Inhibition of tumor metastasis by a circulating suppressor factor

Increased growth of tumor metastases has been reported after primary tumor excision in animal models. Postulated mechanisms for this phenomenon include circulating suppressor factors secreted by the primary tumor, tumor manipulation during surgical excision, and limiting nutritional factors which are consumed by both primary and metastatic tumors. To study this phenomenon, Lewis/Wistar rats with subcutaneous mammary adenocarcinoma implants (MAC-33) were randomized to receive either a standard protein diet (22.0% protein, 4.20 kcal/g) or a protein-depleted diet (0.03% protein, 4.27 kcal/g) ad lib per os. Twenty-one days after tumor inoculation, half of the animals in each dietary group underwent primary tumor excision. Control animals underwent sham excision on the flank contralateral to the tumor and physical manipulation of the primary tumor. At sacrifice 35 days after tumor inoculation, a significant increase in regional metastasis (axillary lymph nodes) and distant metastasis (lungs) occurred after primary tumor excision in animals receiving the standard protein diet. No increase in regional or distant metastases were found in animals receiving the protein-depleted diet after tumor excision. Serum was collected from animals given the standard protein diet following tumor or sham excision and added to MAC-33 tumor cell cultures for in vitro determination of tumor cell proliferation. [H3]Thymidine incorporation by MAC-33 cells in vitro was significantly suppressed by serum from tumor-bearing animals. These results imply that the biologic mechanism mediating this phenomenon is a circulating suppressor factor of tumor metastasis which is produced in tumor-bearing animals receiving standard protein (but not protein-depleted) diets.