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Open AccessArticle

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
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Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 787; https://doi.org/10.3390/ijms21030787
Received: 11 December 2019 / Revised: 15 January 2020 / Accepted: 23 January 2020 / Published: 25 January 2020
(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)
Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB2. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells. View Full-Text
Keywords: WIN 55-212.2 mesylate; cannabidiol; endocannabinoids; cancer-associated fibroblasts; prostate cancer WIN 55-212.2 mesylate; cannabidiol; endocannabinoids; cancer-associated fibroblasts; prostate cancer
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Pietrovito, L.; Iozzo, M.; Bacci, M.; Giannoni, E.; Chiarugi, P. Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression. Int. J. Mol. Sci. 2020, 21, 787.

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