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The utility of genetically altered mouse models for cancer research
Mutation Research 576 (2005) 1–3
Introduction
The utility of genetically altered mouse models for cancer research Beverly Teicher suggested in the preface for the 2002 book “Tumor Models in Cancer Research” that an ideal tumor model would “imitate in scale and mirror in response the human disease” [1]. She also stated that “no ideal models for the diseases that are cancer currently exist”. However, animal models, even with all of their limitations, have contributed significantly to our understanding of the carcinogenesis process and ways to interfere with that process. Furthermore, recent efforts are producing genetically altered mouse models that reflect with greater relevance and precision specific aspects of carcinogenesis in humans [2]. The development of mouse strains with carcinogenesis-related genes overexpressed or inactivated provides investigators with new models for studying the biology of cancer and for testing interventions that can offset specific and highly relevant genetic susceptibilities to cancer in humans. These transgenic and knockout model systems are also providing new tools that inform the risk assessment process [3]. This special issue of Mutation Research provides a series of examples of how genetically altered mice are being used to enhance our basic understanding of cancer as well as to develop new strategies and targeted agents for treating and preventing cancer. Five reviews explore the application of transgenic and knockout models in basic cancer research. Two of the reviews (by Attardi and Donehower and by Sharpless) describe genetically engineered mouse models with germ line alterations in two critical tumor suppressor loci, Trp53 and INK4A/ARF. Alterations in these genes or the pathways they regulate occur in the majority of human cancers. Thus, alteration of these and other cancer-
0027-5107/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2005.04.007
associated genes in the mouse provides an opportunity to understand their normal and aberrant functioning in the context of a highly manipulable mammalian organism. These two reviews also explore some of the evolving genetic engineering methodologies that have allowed investigators to generate ever more sophisticated models that more closely mimic cancer initiation and progression in humans. A third paper by Chang investigates some of the insights obtained from mouse models deficient in telomerase function. Human tumors have consititutive expression of telomerase and the mouse telomerase knockout mouse has been particularly useful in providing insights into the role of telomerase in cancer and organismal aging. The fourth review by Hu and Holland takes a more organ-based approach to describe the modeling of brain tumor formation in mice. In addition to describing the generation and characterization of genetically engineered mice predisposed to brain tumors through manipulation of various oncogenes and tumor suppressor genes, they show how cancer associated genes can be delivered to small numbers of individual brain cells to more closely approximate the origin of somatically arising brain cancers which are the predominant form in humans. Finally, Green and colleagues discuss how gene expression microarray analyses have provided powerful tools for mechanistic analyses of prostate cancers with a view to improving diagnostic and therapeutic options. The application of these technologies to prostate tumor susceptible mouse models will provide additional insights into the usefulness of these mice as pre-clinical tools as well as a rich source for cancer gene discovery.
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Introduction / Mutation Research 576 (2005) 1–3
A major goal in contemporary cancer research is the development of effective mechanism-based strategies for preventing and treating human cancer. Successful attainment of this goal will require the integration of the very best science from multiple levels of investigation, including clinical and epidemiologic research, animal studies and basic molecular and cellular biologic research. All three levels of investigation are essential in this effort, although in our view animal model studies play a critical central role. For instance, animal studies are required to confirm (under controlled experimental conditions) potential leads from human studies showing associations between certain risk factors (both protective and harmful) and cancer risk. In addition, pre-clinical studies are also critical in translating basic mechanistic findings from the bench to the clinic. Thus, the availability of highly relevant animal models will greatly facilitate future progress in cancer prevention and therapy research (Fig. 1). The need for models that closely reflect key aspects of the carcinogenesis process in humans is particularly critical to advancing the cancer prevention field. Most animal models used until recently in cancer prevention research were developed prior to the identification of the major cancer-related genes and epigenetic regula-
tors, as well as recognition of the importance of host susceptibility to a carcinogenic insult. The major goal in the development of these carcinogen-induced tumor models was the rapid generation of neoplasia to provide investigators with sufficient material in a timely fashion for studying the biology of the tumors [4]. While a small number of models are based on low-dose carcinogen exposure, most generally involve high-dose regimens of a single genotoxic carcinogen (often with no apparent relationship to the etiology of human cancer, such as dimethylbenzanthracene) which can induce largescale genetic damage in a random fashion. Although some of the molecular alterations have been identified in the commonly employed models, the types of alterations caused by high-dose chemical exposures do not generally reflect the gene–environment interactions underlying the pathogenesis of cancer in humans. Furthermore, the interpretation of the activity of therapeutic or preventive compounds being evaluated in these models can often be confounded by the effects of those compounds on the metabolic activation or detoxification specific to high-doses of a particular carcinogen, which may be less relevant to typical chronic, low-level human exposures to mixtures of exogenous or endogenous carcinogens.
