A new proposed rodent model of chemically induced prostate carcinogenesis: distinct time-course prostate cancer progression in the dorsolateral and ventral lobes.

BACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes. We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes. METHODS: Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment. Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes. RESULTS: Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency. However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups. Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration. Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining. Moreover, VL lesions emerged throughout the entire lobe. MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining. CONCLUSIONS: There are distinct pathways involved in tumor progression in gerbil prostate lobes. This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes.

Prostate carcinogenesis induced by N-methyl-N-nitrosourea (mnu) in gerbils: histopathological diagnosis and potential invasiveness mediated by extracellular matrix components.

In the present study prostate lesions were induced in gerbils (Meriones unguiculatus) treated with a single N-methyl-N-nitrosourea (MNU) dose; thus, the incidence, latency and histology of these lesions were evaluated. Fibrillar elements of the extracellular matrix associated with microinvasive sites were also investigated. Animals were divided into 5 groups, including 2 control groups: (1) remained untreated; (2) received the corn oil vehicle (vehicle, 0.1 ml/application) and three different tumor induction regimens: (1) received MNU (30 mg/kg) and weekly testosterone (2 mg/kg) (MNU+testosterone); (2) received only MNU (30 mg/kg); (3) received weekly testosterone doses (2 mg/kg). After 3 and 6 months the animals were dissected and the prostates were evaluated morphologically, immunohistochemically and quantitatively. MNU plus androgen contributed to the development of prostatic intraepithelial neoplasia, microinvasive carcinoma and adenocarcinoma in gerbil prostate. However, these lesions occurred earlier in time in groups that received MNU and androgen compared to control animals as they over time also developed to a high extent microinvasive lesions. Cytochemistry and immunohistochemistry showed that these injuries were commonly associated with inflammatory cells whereas the epithelial cells presented proliferative activity. The alpha-methylacyl-CoA racemase (AMACR) expression in prostate cancer cells facilitated diagnosis of gerbil lesions. Testosterone, MNU and MNU+testosterone showed an increased epithelial volume, although the secretory activity was significantly suppressed mainly at neoplastic foci. In the prostatic stroma, reticular fibers increased significantly in MNU, MNU+testosterone and among the lesions found in these groups, while collagen fibers decreased at neoplastic sites. The disruption of the basement membrane was proven at malignant sites by ultrastructural analysis and type IV collagen and laminin degradation. The prostate carcinogenesis mediated by MNU and androgen stimulated the emergence of proliferative lesions in gerbils after short periods and showed the importance of a dynamic remodeling of stromal components for cellular invasiveness.

Age-related histopathological lesions in the Mongolian gerbil ventral prostate as a good model for studies of spontaneous hormone-related disorders.

The Meriones unguiculatus (Mongolian) gerbil has demonstrated significant prostatic responses to hormonal treatments, and to drugs against human prostatic hyperplasia. Spontaneous neoplasia develops in the older animals. Thirty gerbils (age 18 months) were divided into non-affected and prostatic lesion bearers and the prostate lesions were evaluated morphologically, immunohistochemically and quantitatively. The most frequent changes were in epithelial sites and, namely prostatic intraepithelial neoplasias, microinvasive carcinomas and adenocarcinomas. In the stromal compartment, cellular hyperplasia, when verified, was always associated with the sites of anomalous epithelium. Additionally, larger deposition of collagen fibrils, generating stromal fibrosis, was found in all the old gerbils analysed. The quantitative analysis showed that prostatic tissue proportions differed in altered areas, being specific for each lesion type. Isolated nuclear and nucleolar parameters were not effective in diagnosing the malign potential of lesions. However, the cellular proliferation and death indexes indicated larger cellular turnover in invasive lesions such as carcinomas. With these analyses, it could be verified that old gerbils present high propensity to develop spontaneous prostate changes and this may aid in a better understanding of the biological behaviour of human prostate cancer.

