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.

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…McCabe et al (56) observed that SPARC suppressed osteoclast differentiation, a key step during bone tumor growth, wherein SPARC knockout mice showed increased osteolysis after intraosseous implantation of RM1 murine prostate cancer cells. Similarly, when cancer cells were grown in the bone matrices generated in vitro using SPARC knockout osteoblasts, the bone growth of PC3 cells was greatly enhanced (57). Furthermore, the bone metastasis-suppressive function of SPARC was reported previously for breast cancer by utilizing an in vivo systemic inoculation model (51).…”

WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone

“…It is possible the coupled interference of TGF-β1 and BMP-2 by anti-WISP1 treatment could in turn alter the composition of the extracellular matrix (ECM), now known to be affected by and influential to prostate cancer cell behavior [47].…”

Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis

“…SHG directly probes the structure of collagen and has been used to describe ECM alterations in several diseases, such as cancers, fibroses, and connective tissue disorders. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] Multiphoton microscopy of elastin has also been used for several applications, including imaging skin and cardiovascular tissues, often in conjunction with SHG and coherent anti-Stokes Raman scattering. [28][29][30] SHG and TPEF microscopy has not yet been used extensively for lung tissues and has been limited to mouse models.…”