Fig. 1. Molecular pathways relevant to carcinogenesis, cancer therapy and prevention in genetically altered mouse models. This figure depicts the pathways and molecular targets that are discussed in this special issue focused on the utility of genetically altered mouse models for cancer research. Many mutations and targeted changes in the expression of the genes shown in the figure have been engineered into the mouse genome to create models for studying the carcinogenesis process as well as for developing and testing preventive and therapeutic strategies for cancer.
Introduction / Mutation Research 576 (2005) 1–3
Five papers are presented in this issue that provide examples of cancer prevention or treatment studies that have utilized genetically altered mouse models to identify new targets and strategies for interventions. These examples focus on models of mammary (Brown et al.), prostate (Klein and Fisher), intestinal (Greiner et al.) and hematopoietic cancers (Hursting et al. and Letterio) and involve alterations in the Trp53, Wnt/APC, IGF-1, cyclooxygenase, ErbB/ras and TGFß pathways (Fig. 1). Taken together, these examples clearly indicate that mice with specific (and humanlike) genetic susceptibilities for cancer provide powerful new tools for testing agents and interventions that can interfere with the process of carcinogenesis in humans.
References [1] B. Teicher (Ed.), Tumor Models in Cancer Research, Humana Press, Totowa, NJ, 2002. [2] K.F. Macleod, T. Jacks, Insights into cancer from transgenic mouse models, J. Pathol. 187 (1999) 43–60.
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[3] D. Jacobsen-Kram, F.D. Sistare, A.C. Jacobs, Use of transgenic mice in carcinogenicity hazards testing, Toxicol. Pathol. 32 (2004) S49–S52. [4] S.H. Yuspa, M.C. Poirier, Chemical carcinogenesis: from animal models to molecular models in one decade, Adv. Cancer Res. 50 (1988) 25–70.
Lawrence A. Donehower∗ Baylor College of Medicine, Department of Molecular Virology and Microbiology Houston, TX 77030, USA John E. French National Institute of Environmental Health Sciences Research Triangle Park, NC, USA Stephen D. Hursting National Cancer Institute, Bethesda, MD, USA ∗ Corresponding
author. Tel.: +1 713 798 3594 fax: +1 713 798 3490 E-mail address: [email protected] (L.A. Donehower) Available online 27 June 2005
Introduction
The utility of genetically altered mouse models for cancer research Beverly Teicher suggested in the preface for the 2002 book “Tumor Models in Cancer Research” that an ideal tumor model would “imitate in scale and mirror in response the human disease” [1]. She also stated that “no ideal models for the diseases that are cancer currently exist”. However, animal models, even with all of their limitations, have contributed significantly to our understanding of the carcinogenesis process and ways to interfere with that process. Furthermore, recent efforts are producing genetically altered mouse models that reflect with greater relevance and precision specific aspects of carcinogenesis in humans [2]. The development of mouse strains with carcinogenesis-related genes overexpressed or inactivated provides investigators with new models for studying the biology of cancer and for testing interventions that can offset specific and highly relevant genetic susceptibilities to cancer in humans. These transgenic and knockout model systems are also providing new tools that inform the risk assessment process [3]. This special issue of Mutation Research provides a series of examples of how genetically altered mice are being used to enhance our basic understanding of cancer as well as to develop new strategies and targeted agents for treating and preventing cancer. Five reviews explore the application of transgenic and knockout models in basic cancer research. Two of the reviews (by Attardi and Donehower and by Sharpless) describe genetically engineered mouse models with germ line alterations in two critical tumor suppressor loci, Trp53 and INK4A/ARF. Alterations in these genes or the pathways they regulate occur in the majority of human cancers. Thus, alteration of these and other cancer-
0027-5107/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2005.04.007
associated genes in the mouse provides an opportunity to understand their normal and aberrant functioning in the context of a highly manipulable mammalian organism. These two reviews also explore some of the evolving genetic engineering methodologies that have allowed investigators to generate ever more sophisticated models that more closely mimic cancer initiation and progression in humans. A third paper by Chang investigates some of the insights obtained from mouse models deficient in telomerase function. Human tumors have consititutive expression of telomerase and the mouse telomerase knockout mouse has been particularly useful in providing insights into the role of telomerase in cancer and organismal aging. The fourth review by Hu and Holland takes a more organ-based approach to describe the modeling of brain tumor formation in mice. In addition to describing the generation and characterization of genetically engineered mice predisposed to brain tumors through manipulation of various oncogenes and tumor suppressor genes, they show how cancer associated genes can be delivered to small numbers of individual brain cells to more closely approximate the origin of somatically arising brain cancers which are the predominant form in humans. Finally, Green and colleagues discuss how gene expression microarray analyses have provided powerful tools for mechanistic analyses of prostate cancers with a view to improving diagnostic and therapeutic options. The application of these technologies to prostate tumor susceptible mouse models will provide additional insights into the usefulness of these mice as pre-clinical tools as well as a rich source for cancer gene discovery.
