PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche
Elana Godebu,Michelle Muldong,Amy Strasner,Christina C. N. Wu,Seung Chol Park,Jason Woo,Wenxue Ma,Michael A. Liss,Takeshi Hirata,Omer A. Raheem,Nicholas A. Cacalano,Anna A. Kulidjian,Christina Jamieson +12 more
TLDR
PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.Abstract:
Prostate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide. PCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2
−/−
;γ
c
−/−
mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR. PCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < =0.008) and increased AR (p < =0.032) relative to control. PCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.read more
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Bone metastasis: the importance of the neighbourhood
Peter I. Croucher,Peter I. Croucher,Michelle M. McDonald,Michelle M. McDonald,T. John Martin,T. John Martin +5 more
TL;DR: The role of different bone cell types in supporting disseminated tumour cell dormancy and reactivation is discussed, and the new opportunities this provides for targeting the bone microenvironment to control dormancies and bone metastasis are highlighted.
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Translational models of prostate cancer bone metastasis
Richard B Berish,Aymon Naushad Ali,Patrick G. Telmer,John A. Ronald,Hon S. Leong,Hon S. Leong +5 more
TL;DR: The development of currently used models of prostate cancer bone metastasis are outlined and mechanistic and therapeutic advances made made using these models are discussed and future directions to improve the applicability of these models to the metastatic cascade and human disease are suggested.
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WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages
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TL;DR: It is suggested that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.
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Drug discovery in prostate cancer mouse models
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