Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice

Abstract

Prostate cancer is the second most diagnosed cancer in the world, and alternative methods to prevent and treat different lesion grades need to be evaluated. The objective was to evaluate the morphological, hormonal, and inflammatory responses in the prostate anterior lobe in transgenic adenocarcinoma of the mouse prostate (TRAMP), following Celecoxib and Goniothalamin (GTN) treatments. All animals were treated for 4 weeks, from 8 weeks of age and euthanized either immediately after treatment (12-week-old mice: immediate response) or later (22-week-old mice: late response). The results showed a significant increase of high-grade prostatic intraepithelial neoplasia (HGPIN) and well-differentiated adenocarcinoma (WDA), according to the age in the control groups. Celecoxib treatment decreased the WDA incidence in the late response group. GTN led to a significant healthy tissue increase, and an LGPIN and HGPIN decrease in the immediate response group. In the late response group, GTN led to healthy area increase and there was no occurrence of WDA. AR and ERα immunoexpressions were reduced by both treatments in the immediate response groups. However, only GTN was able to decrease the ERα level in the late response group. Regarding COX-2 immunoreactivity, both treatments reduced the frequency of this enzyme. We can conclude that the prostate anterior lobe is a good model to study prostate cancer, considering its slow progression. Both treatments led to cancer delay in the prostate anterior lobe. However, GTN pointed towards a better treatment spectrum in the signaling pathways in the prostate microenvironment, particularly in ERα.

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

“…In different rodent models of prostatic inflammation, both TGF‐β reactivity and the expression of TGF‐β and its downstream cascade genes were decreased in the stroma following celecoxib administration . In agreement with the aforementioned data, previous studies by our group verified that treatment with celecoxib or nintedanib resulted in attenuation of the stromal changes seen in control TRAMP mice, results that corroborate our current findings. However, none of these studies assessed TGF‐β and VIM expression as we have done herein.…”

“…More recent studies corroborated the positive correlation between COX‐2 and AR levels during inflammation and also showed the upregulation of androgen‐responsive genes in this milieu, whereas celecoxib treatment was capable of reversing these effects . Our research group has also registered such celecoxib‐dependent anti‐androgen actions and showed that AR immunolabeling and protein expression were reduced following earlier celecoxib treatment in TRAMP mice from 8 to 12 weeks old . Nevertheless, our present findings are in line with several other studies in which celecoxib treatment of patients with clinically localized prostate cancer prior to radical prostatectomy did not resulted in changes in AR expression, apoptosis and other inflammation specific biomarkers .…”

“…In the present study, we further demonstrated that celecoxib and nintedanib administration, per se or in association, resulted in lower VIM reactivity and protein levels in TRAMP mice prostatic stroma. Once again, αSMA expression remained unchanged regardless of the treatment, agreeing with our previous studies in which celecoxib or nintedanib was administered alone to TRAMP mice . Considering that normal prostatic stroma is mainly composed by αSMA + smooth muscle cells, which are gradually replaced by αSMA + /VIM + myofibroblasts/CAFs during tumorigenesis, our findings collectively suggest that the population of reactive stroma‐associated cells grows along TRAMP tumorigenesis and that treatments applied herein were effective in reducing the recruitment of these cells.…”

“…A recent study by our research group has shown that celecoxib led to decreased ERα expression in TRAMP mice prostate following immediate response treatment from 8 to 12 weeks old . On the other hand, nintedanib by itself was not able to promote any changes in ERα reactivity or protein levels after 4‐week treatments in TRAMP mice beginning at 8 or 12 weeks of age .…”

“…In recent years, our research group has been studying anti‐inflammatory and antiangiogenic drugs in prostate cancer chemoprevention using TRAMP model. Results of these studies, which used celecoxib and nintedanib as inflammation and angiogenesis inhibitors, respectively, have been published elsewhere . However, the present study is, to the best of our knowledge, the first one in the literature to assess the combined effects of these drugs on prostatic carcinogenesis.…”