2
Introduction / Mutation Research 576 (2005) 1–3
A major goal in contemporary cancer research is the development of effective mechanism-based strategies for preventing and treating human cancer. Successful attainment of this goal will require the integration of the very best science from multiple levels of investigation, including clinical and epidemiologic research, animal studies and basic molecular and cellular biologic research. All three levels of investigation are essential in this effort, although in our view animal model studies play a critical central role. For instance, animal studies are required to confirm (under controlled experimental conditions) potential leads from human studies showing associations between certain risk factors (both protective and harmful) and cancer risk. In addition, pre-clinical studies are also critical in translating basic mechanistic findings from the bench to the clinic. Thus, the availability of highly relevant animal models will greatly facilitate future progress in cancer prevention and therapy research (Fig. 1). The need for models that closely reflect key aspects of the carcinogenesis process in humans is particularly critical to advancing the cancer prevention field. Most animal models used until recently in cancer prevention research were developed prior to the identification of the major cancer-related genes and epigenetic regula-
tors, as well as recognition of the importance of host susceptibility to a carcinogenic insult. The major goal in the development of these carcinogen-induced tumor models was the rapid generation of neoplasia to provide investigators with sufficient material in a timely fashion for studying the biology of the tumors [4]. While a small number of models are based on low-dose carcinogen exposure, most generally involve high-dose regimens of a single genotoxic carcinogen (often with no apparent relationship to the etiology of human cancer, such as dimethylbenzanthracene) which can induce largescale genetic damage in a random fashion. Although some of the molecular alterations have been identified in the commonly employed models, the types of alterations caused by high-dose chemical exposures do not generally reflect the gene–environment interactions underlying the pathogenesis of cancer in humans. Furthermore, the interpretation of the activity of therapeutic or preventive compounds being evaluated in these models can often be confounded by the effects of those compounds on the metabolic activation or detoxification specific to high-doses of a particular carcinogen, which may be less relevant to typical chronic, low-level human exposures to mixtures of exogenous or endogenous carcinogens.
Fig. 1. Molecular pathways relevant to carcinogenesis, cancer therapy and prevention in genetically altered mouse models. This figure depicts the pathways and molecular targets that are discussed in this special issue focused on the utility of genetically altered mouse models for cancer research. Many mutations and targeted changes in the expression of the genes shown in the figure have been engineered into the mouse genome to create models for studying the carcinogenesis process as well as for developing and testing preventive and therapeutic strategies for cancer.
Introduction / Mutation Research 576 (2005) 1–3
Five papers are presented in this issue that provide examples of cancer prevention or treatment studies that have utilized genetically altered mouse models to identify new targets and strategies for interventions. These examples focus on models of mammary (Brown et al.), prostate (Klein and Fisher), intestinal (Greiner et al.) and hematopoietic cancers (Hursting et al. and Letterio) and involve alterations in the Trp53, Wnt/APC, IGF-1, cyclooxygenase, ErbB/ras and TGFß pathways (Fig. 1). Taken together, these examples clearly indicate that mice with specific (and humanlike) genetic susceptibilities for cancer provide powerful new tools for testing agents and interventions that can interfere with the process of carcinogenesis in humans.
References [1] B. Teicher (Ed.), Tumor Models in Cancer Research, Humana Press, Totowa, NJ, 2002. [2] K.F. Macleod, T. Jacks, Insights into cancer from transgenic mouse models, J. Pathol. 187 (1999) 43–60.
3
[3] D. Jacobsen-Kram, F.D. Sistare, A.C. Jacobs, Use of transgenic mice in carcinogenicity hazards testing, Toxicol. Pathol. 32 (2004) S49–S52. [4] S.H. Yuspa, M.C. Poirier, Chemical carcinogenesis: from animal models to molecular models in one decade, Adv. Cancer Res. 50 (1988) 25–70.
Lawrence A. Donehower∗ Baylor College of Medicine, Department of Molecular Virology and Microbiology Houston, TX 77030, USA John E. French National Institute of Environmental Health Sciences Research Triangle Park, NC, USA Stephen D. Hursting National Cancer Institute, Bethesda, MD, USA ∗ Corresponding
author. Tel.: +1 713 798 3594 fax: +1 713 798 3490 E-mail address: [email protected] (L.A. Donehower) Available online 27 June 2005