Highly metastatic 13762NF rat mammary adenocarcinoma cell clones stimulate bone marrow by secretion of granulocyte-macrophage colony-stimulating factor/interleukin-3 activity

Circulating neutrophil (polymorphonuclear leukocyte levels rise 50-fold in 13762NF tumor-bearing rats in proportion to the tumor's metastatic potential. Purified tumor-elicited neutrophils enhance metastasis of syngeneic tumor cells when co-injected intravenously; however, circulating and phorbol ester- activated polymorphonuclear neutrophils do not. The purpose of this study was to elucidate the source of tumor-elicited neutrophils in metastatic tumor- bearing rats. We examined the bone marrow in rats bearing tumors of poorly, moderately, and highly metastatic cell clones. Marrow from rats with highly metastatic tumors had increased cellularity (100%), myeloid to erythroid ratio (10:1), and megakaryocytes compared with control rats (cellularity, ~80% myeloid to erythroid ratio, 5:1), with marrows from rats with moderately metastatic tumors having intermediate values. This suggested production of a colony-stimulating factor by the metastatic cells. To confirm this, bone marrow colony formation from control and tumor-bearing rats was compared. Colony number increased in proportion to the metastatic potential of the tumor. Conditioned medium from metastatic cells supported growth of the granulocyte-macrophage colony-stimulating factor/interleukin-3-dependent 32Dcl3 cell line, but media from nonmetastatic or moderately metastatic cells did not. Antibodies to murine granulocyte-macrophage colony-stimulating factor neutralized 32Dcl3 growth in tumor cell conditioned medium. These results suggest production of a granulocyte-macrophage colony-stimulating factor or interleukin-3-like activity by highly metastatic 13762NF clones and implicate a possible role for colony-stimulating factors in regulating the metastatic potential of mammary adenocarcinoma cell clones.