Dormancy versus extinction of mouse Leydig cell tumors following endocrine-induced regression

Although a majority of malignant testicular Leydig cell tumors induced in the mouse by chronic estrogenization remain dependent upon estrogen stimulation for growth during early transplant generations, we have observed tumors of two lines, no longer growth dependent upon estrogen, that regressed when hosts bearing palpable tumor grafts were given the same dosage of diethylstilbestrol that had induced the original tumors. Both estrogen-"dependent" and -"responsive" tumors were found to possess a similar estrogen receptor system. The present study compares light and electron microscopic changes occurring during regression and determines the ultimate outcome of the process under these seemingly opposite endocrine conditions. The individual neoplastic cells of the dependent tumors decreased in size, mitochondria with typical tubular cristae rapidly converted to a fully condensed configuration, and endoplasmic reticulum, both rough and smooth, as well as polyribosomes gradually disappeared. A few dormant, RNA-depleted tumor cells always remained, however. After 5 months of dormancy, mitotic activity was induced in many of these cells in 2 to 3 days by reinstituting estrogen administration. This activity began prior to conversion of the mitochondria to an orthodox configuration, to the accumulation of cytochemically demonstrable RNA, or to the appearance of RNA-containing organelles. These observations suggest that at least many of the dormant tumor "stem" cells had been blocked in G2. Contrariwise, the cytoplasmic volumes of the cells of regressing estrogen-responsive tumors increased with a considerable accumulation of lipid droplets, while alterations of the cytoplasmic organelles were much less marked, the mitochondria retaining their pretherapy morphology. Biochemical studies confirmed the fact that, although DNA synthesis ceased within a few days. RNA synthesis was maintained at a near normal level, at least during the first month of tumor regression, during which time the RNA to DNA ratio increased significantly. After 2 months or more of a sustained complete remission, no tumor cells could be found at the transplantation sites, and removing the estrogenic stimulus did not result in tumor regrowth. In short, the treatment had completely obliterated the cancer. It is concluded, therefore, that the molecular events that result in tumor regression from these diametrically opposite endocrine therapies must differ significantly. Both bring about an abrupt cessation of mitotic activity in the neoplastic cells.(ABSTRACT TRUNCATED AT 400 WORDS)