Surgical and chemical castration induce differential histological response in prostate lobes of Mongolian gerbil.

The present study describes the short-term alterations in the prostate ventral and dorsal lobe of the adult Mongolian gerbil, in response to two different androgen suppression approaches. Groups (n=6) of 16-week-old gerbils were maintained intact or subjected, either to the bilateral surgical castration 1 week previously or to daily subcutaneous injections of Flutamide (10mg/kg body weight) for 7 days. The main microscopic features of both prostate lobes in these groups were compared using conventional paraffin tissue sections, measurements of acinar epithelial height and stereological data of main gland components (acini, collagen fibers and fibromuscular stroma). Marked alterations were observed in the basement membrane of the ventral lobe after both surgical and chemical castration, such as an increase in thickness and collagen staining. A low degree of epithelial atrophy was detected in the dorsal lobe following both androgen suppression approaches in comparison with that found in the ventral lobe, indicating that this lobe is not so responsive to testosterone ablation induced by castration or Flutamide treatment, at least insofar as secretory activity is concerned. However, the dorsal lobe exhibited marked stromal modification, such as an increase in collagen fibers following castration and an increase in fibromuscular stroma following Flutamide-treatment. Thus, the histological and quantitative data indicates a differential short-term response of the prostate dorsal lobe to surgical castration and Flutamide therapy, suggesting the existence of lobe-specific mechanisms for stromal remodeling.

Biological behavior of the gerbil ventral prostate in three phases of postnatal development.

In this study, we characterized the gerbil's ventral prostate histology ultrastructurally and quantitatively throughout three phases of postnatal development (young, adult, and old) in order to comprehend its biological behavior and propensity to developing spontaneous lesions with aging. The gerbil prostate is composed of alveoli and ducts immersed in a stroma composed of smooth muscle, fibroblasts, collagen and elastic fibers and vessels. The prostate tissue components present morphological and quantitative aspects that vary according to age. Young animals have an immature gland with modest secretory activity. Synthetic activity remained stable in adult and old gerbil. However, prostatic morphology was altered in the aging, showing an increased epithelium and stromal fibrosis. The nuclei of the secretory cells increased with aging, whereas nucleoli presented few alterations during postnatal development. The epithelial proliferation and stromal remodeling noted in this study indicate that the gerbil prostate may respond to the androgen declines typical of senescence through epithelial proliferation and stromal remodeling.

Morphological observations on the testes of physalaemus cuvieri: Amphibia, Anura

Generalmente, los testículos de anuros constituyen órganos ovoides, pares, formados por masa de estructuras seminíferas, envueltas en una capa de tejido conjuntivo fibroso, que contiene un epitelio germinativo provisto de tipo celulares característicos. En este trabajo se describe la anatomía y la arquitectura histológica de los testículos, así como también la organización y morfología de las células germinativas. Se utilizaron cinco ejemplares machos de la especie Physalaemus cuvieri (Leptodactylidae), proveniente de la zona de Botucatu (Säo Paulo, Brasil). Tras el análisis macroscópico y la obtención de los fragmentos testiculares, el material se sometió a las técnicas histológicas rutinarias para su inclusión en parafina y coloración con hematoxilina/eosina. Se constató como rara peculiaridad la presencia de numerosas células con pigmento distribuidas de forma aleatoria en la túnica albugínea e intersticio testicular, las cuales otorgan al testículo una coloración marrón oscura. En el tejido germinativo las espermatogonias I son las mayores células espermatogenéticas. En la secuencia de la diferenciación y proliferación celulares, se siguen los demás tipos de células (espermatogonias II, espermatocitos I y II, espermátidas I y II, y espermatozoides) que presentan una organización cística, es decir, grupos de células se asocian a las células de Sertoli, formando los cistos espermatogenéticos o espermatocistos. Se diferenciaron e identificaron las células del linaje espermatogenético, según la morfología de las células y del propio cisto