Determining osteoclasts’ role in hematopoietic stem cell mobilization and metastasis

Objective: Prostate cancer (PCa) is the most common neoplasm that metastasizes to bone. The aim of this study was to determine if osteoclasts play a role in initial bone metastasis of PCa by participating in mobilizing hematopoietic stem cells (HSCs) out of their marrow niche.

Method: Human PC-3Luc cells were introduced into male SCID mice by intracardiac (i.c.) injections after pretreatment with antiresorptive agents, Zoledronic Acid (bisphosphonate (BP)) and/or AMD3100, which mobilizes HSCs out of the marrow.  Short term homing of PC-3 was assessed at 24 hours by QPCR for human Alu and HSC number in marrow was counted by FACS.  TRAP assays were used to determine the osteoclast (OC) number.

Result: AMD3100 enhanced the release of HSCs from the bone marrow while BP increased the retention of HSCs.  PCa entry was facilitated in AMD3100, BP, and AMD3100+BP treatments.  Before PCa injection, the number of TRAP+ OC increased from the AMD3100 treatment, while BP produced lower TRAP+ OCs in comparison.    TRAP+ OCs were not detected in the AMD3100 + BP treatment. After PCa injection, the number of TRAP+ OCs was dramatically increased but did not differ significantly amongst the treatment groups.

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Conclusion: Our data suggests that AMD3100 administration prior to PCa inoculation increases PCa metastasis to bone.  The results indicate that OC activation is not necessary for PCa metastasis to bone at the most early stages. These findings are critical in proving that OCs’ contribution to metastasis occur during the growth phase of the tumor rather than at the initiation phase.