Abstract
Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions.MethodsA femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2-/-;γc-/- mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT).ResultsPCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2-/-;γc-/- mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture.ConclusionsPCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.
Highlights
Prostate cancer metastasis to bone leads to debilitating fractures and severe bone pain in men with advanced disease for which there is no treatment and is associated with poor prognosis and rapid decline [1]
Histologic and micro-computed tomography (microCT) analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions
PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture
Summary
Prostate cancer metastasis to bone leads to debilitating fractures and severe bone pain in men with advanced disease for which there is no treatment and is associated with poor prognosis and rapid decline [1]. Zolendronic acid, and the RANKL inhibitor, denosumab, which inhibit osteoclasts and osteolysis - have been effective in delaying the onset of skeletal related events (SREs) and new bone metastases in bone metastatic cancers with primarily osteolytic bone lesions [6,7,8,9,10,11]. A characteristic of prostate cancer bone metastases, is that they typically produce osteoblastic or mixed osteoblastic/osteolytic bone lesions that are not as efficiently treated with the osteoclast inhibitors [12,13,14,15,16]. There is currently no curative treatment for prostate cancer bone metastases [1]
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