There is considerable interest in understanding
prostate cancer metastasis to bone and the interaction of these cells with the bone microenvironment.
Osteonectin/SPARC/BM-40 is a
collagen binding matricellular
protein that is enriched in bone. Its expression is increased in
prostate cancer metastases, and it stimulates the migration of prostate
carcinoma cells. However, the presence of
osteonectin in
cancer cells and the stroma may limit prostate
tumor development and progression. To determine how bone matrix
osteonectin affects the behavior of
prostate cancer cells, we modeled
prostate cancer cell-bone interactions using the human
prostate cancer cell line PC-3, and mineralized matrices synthesized by wild type and
osteonectin-null osteoblasts in vitro. We developed this in vitro system because the structural complexity of
collagen matrices in vivo is not mimicked by reconstituted
collagen scaffolds or by more complex substrates, like basement membrane extracts. Second harmonic generation imaging demonstrated that the wild type matrices had thick
collagen fibers organized into longitudinal bundles, whereas
osteonectin-null matrices had thinner fibers in random networks. Importantly, a mouse model of
prostate cancer metastases to bone showed a
collagen fiber phenotype similar to the wild type matrix synthesized in vitro. When PC-3 cells were grown on the wild type matrices, they displayed decreased cell proliferation, increased cell spreading, and decreased resistance to radiation-induced cell death, compared to cells grown on
osteonectin-null matrix. Our data support the idea that
osteonectin can suppress
prostate cancer pathogenesis, expanding this concept to the microenvironment of skeletal
metastases.