Metastatic breast cancer cells colonize and degrade three-dimensional osteoblastic tissue in vitro

  • Ravi Dhurjati
  • Venkatesh Krishnan
  • Laurie A. Shuman
  • Andrea M. Mastro
  • Erwin A. Vogler
Research Paper

DOI: 10.1007/s10585-008-9185-z

Cite this article as:
Dhurjati, R., Krishnan, V., Shuman, L.A. et al. Clin Exp Metastasis (2008) 25: 741. doi:10.1007/s10585-008-9185-z

Abstract

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.

Keywords

Bone metastases Breast cancer Colonization Inflammation Invasion Osteoblast Three-dimensional cell culture model 

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Ravi Dhurjati
    • 1
  • Venkatesh Krishnan
    • 2
  • Laurie A. Shuman
    • 2
  • Andrea M. Mastro
    • 2
  • Erwin A. Vogler
    • 1
    • 3
    • 4
  1. 1.Department of Materials Science and EngineeringThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.Department of Biochemistry and Molecular BiologyThe Pennsylvania State UniversityUniversity ParkUSA
  3. 3.Materials Research Institute and the Huck Institutes of Life SciencesThe Pennsylvania State UniversityUniversity ParkUSA
  4. 4.Department of BioengineeringThe Pennsylvania State UniversityUniversity ParkUSA

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