title: Bone matrix osteonectin limits prostate cancer cell growth and survival.
abstract: 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.
authors.affiliation: Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kapinas
authors.forename: Katie M
authors.initials: KM
authors.lastname: Lowther
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Kessler
authors.forename: Karissa
authors.initials: K
authors.lastname: Tilbury
authors.forename: Jay R
authors.initials: JR
authors.lastname: Lieberman
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Tirnauer
authors.forename: Paul
authors.initials: P
authors.lastname: Campagnola
authors.forename: Anne M
authors.initials: AM
authors.lastname: Delany
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D002450:Cell Communication; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D005720:Gamma Rays; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D015676:Osteonectin; D011994:Recombinant Proteins