Abstract
Abstract Introduction: Nearly 30% of prostate cancer patients presenting with organ confined disease experience biochemical recurrence within 10 years of curative prostatectomy. A recent analysis of bone marrow aspirates reported the presence of disseminated tumor cells (DTCs) in 57% of patients with no evidence of disease following prostatectomy, suggesting that early bone homing prostate cancer DTCs may contribute to disease recurrence. Little is currently known about the biology of these cells. Procedures: Murine models were developed to isolate and study early bone homing prostate cancer disseminated tumor cells. Early dissemination was modeled through intracardiac injection of 1 × 106 prostate cancer cells of the PC3 cell line into SCID mice 15-24 hours prior to euthanasia. Spontaneous early tumor cell dissemination was modeled using subcutaneous prostate cancer tumors formed in SCID mice by injecting 5 × 105 DU145 cells in matrigel three weeks prior to euthanasia. Bone marrow was flushed from the femurs of euthanized mice and depleted of cells of hematopoietic-lineage using the Lineage Cell Depletion Kit (Miltenyi Biotec, 130-092-211). DTCs were identified in lineage depleted murine marrow using a FITC conjugated antibody for human leukocyte antigen (>90% of PC3 and DU145 cells are HLA-ABC+) and isolated by fluorescence-activated cell sorting (FACS). Cell surface expression of the cancer stem cell markers CD133 and CD44 on bone homing DTCs were analyzed by flow cytometry. Results: Prostate cancer DTCs were detected in murine bone marrow, representing 3.1% ± 0.9% (n=4-mice) and 1.2% ± 0.2% (n=4-mice) of lineage depleted femoral marrow cells from the intracardiac and subcutaneous models, respectively. Early bone disseminated PC3 cells in the intracardiac injection model demonstrated a large fraction of CD133+/CD44+ cancer stem cells (25.3% ± 4.2%, n=4). This is substantially greater than the 0.73% fraction found with the injected PC3 cells. Spontaneous early disseminated bone homing DTCs from subcutaneous DU145 tumors demonstrated similar results. A large fraction of DTCs were positive for both stem cell markers (17.3% ± 3.6%, n=4), considering that the injected DU145 cells only had a 0.28% fraction of CD133+/CD44+ cells. Conclusions: Early bone disseminated prostate cancer cells in murine xenograft models can be enriched by lineage depletion, identified by human leukocyte antigen, and subsequently isolated and characterized by flow cytometry. Early prostate cancer bone disseminations in both intracardiac injection and subcutaneous tumor models have a disproportionately large fraction of cancer stem cells identified using the surface markers CD133 and CD44. This suggests a proclivity for bone dissemination by CD133+/CD44+ prostate cancer stem cells and a possible role for these cells as DTCs responsible for biochemical failure after curative prostatectomy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2229.
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