Next generation patient-derived prostate cancer xenograft models

leading cause of cancer-related death of North American males.1 The disease is at present incurable once it has metastasized, and most deaths from this disease are due to metastases that are highly resistant to current conventional therapies. Prostate cancer is considered a multifocal disease that generally consists of a dominant cancer and one or more concurrent cancers of smaller volume with different histological features covering a wide spectrum of biological behavior.2–5 The biological and genetic heterogeneity of the cancers suggests that the foci arise from different clones.6–9 The development of localized prostate cancer and the diversification and malignant progression to metastatic and castration-resistant forms are highly complex processes and thought to result from (i) changes in the expression of specific genes particularly in epithelial prostatic cells and (ii) alterations in the interactions between epithelial and stromal tissues. Other important factors are systemic conditions such as the hormonal status of the patient, the microenvironment of the malignancy and tumor-evoked immune responses.10,11 Prostate cancers usually present as androgen-dependent tumors, and androgen ablation is at present the treatment of choice, in particular for metastatic cancer. While this therapy can initially lead to substantial remissions, tumors frequently return in an androgen-independent, castration-resistant form that is highly resistant to further hormonal therapy and also to other available regimens, including chemotherapy. There is therefore a critical need for new, more effective treatments to improve disease management and patient survival. However, research in this area has been seriously hampered by a lack of clinically relevant, experimental in vivo T is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/ severe combined immunodeficient (NOD/ SCID) mice. This technique al lows successful development of transplantable, patient‐derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next‐generation models of prostate cancer.