Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer

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Abstract

The ability to model cancer in the mouse has provided a robust methodology to dissect the molecular etiology of cancer. These models serve as potentially powerful platforms to preclinically evaluate novel therapeutics. In particular, the recent development of strategies to conditionally induce the or knockout the function of genes in a tissue specific manner has enabled investigators to engineer mice to demonstrate that the targeted inactivation of specific oncogenes can be effective in inducing sustained regression of tumors. Thus, these animal models will be useful to define the specific genes that will be therapeutically useful to target for the treatment of particular human cancers.

Introduction

Mouse models are powerful research tools to interrogate how many oncogenes cause cancer [1], [2], [3]. Recently, several robust strategies have been developed to generate transgenic mice that conditionally express a particular gene. Several methods have been utilized, including the Tetracycline Regulatory System (Tet System), the Tamoxifen System, the Cre/loxP System, and the Avian Retroviral Receptor (RCAS-TVA) System. The unprecedented ability to switch gene expression on and off in transgenic mice has been used to demonstrate that the inactivation of a single oncogene can be sufficient to revoke cancer [3]. These results suggest that there are circumstances when the targeted inactivation of a single oncogene will be effective in the treatment of cancer. However, it has also been found in these animal models that tumors can escape dependence upon the oncogene that initiated the process of tumorigenesis [4]. Hence, in order to determine when the inactivation of an oncogene will be effective in the treatment of cancer, it is important to understand how oncogene activation sustains tumorigenesis. Here, we will outline how conditional animal model systems can be used to define when and how oncogene inactivation induces sustained tumor regression.

We will focus our review first on describing the various methods that have been employed to generate conditional mouse models of cancer. We will then discuss how these conditional models have been used to define when oncogene inactivation induces tumor regression; to evaluate the duration and degree to which an oncogene must be inactivated to induce tumor regression; to determine the mechanism by which tumors regress upon oncogene inactivation; and to predict when tumors will relapse and the mechanisms by which they escape dependence upon a particular oncogene. Finally, we will discuss how these strategies may be useful in the development of new, targeted treatments for cancer.

The ability to generate mice that exhibit the tight and regulated control of oncogene expression is useful both to illuminate the cellular and molecular mechanisms by which oncogenes cause and sustain tumorigenesis, and more importantly to validate the use of oncogenes as therapeutic targets for the treatment of cancer.

Section snippets

The Tetracycline and Tamoxifen Systems

The Tet System allows both tissue-specific and temporal regulation of gene expression [5], [6], [7]. It incorporates tissue-specific expression of the tetracycline-controlled transactivator (tTA) and a responder transgene that links the tetracycline response element (Tet-O) to the gene of interest (Fig. 1). The Tet System exists in two versions, Tet-Off (Fig. 1a) and Tet-On (Fig. 1b), depending whether the engineered transcription factor (tTA or rtTA) binds the Tet-O sequence in the absence

The Tet and Tamoxifen Systems

To conditionally regulate oncogene expression in a tissue-specific and temporally controlled manner, most investigators have chosen either the Tet System or the Tamoxifen System. Both approaches have been used to ask the fundamental question, how does oncogene activation induce tumorigenesis, and when is oncogene inactivation sufficient to result in tumor regression? Now many reports have confirmed the surprising finding that the inactivation of even a single oncogene in an established and even

Mechanisms of tumor regression

We and others have previously documented the remarkable finding, using the Tet System to conditionally regulate expression of several different oncogenes, cancer is a reversible disease [3], [13], [49]. Even highly genomically complex and/or metastatic tumors are reversible upon oncogene inactivation [26], [34], [37]. One might imagine that the regression of tumors would involve different pathways depending on the oncogene and the cancer type. However, tumor regression that occurs upon oncogene

Therapeutic implications

The results obtained from these powerful conditional animal model systems will be useful in identifying and validating targets for the therapy of cancer. If turning oncogene expression off leads to tumor regression in an animal model, this oncogene may be a good pharmacological target. Then, by identifying the downstream effector genes critical for this oncogene to sustain tumorigenesis, it may be possible to identify genes that are better drug targets. Moreover, these strategies will be useful

Conclusion

Animal models for conditional oncogene expression are now widely used to investigate many different types of cancer that in many cases closely mimic human cancers [4]. These models have facilitated a detailed analysis of the mechanisms by which specific oncogenes initiate and sustain tumorigenesis, to define when oncogene inactivation will induce tumor regression, and to predict and account for how tumors escape dependence upon oncogenes and relapse. Ultimately, through these models, it may be

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