Kinetics of marked development of lung metastasis of rat prostatic carcinomas transplanted in syngeneic rats

In order to investigate how and when metastases develop under experimental conditions, kinetics of the size and the number of lung metastasis lesions in F344 rats were examined after syngeneic transplantation of rat prostate carcinomas induced by 3,2′-dimethyl-4-aminobiphenyl (DMAB). Cell proliferation of the subcutaneous tumor and lung metastatic lesions was evaluated along with the expression of VEGF-A splicing variants and endostatin, serum VEGF levels and vascular density in the tumor. Several pieces of tumor tissue were introduced subcutaneously into two different sites on the dorsal side of F344 rats through a 14G needle. Average body weight of recipient rats markedly decreased despite only a gradual increase in tumor volume. The absolute total number of metastatic lesions in rats (n=5) were 2, 10, 19 and 194 at weeks 7.5, 9, 11 and 13, respectively, and a notable increase was observed at week 13. Similarly, the mitotic index of lung metastatic lesions increased remarkably at week 9 while the mitotic index and apoptotic index of transplanted tumors did not change throughout the experimental period. Expression of VEGF-A121, A164, A188 and endostatin, serum VEGF levels and vascular density did not correlate with the spread of lung lesions. In conclusion, both the number and the size of metastatic lesions increased at the same time after a notable increase in cell proliferation. Factors other than VEGF or endostatin may be involved in the mechanism of explosive lung metastasis spread.