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

Abstract

Background Chronic inflammation has been implicated in cancer etiology and angiogenesis is stimulated in this disease. In prostate, the crosstalk between malignant epithelial cells and their microenvironment is an essential step of tumorigenesis during which glandular stroma undergo changes designated as reactive stroma. Thus, the aim herewith was to evaluate the effects of associating anti‐inflammatory and antiangiogenic therapies on cancer progression, correlating them with steroid hormone receptor (AR and ERα), reactive stroma (vimentin, αSMA, and TGF‐β), and cell proliferation (PCNA) markers expression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Methods TRAMP mice (12‐week old) were divided into the groups: Control (TRCON): received the vehicles used for drug dilution; Celecoxib (TRCEL): received oral doses of the anti‐inflammatory drug celecoxib (15 mg/kg) twice daily; Nintedanib (TRNTB): received oral doses of the antiangiogenic drug nintedanib (10 mg/kg) daily; Nintedanib+Celecoxib (TRNTCEL): received the combination of drugs. After 6 weeks, mice were euthanized and ventral prostate samples were harvested for morphological, immunohistochemical, and Western blotting analyses. Results While celecoxib led to fibromuscular hypertrophy attenuation, nintedanib significantly reduced the incidence of well‐differentiated adenocarcinoma (WDAC) foci in relation to controls, both when administered per se or in association to celecoxib. Furthermore, drug combination was associated with unique effects, including lower incidence of HGPIN lesions; lower AR stromal distribution; changes in ERα localization from epithelial nuclei to stroma as well as significant decrease of TGF‐β levels and associated angiogenesis. In parallel, all treatments applied resulted in reduced inflammatory marker and vimentin (VIM) expression. Conclusions Celecoxib plus nintedanib is an effective antitumor combination against prostate cancer progression in TRAMP mice, showing remarkable efficacy in relation to isolated therapies. Importantly, this efficacy might be due to drug association effect on driving AR and mainly ERα distribution in the prostatic tissue towards benign patterns. In addition, celecoxib and nintedanib impaired the development of a stromal reaction by reducing the recruitment of reactive stroma cells and maintaining a normal smooth muscle cell‐rich prostate stroma in TRAMP mice. Collectively, these findings pointed to the beneficial effects of combining anti‐inflammatory and antiangiogenic strategies to prevent or delay prostatic tumorigenesis.

Corpora amylacea in benign prostatic acini are associated with concurrent, predominantly low‐grade cancer

“…Other studies supported a positive association of inflammation and cancer with inflammation being associated with higher risk or more aggressiveness of prostate cancer 22,31 . Numerous studies have been done, including mouse models, in search of inflammatory‐related prostate cancer pathways and for preventive and therapeutic purposes 32‐34 . On the other hand, several studies showed a negative association of inflammation with prostate cancer, whereby inflammation presence was associated with a lower risk or less aggressiveness of cancer, and better prognosis 35‐41 .…”

Differential effects of omega‐3 PUFAS on tumor progression at early and advanced stages in TRAMP mice

“…In this scenario, controlled rodent studies in which hormonal, metabolic, and homeostatic context are also considered, as well as the interplay among several tissue components in the gland, may provide new information on this issue. Here we employed TRAMP mice, a model that replicates most parameters of human PCa progression, 31,41,42 to evaluate whether an ( n −3) PUFA‐enriched diet affects tumor progression at early and advanced stages of disease. The present data shows that dietary intervention at an early stage of PCa was able to lower the severity of the disease in the TRAMP ventral prostate.…”

“…[22][23][24][25][26] In this scenario, controlled rodent studies in which hormonal, metabolic, and homeostatic context are also considered, as well as the interplay among several tissue components in the gland, may provide new information on this issue. Here we employed TRAMP mice, a model that replicates most parameters of human PCa progression, 31,41,42 33,44,45 which is reasonable considering the intensity of androgen signaling in this model. In this scenario, the maintenance of healthy areas and reductions in HGPIN and CIS suggest a delay in tumor progression and a protective role of (n−3) PUFA at initial phases of PCa (Table 1).…”

“…The result was expressed as relative frequency. In order to quantify PHH3 and CD3, the absolute number of positive cells in the 10 random microscopy fields of each animal were counted 41 and expressed as positive cells/field. prostate lobe change in these groups (C8: 9.2 ± 3.8; C12: 12.4 ± 6.7; T12: 12.6 ± 3.2 mg).…”

Angiogenesis Inhibition in Prostate Cancer: An Update

“…Increased amounts of VEGFA are also present in the urine samples of PCa patients, which has been reported to serve as a prognostic indicator of hormone-refractory PCa progression and survivability of these patients [ 46 , 47 ]. In addition, the results from several preclinical studies indicate that VEGFA inhibition or treatment with anti-VEGFA antibodies blocks the growth of human prostate tumors through suppression of angiogenesis [ 21 , 22 , 48 ], further supporting the role of VEGFA-mediated angiogenesis in PCa growth and progression. Reports also show the efficacy of anti-VEGFA treatment in combination with other therapeutic agents in preclinical mouse PCa models [ 49 , 50 ].…”