Spontaneous and induced metastasis of naturally occurring tumors in mice: analysis of cell shedding into the blood.

The lung colonization capability (after iv inoculation) of each of 77 autochthonous virus-induced mammary tumors in C3H/Avy female mice was compared with its own spontaneous metastatic behavior. Twenty-four of these neoplasms had spontaneously metastasized to the lungs of the tumor bearer. The results were interpreted in the framework of dose-response studies on experimentally induced metastasis. These results indicate that tumors of high lung colonization potential (HCP) overgrow the lungs with iv doses as low as 10(4) cells, whereas tumors of low lung colonization potential (LCP) require at least 250 times this dose to achieve the same result. No general similarity was found between spontaneous and induced metastatic capability. Although some tumors showed good correspondence, others showed discrepancies and provided new information on mechanisms of cell shedding from primary tumors and on rate-limiting steps in metastasis. For example, from the dose-response studies, nonmetastatic tumors of HCP (iv) are deduced to be shedding very few cells. These findings suggest that escape from the primary tumor is an active process or else passive leakage of cells into vessels by hemorrhage, necrosis, or palpation should have resulted in spontaneous metastasis. Spontaneously metastatic tumors of LCP corroborate the view that metastasis is effected by a highly active subpopulation with special properties; otherwise, the required scale of passive cell release into the blood would be unrealistically large. Blood bioassay and time-course studies on pulmonary deposit formation indicate that shedding of metastatic cells occurs early in mammary tumor development.