Inhibition of tumor production of granulocyte-macrophage colony-stimulating factor by 1 alpha, 25-dihydroxyvitamin D3 reduces tumor motility and metastasis.

Production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by metastatic Lewis lung carcinoma tumors (LLC-LN7) has been shown to increase their migration and invasion in vitro, and metastasis in vivo. The present studies showed that treatment of the LLC-LN7 cells by 2 days culture with 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibited their production of GM-CSF. The 1,25(OH)2D3-treated cells also became less migratory and invasive. This inhibitory effect on tumor motility could not be readily reversed upon removal of 1,25(OH)2D3. The mechanism by which 1,25(OH)2D3 reduced tumor motility was attributed to the inhibition of tumor GM-CSF production since the capacity to migrate and invade could be restored by supplementing the medium with recombinant GM-CSF. In vivo studies showed that treatment of LLC-LN7-bearing mice with 1,25(OH)2D3 had no effect on growth of s.c. primary tumors, but reduced the formation of tumor metastases. These results show that 1,25(OH)2D3 can interrupt the autocrine motility-stimulation cascade by reducing tumor production of GM-CSF, thus reducing the expression of properties that are characteristic of metastatic tumor cells.