Establishing prostate cancer patient derived xenografts: Lessons learned from older studies

Abstract

BackgroundUnderstanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling.MethodsWe subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding.ResultsTissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43–46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8].ConclusionsXenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model. Prostate 75: 628–636, 2015. © The Authors. The Prostate published by Wiley Periodicals, Inc.

Patient-derived xenografts: a relevant preclinical model for drug development

“…Due to different immunological impairments, it is assumed that the more permissive mouse strains such as NOD-SCID, SCID or NSG, can strongly increase the efficiency of xenotransplantation, as compared to nude mice. Indeed, a very low tumour rate take (10–25%) was reported after implanting tumour fragments of different histotypes in nude mice [8–10]. The use of NOD-SCID resulted in an increased engraftment rate (25–40%) for non-small cell lung cancer, breast cancer and melanoma [11–15] and a very high tumour take-rate (from 50 to 80%) has been observed for ovarian cancer, head and neck tumours, metastatic colon and bladder cancer [6, 16–18].…”

Low testosterone level is an independent risk factor for high‐grade prostate cancer detection at biopsy

“…In contrast, when the testosterone level was insufficient, the cycle of prostate proliferation was affected, and showed an abnormal epithelium, that is, poor differentiation. This phenomenon is related to the relationship between a low testosterone level and high-grade, that is poorly differentiated prostate cancer [25,26].…”

Drug discovery in prostate cancer mouse models

“…This can be done using tissue obtained during surgery, or through needle biopsy at diagnosis 117 . Prostate tumors have been difficult to establish, as they require high quality tumor tissue and thorough characterization 117–122 . While PDX models capture more of the genomic, epigenetic, and proteomic diversity within prostate cancer, it has been difficult to use PDXs for drug discovery 123 .…”

“…It is believed, however, that PDXs represent the future of personalized or individualized medicine – each patient will some day be able to have their tumor grown as a PDX (or avatar) and analyzed for genomic alterations, identifying actionable targets for therapy 123 . Lessons learned from the many existing and ever-increasing number of PDXs should facilitate the harnessing of this technology for novel biological discoveries at each stage of prostate cancer 122 .…”