Genetically modified mouse models in cancer studies
Clinical and Translational Oncology, 2008
Genetically modified animals represent a resource of immense potential for cancer research. Classically, genetic modifications in mice were obtained through selected breeding experiments or treatments with powerful carcinogens capable of inducing random mutagenesis. A new era began in the early 1980s when genetic modifications by inserting foreign DNA genes into the cells of an animal allowed for the development of transgenic mice. Since that moment, genetic modifications have been able to be made in a predetermined way. Gene targeting emerged later as a method of in vivo mutagenesis whereby the sequence of a predetermined gene is selectively modified within an intact cell. In this review we focus on how genetically modified mice can be created to study tumour development, and how these models have contributed to an understanding of the genetic alterations involved in human cancer. We also discuss the strengths and weaknesses of the different mouse models for identifying cancer genes, and understanding the consequences of their alterations in order to obtain the maximum benefit for cancer patients.
Oncogene, 2002
The laboratory mouse is one of the most powerful tools for both gene discovery and validation in cancer genetics. Recent technological advances in engineering the mouse genome with chromosome translocations, latent alleles, and tissue-specific and temporally regulated mutations have provided more exacting models of human disease. The marriage of mouse tumor models with rapidly evolving methods to profile genetic and epigenetic alterations in tumors, and to finely map genetic modifier loci, will continue to provide insight into the key pathways leading to tumorigenesis. These discoveries hold great promise for identifying relevant drug targets for treating human cancer.
Genetically Engineered Mouse Models in Cancer Research
Advances in Cancer Research, 2010
Mouse models of human cancer have played a vital role in understanding tumorigenesis and answering experimental questions that other systems cannot address. Advances continue to be made that allow better understanding of the mechanisms of tumor development, and therefore the identification of better therapeutic and diagnostic strategies. We review major advances that have been made in modeling cancer in the mouse and specific areas of research that have been explored with mouse models. For example, although there are differences between mice and humans, new models are able to more accurately model sporadic human cancers by specifically controlling timing and location of mutations, even within single cells. As hypotheses are developed in human and cell culture systems, engineered mice provide the most tractable and accurate test of their validity in vivo. For example, largely through the use of these models, the microenvironment has been established to play a critical role in tumorigenesis, since tumor development and the interaction with surrounding stroma can be studied as both evolve. These mouse models have specifically fueled our understanding of cancer initiation, immune system roles, tumor angiogenesis, invasion, and metastasis, and the relevance of molecular diversity observed among human cancers. Currently, these models are being designed to facilitate in vivo imaging to track both primary and metastatic tumor development from much earlier stages than previously possible. Finally, the approaches developed in this field to achieve basic understanding are emerging as effective tools to guide much needed development of treatment strategies, diagnostic strategies, and patient stratification strategies in clinical research.
Developing genetically engineered mouse models to study tumor suppression
Current protocols in mouse biology, 2012
Since the late 1980s, the tools to generate mice with deletions of tumor suppressors have made it possible to study such deletions in the context of a whole animal. Deletion of some tumor suppressors results in viable mice while deletion of others yield embryo lethal phenotypes cementing the concept that genes that often go awry in cancer are also of developmental importance. More sophisticated mouse models were subsequently developed to delete a gene in a specific cell type at a specific time point. Additionally, incorporation of point mutations in a specific gene as observed in human tumors has also revealed their contributions to tumorigenesis. On the other hand, some models never develop cancer unless combined with other deletions suggesting a modifying role in tumorigenesis. This review will describe the technical aspects of generating these mice and provide examples of the outcomes obtained from alterations of different tumor suppressors.
The comparative genetics and genomics of cancer: of mice and men
2003
The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, however, remain problematic. Recent advances in genomic technologies offer significant opportunities to identify critical changes that occur during cancer evolution and to distinguish in a complex and comprehensive manner the key similarities and differences between mouse models and human cancer. Comparisons between mouse and human tumors are being performed using comparative genomic hybridization, gene expression profiling, and proteomic analyses. The appropriate use of genetically engineered mouse models of mammary cancer in preclinical studies remains an important challenge which may also be aided by genomic technologies. Genomic approaches to cancer are generating huge datasets that represent a complex system of underlying networks of genetic interactions. Mouse models offer a tremendous opportunity to identify such networks and how they relate to human cancer. The challenge of the future remains to decipher these networks in order to identify the genetic nodes of oncogenesis that may be important targets for chemoprevention and therapy.