EDITORIAL

It's not my fault, blame it on my microenvironment

Diabetes causes harmful effects on prostatic function. Thus, the aims of this study were to characterize morphological and proliferative features of the prostate of diabetic mice after long-term glycemic control and testosterone and estrogen replacement. A total of 48 mice (Nod and BALBc) were used. After 20 days in a diabetic state, the mice were divided into six groups: the control group received a 5 mL/kg dose of peanut oil; the diabetic group received the same treatment as the control group; the diabetic-insulin group received 4 IU doses of insulin; the diabetic-testosterone group received a 5 mg/kg dose of testosterone cypionate; the diabetic-estrogen group received a 25 μg/kg dose of 17β-estradiol; the diabetic-insulin–testosterone–estrogen group received insulin, testosterone and estrogen at the same concentration as the other groups. After 20 days, the ventral lobe was processed for morphological and immunological analyses. The results showed structural disorganization, which was more intense in the diabetic group than in the other groups. The diabetic state showed a proliferation and apoptosis rate that was two times higher than that found in the control group. To conclude, diabetes disturbed the prostatic secretory activity and the association of insulin, testosterone and estrogen was crucial for glandular structural restoration, characterizing the complex activity of the prostate. The imbalance verified between the proliferation process and apoptosis in diabetic mice showed diabetes to be a triggering factor for prostatic pathogenesis.

Francis and colleagues reported an association between blood transfusion and worsened cancer prognosis. Since then there has been much debate over whether there is in fact such an association.

We propose a possible mechanism which could explain much of the conflicting clinical and experimental evidence, and which can be readily tested experimentally.

It is suggested that the extracellular accumulation of bioactive factors in blood transfusion products can directly and indirectly cause tumour growth and hence a worsening of prognosis. This theory can be applied both in vitro and in vivo.

Two separate UK studies have shown that perioperative blood transfusion is associated with worsened prognosis in head and neck squamous cell cancer patients. Furthermore, pilot experiments have shown that as blood ages, endothelial growth factors are leached from the metabolically compromised red cell.

We believe that we have provided a rationale to explain the conflicting findings of research to date in this area. That red cells should store endothelial reparative growth factors would seem logical, as would the release of any factors as the metabolic processes of the anucleate red cell decline over time.

As a result, leuco-depletion should be promoted and blood transfusion should be avoided if possible.

Due to a lack of experimental systems, little is known about ovarian stroma. Here, we introduce an in vivo-like 3-D system of mesenchymal stromal progression during ovarian tumorigenesis to support the study of stroma permissiveness in human ovarian neoplasias.

To sort 3-D cultures into ‘normal,’ ‘primed’ and ‘activated’ stromagenic stages, 29 fibroblastic cell lines from 5 ovarian tumor samples (tumor ovarian fibroblasts, TOFs) and 14 cell lines from normal prophylactic oophorectomy samples (normal ovarian fibroblasts, NOFs) were harvested and characterized for their morphological, biochemical and 3-D culture features.

Under 2-D conditions, cells displayed three distinct morphologies: spread, spindle, and intermediate. We found that spread and spindle cells have similar levels of α-SMA, a desmoplastic marker, and consistent ratios of pFAKY³⁹⁷/totalFAK. In 3-D intermediate cultures, α-SMA levels were virtually undetectable while pFAKY³⁹⁷/totalFAK ratios were low. In addition, we used confocal microscopy to assess in vivo-like extracellular matrix topography, nuclei morphology and α-SMA features in the 3-D cultures. We found that all NOFs presented ‘normal’ characteristics, while TOFs presented both ‘primed’ and ‘activated’ features. Moreover, immunohistochemistry analyses confirmed that the 3-D matrix-dependent characteristics are reminiscent of those observed in in vivo stromal counterparts.

We conclude that primary human ovarian fibroblasts maintain in vivo-like (staged) stromal characteristics in a 3-D matrix-dependent manner. Therefore, our stromal 3-D system offers a tool that can enhance the understanding of both stromal progression and stroma-induced ovarian tumorigenesis. In the future, this system could also be used to develop ovarian stroma-targeted therapies.

Stromal–epithelial interactions mediated by paracrine signaling mechanisms dictate prostate development and progression of prostate cancer. The regulatory role of androgens in both the prostate stromal and epithelial compartments set the prostate apart from many other organs and tissues with regard to gene targeting. The identification of androgen-dependent prostate epithelial promoters has allowed successful gene targeting to the prostate epithelial compartment. Currently, there are no transgenic mouse models available to specifically alter gene expression within the prostate stromal compartment. As a primary metastatic site for prostate cancer is bone, the functional dissection of the bone stromal compartment is important for understanding stromal–epithelial interactions associated with metastatic tumor growth. Use of currently available methodologies for the expression or deletion of gene expression in recent research studies has advanced our understanding of the stroma. However, the complexity of stromal heterogeneity within the prostate remains a challenge to obtaining compartment or cell-lineage-specific in vivo models necessary for furthering our understanding of prostatic developmental, benign, tumorigenic, and metastatic growth.

Previous studies have shown that long-term alcohol treatment has negative effects on prostatic stromal–epithelial interaction. Thus, the aim of the present study was to analyze the histochemical, immunohistochemical and ultrastructural alterations that occur in the prostatic stroma and epithelium of rats submitted to chronic alcohol ingestion and alcohol abstinence, as well as to establish the relationship between these changes and prostatic diseases. Thirty male rats (10 Wistar and 20 UChB rats) were divided into three experimental groups: the control group received tap water, the alcoholic group received ethanol diluted to 10° G.L. for 150 days, and the abstinent group received the same liquid diet as the alcoholic group up to 120 days of treatment and only tap water for 30 days thereafter. At the end of treatment, all animals were sacrificed and the ventral lobe of the prostate was removed and processed for histochemical, immunohistochemical and ultrastructural analyses. In addition, plasma testosterone levels were measured. The results showed prostatic intraepithelial neoplasia, infolding of the epithelium towards the stroma, stromal hypertrophy and the presence of inflammatory cells in alcoholic animals. In the abstinent group, alterations were noted mainly in the stromal area. In conclusion, ethanol triggers alterations in prostatic epithelial and stromal compartments, affecting the stromal microenvironment and predisposing the organ to pathological processes.

This review of the male accessory sex organs, including the prostate gland, seminal vesicles, and bulbourethral gland, focuses on their development, normal function, and disease from the viewpoint of a physiologist/biologist. An initial overview of the development and structure of these organs is followed by details of the cell–cell interactions involved in normal homeostasis and perturbations thereof that lead to disease. Emerging research priorities include the implications of specific cell–cell interactions and tissue heterogeneity, the identity of stem cells in normal and diseased tissue, and the early fetal or postnatal origins of adult disease.