A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions

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.

Patient-derived xenografts and organoids model therapy response in prostate cancer

“…Patient-derived xenografts (PDX) are used to address intra-tumor characteristics and drug response since they model the original tumor in a more representative manner than other models such as two-dimensional cell culture [4]. Various PDX study programs have evaluated the take of various PDX models of primary and metastatic PCa [5][6][7], with the use of different immunocompromised strains, sites of implantations (subrenal [8], subcutaneous [9], orthotopic [5], intrafemoral [10]), grafting of biopsies, cells, circulatory tumor cells [11] and patient-derived organoids [9,12]. Nonetheless, the few PCa PDXs which are available and suitable for characterizing androgen dependency in PCa are predominantly from metastasis [13] (e.g.…”

SATB1 is overexpressed in metastatic prostate cancer and promotes prostate cancer cell growth and invasion

“…With the development of PSA screening, MRI imaging and new prostate biopsies protocols, the accuracy of detection and localization of prostate tumors has been increased, but still 5% of cases present with metastatic lesions at the time of diagnosis [1]. The most common site of metastasis for prostate cancer is bone, and frequently metastasis is symptomatic, with pain, debility, and functional impairment [2]. Therefore, it is important to investigate the molecular mechanisms underlying the progression and metastasis of prostate cancer to provide better strategies for the prevention and therapy of prostate cancer.…”

An improved intrafemoral injection with minimized leakage as an orthotopic mouse model of osteosarcoma

“…This percutaneous injection is simple but does not allow investigators to confirm whether tumor cells indeed stay in the intramedullary space during and after tumor cell injections. Additionally, intrafemoral injection method was previously published [9, 10]. However, details of these methods, including reaming of the intramedullary space and the way to minimize leakage, were not described.…”

“…Moreover, reaming the intramedullary space of the tibia is not done, likely due to the curved anatomical feature of this bone. Although the intrafemoral injection method also showed successful tumor establishment in the femur [9, 10], no publication described details of the procedures to minimize the leakage. Leakage from the bone marrow cavity could alter the onset of tumor formation and result in experimental variation or inconsistency.…”