RESUMEN
Prostate cancer is a prevalent disease that affects the aging male population. Whilst there have been significant advances of our biological understanding of the disease, clinical translation of promising agents continues to lag behind. In part, this is due to a paucity of relevant experimental and pre-clinical models required to further develop effective prevention and therapeutic strategies. Genetically modified cell lines fail to entirely represent the genetic and molecular diversity of primary human specimens, particularly from localised disease. Furthermore, primary prostate cancer tissues are extremely difficult to grow in the laboratory and virtually all human models, whether they grow as xenografts in immune-deficient animals or as cell cultures, are genetically modified by the investigator or derived from patients with advanced metastatic disease. In this review, we discuss the latest advances and improvements to current methods of xenografting human primary prostate cancer, and their potential application to translational research.
Asunto(s)
Modelos Biológicos , Neoplasias de la Próstata/prevención & control , Neoplasias de la Próstata/terapia , Investigación Biomédica Traslacional , Animales , Antineoplásicos Hormonales/uso terapéutico , Línea Celular Transformada , Línea Celular Tumoral , Resistencia a Antineoplásicos , Antagonistas de Hormonas/uso terapéutico , Humanos , Masculino , Trasplante de Neoplasias , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Investigación Biomédica Traslacional/tendencias , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The normal growth and development of the prostate requires the presence and action of androgens, which are also known risk factors in the origins of benign and malignant prostate disease. Paradoxically, the incidence of prostate disease increases with age when serum androgen levels are in decline and emerging evidence suggests that estrogens may also be important in the normal prostate, as well as in the etiology of prostate disease. Both estrogen receptor subtypes are present in the prostate, demonstrating that the gland responds directly to estrogens. Recent data suggests that estrogens play a role in prostate disease and has demonstrated that high doses of estrogens induce premalignant dysplasia and in combination with high doses of androgens, malignancy. The production of estrogens from androgens is mediated by the aromatase enzyme, the aberrant expression of which plays a critical role in the disease process in other tissues, most notably the breast. The prostate expresses aromatase within the stroma of benign tissue, while in malignancy there is an induction of epithelial expression with altered promoter utilisation. Although the presence of aromatase in the prostate and its aberrant expression in prostate cancer is significant, its role and contribution to prostate carcinogenesis remains unclear. Transgenic mouse models lacking aromatase (ArKO) and over-expressing aromatase (AROM+) have provided an ideal means to examine aromatase expression in the prostate. Studies using these animals may lead to a better understanding of the role that aromatase--and therefore estrogen--plays in the development and progression of prostate disease.
Asunto(s)
Adenocarcinoma/etiología , Aromatasa/fisiología , Próstata/enzimología , Neoplasias de la Próstata/etiología , Adenocarcinoma/enzimología , Factores de Edad , Andrógenos/metabolismo , Animales , Aromatasa/deficiencia , Aromatasa/genética , Transformación Celular Neoplásica , Inducción Enzimática , Células Epiteliales/enzimología , Estrógenos/biosíntesis , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Ratones Noqueados , Neoplasias Hormono-Dependientes/enzimología , Neoplasias Hormono-Dependientes/etiología , Neoplasias de la Próstata/enzimología , Prostatitis/enzimología , Grupos Raciales , Receptores de Estrógenos/metabolismo , Células del Estroma/enzimologíaRESUMEN
Androgens are known regulators of the growth and differentiation of the prostate gland and are effective during development and maturity as well as in disease. The role of estrogens is less well characterized, but dual direct and indirect actions on prostate growth and differentiation have been demonstrated, facilitated via both ERalpha, and ERbeta. Previous studies using animal models to determine the role of ERbeta in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERalpha that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERbeta. Our alternate approach was to use the estrogen-deficient aromatase knockout (ArKO) mouse and the method of tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Firstly, utilizing homo- and heterotypic tissue recombinants, we demonstrate that stromal aromatase deficiency results in the induction of hyperplasia in previously normal prostatic epithelium and that this response is the result of local changes to the paracrine interaction between stroma and epithelium. Secondly, using tissue recombination and an ERbeta-specific agonist, we demonstrate that the activation of ERbeta results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERalpha. Finally, using intact ArKO mice this study demonstrates that the administration of an ERbeta-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERbeta-specific agonist does not. Therefore, in the absence of stromal aromatase gene expression, epithelial proliferation, leading to prostatic hypertrophy and hyperplasia, may result from a combination of androgenic stimulation of proliferation and failed activation of ERbeta by locally synthesized estrogens. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguish them from those that adversely alter prostate growth and differentiation. This indicates the potential of antiandrogens and SERMS, as opposed to aromatase inhibitors, for the management of prostate hyperplasia and hypertrophy.
Asunto(s)
Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/fisiología , Próstata/crecimiento & desarrollo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Aromatasa/fisiología , Humanos , Ligandos , Masculino , Ratones , Ratones Noqueados , Hiperplasia Prostática/etiologíaRESUMEN
Androgens are essential for stimulating normal development, growth and secretory activities of the prostate whereas oestrogens are generally regarded as inhibitors of growth. Evidence for the local synthesis of oestrogens includes the detection of aromatase mRNA and protein in the stroma of human non-malignant tissues and in malignant tissue, where it is detected in epithelial tumour cells. As well, aromatase activity was measured by biochemical assay and protein was detected in prostatic non-malignant and tumour cell lines. Taken together with the identification of direct oestrogenic actions on the prostate, these results suggest that alterations in local oestrogen synthesis may have significant consequences in malignancy of these organs. Genetically modified mouse models were studied in order to evaluate the action of oestrogens alone or in combination with androgens on the prostate gland. Hypogonadal (hpg) mice are deficient in gonadotrophins and androgens but showed direct proliferative responses to oestradiol. The responses were characterised by discrete lobe-specific changes including smooth-muscle regression, fibroblast proliferation, inflammation, and basal epithelial cell proliferation and metaplasia. The aromatase knockout (ArKO) mouse, deficient in oestrogens due to a non-functional aromatase enzyme, developed prostatic hyperplasia during the lifelong exposure to elevated androgens, however, no malignant changes were detected in the prostate at any time. In contrast, combined androgen and oestrogen treatment has been shown to induce prostatic dysplasia and adenocarcinoma. These results demonstrate that malignant changes to the prostate gland are dependent upon both androgenic and oestrogenic responses and that neither hormone alone is sufficient to evoke aberrant patterns of growth, resulting in malignancy.