{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:24:21Z","timestamp":1788312261297,"version":"build-2803163510"},"reference-count":87,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,12,25]],"date-time":"2018-12-25T00:00:00Z","timestamp":1545696000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Student Support Service (SAE\/UNICAMP)"},{"name":"S\u00e3o Paulo Research Foundation (FAPESP)"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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\u2010inflammatory and antiangiogenic therapies on cancer progression, correlating them with steroid hormone receptor (AR and ER\u03b1), reactive stroma (vimentin, \u03b1SMA, and TGF\u2010\u03b2), and cell proliferation (PCNA) markers expression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>TRAMP mice (12\u2010week old) were divided into the groups: Control (TRCON): received the vehicles used for drug dilution; Celecoxib (TRCEL): received oral doses of the anti\u2010inflammatory drug celecoxib (15\u2009mg\/kg) twice daily; Nintedanib (TRNTB): received oral doses of the antiangiogenic drug nintedanib (10\u2009mg\/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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>While celecoxib led to fibromuscular hypertrophy attenuation, nintedanib significantly reduced the incidence of well\u2010differentiated 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 ER\u03b1 localization from epithelial nuclei to stroma as well as significant decrease of TGF\u2010\u03b2 levels and associated angiogenesis. In parallel, all treatments applied resulted in reduced inflammatory marker and vimentin (VIM) expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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 ER\u03b1 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\u2010rich prostate stroma in TRAMP mice. Collectively, these findings pointed to the beneficial effects of combining anti\u2010inflammatory and antiangiogenic strategies to prevent or delay prostatic tumorigenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.23758","type":"journal-article","created":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T04:45:01Z","timestamp":1545799501000},"page":"515-535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Association of anti\u2010inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice"],"prefix":"10.1002","volume":"79","author":[{"given":"Pedro Augusto Marischka","family":"Mateus","sequence":"first","affiliation":[{"name":"Department of Structural and Functional Biology Institute of Biology University of Campinas (UNICAMP) Campinas S\u00e3o Paulo 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