Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in the disease process requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, and noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. Since light is transmitted through mammalian tissues, it is possible to externally, and quantitatively monitor growth and regression of labeled tumors. Development of spontaneous tumor models allows the complete disease course to be interrogated. In the first aim in this proposal we will develop a spontaneous breast tumor model where the cells acquire an optical tag in the form of an expressed bioluminescent reporter gene at the time of transformation.
The second aim of the proposal is to utilize our demonstrated ability to detect small numbers of labeled tumor cells in living animals noninvasively to externally monitor the full disease course and reveal the natural history of the disease at the cellular level. In the third specific aim we will evaluate therapies that are designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor, which can be accelerated with this approach. We will evaluate both chemotherapy, and immunotherapeutic treatments with ex vivo expanded T cell derived effector cells which share functional and phenotypic properties with natural killer (NK) cells. The immune control of breast cancer early in the course of the disease process and in particular the mechanism(s) of anti-tumor activity of ex vivo expanded T cell populations (CD3+CD8+NK1.l+ NK-like T cells) will be evaluated as a model of immune surveillance. Since whole body images are generated it may be possible to monitor micrometastases and evaluate the immune cell therapy in controlling metastatic processes. This model system should allow sensitive, quantitative, real time analyses of the dynamics of neoplastic cell growth and facilitate rapid optimization of effective treatment regimens for breast cancer. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time. This proposal combines sophisticated transgenic sciences with advanced cellular and molecular imaging for a robust in vivo analysis of a breast cancer model that is relevant to human disease. These studies are likely to provide basic biological insights and therapeutic strategies useful for more effective treatment of patients.
