Role of p53 Mutations in Metastasis of Prostate Cancer to Bone

摘要

The spread of prostate cancer (CaP) to bone causes morbidity and death, yet interactions between CaP cells and bone are poorly understood. To test if specific mutations of the tumor suppressor gene, p53, that occur in CaP cause disease progression, we generated cell lines from the human LNCaP cell line that stably express normal or mutant p53. Purpose: To test whether p53 mutations affect establishment/growth of experimentally-induced CaP in the bone. Score: LNCaP cell lines were tested in tissue culture for factors that alter normal bone remodeling and angiogenesis and were implanted in immuno- incompetent mice to analyze their ability to form tumors and to spread to the bone. Results/Progress: p53-mutant CaP cells modulated osteoclastogenesis and affected osteoblast proliferation; different p53 mutations showed differentiation stage-dependent effects. Osteoblasts also stimulated the growth of p53 mutant CaP cells, suggesting that osteoblast-CaP interactions lead to new bone formation and allow CaP to establish in bone. When implanted in mice, some p53 mutant CaP cells inhibited angiogenesis, and were cytotoxic to bone marrow derived endothelial cells in vitro. We aim to identify the molecules responsible for these effects. Significance: Further studies will explain how specific mutations of p53 found in patients impact on progression, and could allow development of new therapeutic strategies.