Abstract 2402: Prostate cancer cell homing to bone invivo is modulated by zoledronic acid

Abstract

Abstract Cancer metastasis to the skeleton is the cause of significant mortality in prostate cancer. Intervention to prevent metastasis would be the most significant advance for the majority of patients. Despite its prevalence, the mechanisms involved in the development of bone metastases remain unclear. A metastatic initiating cell (MIC) phenotype CD44+/CD24− has been identified in prostate cancer. A complementary approach to aid MIC cell recognition, involves identification of aldehyde dehydrogenase (ALDH) activity. Zoledronic acid (zol), a bone anti-resorptive agent, is currently the only bisphosphonate with proven benefit in prostate cancer. The aim of this work is to use a novel in vivo model to investigate whether zol modulates the homing of metastasis initiating cells in the early stages of prostate cancer metastasis to bone. Metatarsals from newborn mice (1-3 day old) are engrafted into a Dorsal Skinfold Chamber (DSC) implanted on a SCID mouse (5-6 weeks old) followed by intra-cardiac (i.c) injection of fluorescently labelled tumour cells (1 × 105). Prostate (PC3-GFP) tumour cells have previously been shown to home to the metatarsal within the DSC, whereas oral cancer cells (SCC4-GFP; negative control) do not home to the bone within the DSC but to lymph nodes. ZOL treatment: Animals were subdivided into groups and treated either before or after i.c. PC3-GFP tumour cell injection with i) weekly s.c injection of zol for 4 weeks (25µg/kg/inection=100μg/kg in total) or PBS or ii) a single s.c injection of zol (100μg/kg) or PBS. ALDH activity: PC3-RFP cells were sorted into ALDHhi (7%) and ALDHlow (20%) subpopulations using the ALDEFLUORkit and flow cytometry then injected into separate groups of animals and treated with zol prior to tumour cell injection. Recordings of the DSC were made at 48 hr intervals for up to 4 weeks. At the end of the study, tissue was harvested and processed for microCT, multi-photon analysis, histology and immunohistochemistry. Zol treatment significantly (p<0.005) reduced the adhesion of PC3-GFP cells to bone when compared to control animals. Day 15: Control 15.9±1.4 cells; weekly treatment before PC3-GFP cells, 2.1±0.3* cells; weekly treatment after, 4.4±0.7*cells; single treatment before cells, 13.6±0.8 cells; single treatment after, 14.2±1.8 cells (*p<0.005). ALDHhigh cells home to bone in significantly higher numbers than ALDHlow cells (Day 15: ALDHhi 12.3±1.8 cells vs. ALDHlow 1.9±0.5 cells). Treatment with weekly zol (before cell injection) reduced the number of PC3 cells homing to the bone but this was not significant (ALDHhi 12.3±1.8 cells vs. ALDHhi plus zol; 9.7±2.1 cells). Treatment with zol reduces prostate tumour cell homing to bone, with weekly treatment prior to cell administration demonstrating the greatest reduction in homing. ALDHhi cell (likely metastatic phenotype) homing appears resistant to treatment with zol in this model. Funded by Sixth European Framework Programme (PROMET). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2402. doi:10.1158/1538-7445.AM2011-2402