Malignant tumors disseminate throughout the body by hematogenous routes leading to distant tumor metastasis. The mechanisms that lead to colony formation after tumor cells have entered the circulation are only imperfectly understood. The lungs are a frequent site for metastasis by human tumors of most types and a common site in experimental murine models as well. The investigator has developed methods that allow direct visualization of tumor cells in the pulmonary circulation of mouse or rat lung cells during the process of hematogenous metastasis. In summary, metastatic tumor cells adhered to endothelia of the precapillary arterioles, and also to that of the capillaries. Extravasation occurred infrequently at 6-24h after introduction of the tumor cells, but colonies did not arise from the extravasated cells; instead the intravascular tumor cells attached to the endothelium gave rise to proliferating colonies that remained intravascular. The formulation of a model for metastasis in which tumor cells attach to the endothelium and initially proliferate within the circulation leads to the prediction that metastasis could be blocked by specific targeting of these steps. Metastatic inefficiency, the process whereby most circulating tumor cells fail to establish metastatic colonies was also revealed in this system. Although virtually all cells introduced into the circulation attached in the lungs, at later times many of these cells had disappeared. These tumor cells die by apoptosis leading the investigator to hypothesize that death by apoptosis is an important component of metastatic inefficiency and could be a rate-limiting step in metastasis. Although many non-metastatic, but tumorigenic cell lines have been isolated and described, it is not known which step is the barrier to metastasis. Better definition of the early rate limiting steps should lead to more precise means for designing anti-metastasis therapies.
