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Prolonged Dormancy and Site-specific Growth Potential of Cancer Cells Spontaneously Disseminated from Nonmetastatic Breast Tumors as Revealed by Labeling with Green Fluorescent Protein

University of California San Diego, Cancer Center and Departments of Pathology [S. G., K. K., J. H., V. U., D. T.] and Surgery [R. H.], La Jolla, California 92093; AntiCancer, Inc., San Diego, California 92111 [P. J., M. Y., R. H.]

This study used an isogenic pair of metastatic (M4A4) and nonmetastatic (NM2C5), green fluorescent protein-labeled human breast cancer cell lines derived from the same patient and inoculated into the mammary glands of nude mice to investigate the dissemination patterns and fate of cells that escaped spontaneously from the resulting tumors. After tumors appeared, fluorescing single tumor cells were regularly seen in the lungs, even in animals inoculated with NM2C5, which fails to form secondary tumors in other organs. The sensitivity of the technique confirmed the continuing presence of scattered NM2C5 cells after primary tumor resection, although they formed no metastases by 6 months. These self-disseminated human tumor cells were retrievable from the tissues and were still viable and malignant, manifested by indefinite proliferation in vitro and green fluorescence and local tumorigenicity in vivo. Therefore, these scattered tumor cells were still immortal but rendered indefinitely quiescent by the microenvironmental conditions in the lung tissue. This is the first unequivocal demonstration of spontaneous distant dissemination of human cancer cells by undisturbed nonmetastatic tumors and comprises a valuable system for the analysis of tumor dormancy. In contrast, although many of the cells disseminating from M4A4 tumors grew into fluorescing metastases in the lungs, others remained solitary and quiescent. Therefore, even in a clonally derived cell population with metastatic properties, many cells do not, or cannot, mobilize the organ-specific growth properties needed to generate metastases. This experimental approach, by using self-disseminating, green fluorescent protein-labeled, sister cell lines of opposing metastatic phenotypes, opens new avenues for investigating topics of clinical relevance, including tumor cell dormancy, anatomical distribution of metastases, and host factors influencing the metastatic process.

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