Metastases to bone are the incurable final outcomes of cancer, reducing both length and quality of life in an aggressive way. Despite discovery of many factors involved, no cure has been found yet. Bone metastatic cancer cells affect the bone by de-arranging bone metabolism in a way that stimulates cancer cell growth. Compounds that restore bone integrity in bone metastases are promising therapies. One important candidate is vitamin D (1,25-OH2D3), known to both stimulate osteoblast differentiation and inhibit cancer cell growth. Our aim is to study the therapeutic possibilities of vitamin D in the crosstalk of osteoblasts and bone metastatic cancer cells and to understand underlying mechanisms. We developed a human co-culture model of differentiating osteoblasts (SV-HFO) and GFP-labeled bone metastatic prostate cancer cells (PC-3). Cells were grown in direct contact co-cultures or mono-cultures for three weeks. Osteoblast growth, differentiation (alkaline phosphatase (ALP) activity) and mineralisation as well as cancer cell growth were monitored in the continuous presence or absence of vitamin D. PC-3 cells significantly (P<0.00006) reduced ALP activity in osteoblasts by 74% (32,2 to 8,4 mU/cm2) starting in the first week and persisting throughout the 3 weeks of co-culture. Mineralisation was almost completely abolished by PC-3 cells. Treatment with 10−7 M vitamin D limited the decrease in ALP activity to 20% (32,2 to 25,8 mU/cm2) and fully restored mineralization. Vitamin D decreased the amount of PC-3 cells by 90% already in the second week of co-culture. In contrast, in the absence of osteoblasts this was only 23% after 2 weeks. These are the first observations that vitamin D may act as a therapeutic agent in bone metastases with a dual function: both directly on cancer cells and via restoring osteoblast activity, and thereby restoring skeletal integrity, quality of life and survival.
Disclosure: The authors declared no competing interests. This work was supported by the Dutch ZonMw (114011021).