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

• Published in: The Prostate 2019-04, Vol.79 (5), p.515-535
• Main Authors: Mateus, Pedro Augusto Marischka, Kido, Larissa Akemi, Silva, Rafael Sauce, Cagnon, Valéria Helena Alves, Montico, Fabio
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antiangiogenic agents; Antitumor activity; Celecoxib; Celecoxib - pharmacology; Cell proliferation; Disease Progression; Drug dosages; Drug Synergism; Drug Therapy, Combination; Epithelial cells; Estrogen Receptor alpha - biosynthesis; Etiology; Hypertrophy; Indoles - pharmacology; Inflammation; Localization; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Precancerous Conditions - drug therapy; Precancerous Conditions - pathology; Proliferating cell nuclear antigen; Prostate - blood supply; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - prevention & control; reactive stroma; Receptors, Androgen - biosynthesis; Smooth muscle; Stroma; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; TRAMP; Tumorigenesis; Vimentin; Western blotting
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.23758

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 combi