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Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells

Abeer Alasmari1, Shih-Chun Lin1, Serge Dibart1

  • 1Department of Periodontology, Goldman School of Dental Medicine, Boston University, 650 Albany Street, Boston, MA, 02118, USA.

Clinical & Experimental Metastasis
|May 9, 2016
PubMed

Insights

Anti-resorptive bisphosphonates (BPs) do not directly kill cancer cells within bone. Instead, mineral-bound BPs inhibit bone remodeling, impacting bone cells and creating an environment where cancer cells adapt and survive.

Area of Science:

  • Biomedical Science
  • Oncology
  • Bone Biology

Background:

  • Anti-resorptive bisphosphonates (BPs) are used to manage bone metastases.
  • The effect of BPs on cancer-bone interactions in vivo remains largely unknown.
  • Cancer stem cells interact dynamically with the bone microenvironment.

Purpose of the Study:

  • To investigate the impact of alendronate (ALN), a bisphosphonate, on cancer cells within a live bone microenvironment.
  • To elucidate the mechanisms underlying cancer-bone interactions under BP treatment.
  • To assess the role of bone remodeling stages in BP efficacy against bone metastasis.

Main Methods:

  • Utilized a three-dimensional (3D) live cancer-bone interactive model.
  • Administered alendronate (ALN) to the model under specific bone remodeling conditions.
  • Complemented in vitro studies with mass spectrometric analysis of organ culture media.

Main Results:

  • Cancer cells, unaffected by ALN in isolation, survived and colonized live bone.
  • ALN inhibited osteoclast differentiation and bone resorption.
  • Mineral-bound ALN impaired osteoblast differentiation and mesenchymal stem cell transformation, leading to osteocyte degeneration.

Conclusions:

  • Direct anti-cancer effects of BPs within the bone microenvironment are unlikely.
  • Cancer cells exhibit morphological adaptations to colonize bone, irrespective of remodeling stage.
  • BPs primarily affect bone cells, indirectly influencing the cancer-bone interplay.
Keywords:
Alendronate (Fosamax)BiomineralizationBisphosphonatesBone resorption/formationCancer-bone metastasis, prostate and breast cancer cellsEx-vivo three-dimensional modelsOsteocytesOsteoporosisStem cells

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