Prostate cancer (PCa), a major health problem, is now the most commonly diagnosed male malignancy. In 85% of cases, PCa spreads to and grows in the bone, causing a breakdown in normal bone biology and extreme pain. The role of factors made by immune cells called immune modulators in allowing PCa to grow in bone is not known. This study investigates the interaction between PCa, bone and immune cells. Based on the hypothesis that overexpression by PCa cells of the immune modulator, interleukin-18 (IL18) inhibits bone degradation (osteoclastogenesis) and bone building (osteoblastogenesis), and induces an immune response with release of the modulator, interferon gamma, to prevent bone growth, experiments will be performed to see if IL18 can inhibit the PCa growth in the bone in animal models.
Specific aims are to construct mouse PCa cells that overexpress and secrete IL18 (PCa-IL18), and to test their effects on activating immune cells, (cytotoxic T cells and Natural Killer cells that kill tumor cells) and on bone cell proliferation and differentiation in tissue culture and in mouse models in which PCa-IL18 are implanted in the bone, or can spread to the bone. The ability of PCa-IL18 cells to stimulate an immune response and to suppress tumor growth in the bone will then be assessed. Immune cells from the experimental mice, will be characterized (FACscan) and assessed for their ability to kill tumor cells in tissue culture. In the circulation, such immune cells would kill cancer cells preventing their spread to the bone. As IL18 can stop PCa cells from entering bone by stimulating T cells to secrete interferon gamma, and by increasing expression of osteoprotegerin (OPG) by osteoblasts, both of which inhibit osteoclastogenesis, the levels of these modulators in mice implanted with PCa-IL18 will also be measured. The effects of PCa-IL18 on bone biology will be assessed by X-ray analysis of the bones (Faxitron analysis) and by morphological studies (histomorphometry). Lastly, the ability of PCa-IL18 to inhibit the growth of established PCa deposits in bone will be assessed. These PCa deposits are engineered to fluoresce allowing their visualisation in the bones. This study will clarify the relationship between PCa spread and the bone microenvironment. If IL18 inhibits PCa growth in bone, its delivery by adenovirus vectors into the prostate of patients prior to radical prostatectomy may prevent the development of bone metastasis.
