TY - JOUR
T1 - Metastatic breast cancer cells colonize and degrade three-dimensional osteoblastic tissue in vitro
AU - Dhurjati, Ravi
AU - Krishnan, Venkatesh
AU - Shuman, Laurie A.
AU - Mastro, Andrea M.
AU - Vogler, Erwin A.
N1 - Funding Information:
Acknowledgments This work was supported by U.S. Army Medical Research and Material Command Breast Cancer Research Program WX81XWH-06-1-0432, and the Susan G. Komen Breast Cancer Foundation BCTR 0601044, National Foundation for Cancer Research, Center for Metastasis Research, The University of Alabama-Birmingham. Authors appreciate the expert technical assistance of Ms. Donna Sosnoki and the assistance of the Cytometry Facility and the Electron Microscopy Facility at the Huck Institutes of Life Sciences, Penn State University.
PY - 2008/11
Y1 - 2008/11
N2 - Metastatic breast cancer cells (BCs) colonize a mineralized three-dimensional (3D) osteoblastic tissue (OT) grown from isolated pre-osteoblasts for up to 5 months in a specialized bioreactor. Sequential stages of BC interaction with OT include BC adhesion, penetration, colony formation, and OT reorganization into "Indian files" paralleling BC colonies, heretofore observed only in authentic pathological cancer tissue. BCs permeabilize OT by degrading the extra-cellular collagenous matrix (ECM) in which the osteoblasts are embedded. OT maturity (characterized by culture age and cell phenotype) profoundly affects the patterns of BC colonization. BCs rapidly form colonies on immature OT (higher cell/ECM ratio, osteoblastic phenotype) but fail to completely penetrate OT. By contrast, BCs efficiently penetrate mature OT (lower cell/ECM ratio, osteocytic phenotype) and reorganize OT. BC colonization provokes a strong osteoblast inflammatory response marked by increased expression of the pro-inflammatory cytokine IL-6. Furthermore, BCs inhibit osteoblastic bone formation by down-regulating synthesis of collagen and osteocalcin. Results strongly suggest that breast cancer disrupts the process of osteoblastic bone formation, in addition to upregulating osteoclastic bone resorption as widely reported. These observations may help explain why administration of bisphosphonates to humans with osteolytic metastases slows lesion progression by inhibiting osteoclasts but does not bring about osteoblast-mediated healing.
AB - Metastatic breast cancer cells (BCs) colonize a mineralized three-dimensional (3D) osteoblastic tissue (OT) grown from isolated pre-osteoblasts for up to 5 months in a specialized bioreactor. Sequential stages of BC interaction with OT include BC adhesion, penetration, colony formation, and OT reorganization into "Indian files" paralleling BC colonies, heretofore observed only in authentic pathological cancer tissue. BCs permeabilize OT by degrading the extra-cellular collagenous matrix (ECM) in which the osteoblasts are embedded. OT maturity (characterized by culture age and cell phenotype) profoundly affects the patterns of BC colonization. BCs rapidly form colonies on immature OT (higher cell/ECM ratio, osteoblastic phenotype) but fail to completely penetrate OT. By contrast, BCs efficiently penetrate mature OT (lower cell/ECM ratio, osteocytic phenotype) and reorganize OT. BC colonization provokes a strong osteoblast inflammatory response marked by increased expression of the pro-inflammatory cytokine IL-6. Furthermore, BCs inhibit osteoblastic bone formation by down-regulating synthesis of collagen and osteocalcin. Results strongly suggest that breast cancer disrupts the process of osteoblastic bone formation, in addition to upregulating osteoclastic bone resorption as widely reported. These observations may help explain why administration of bisphosphonates to humans with osteolytic metastases slows lesion progression by inhibiting osteoclasts but does not bring about osteoblast-mediated healing.
UR - http://www.scopus.com/inward/record.url?scp=53949085763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=53949085763&partnerID=8YFLogxK
U2 - 10.1007/s10585-008-9185-z
DO - 10.1007/s10585-008-9185-z
M3 - Article
C2 - 18543066
AN - SCOPUS:53949085763
SN - 0262-0898
VL - 25
SP - 741
EP - 752
JO - Clinical and Experimental Metastasis
JF - Clinical and Experimental Metastasis
IS - 7
ER -