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Updated: Dec 29, 2025

Isolation, Culture, and Characterization of Prostate Cancer-Associated Fibroblasts
Published on: August 1, 2025
Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer
Laura Pietrovito1, Marta Iozzo1, Marina Bacci1
1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
Abstract:
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.
Insights
Cannabinoids show promise against prostate cancer by targeting both cancer cells and cancer-associated fibroblasts (CAFs). This study reveals cannabinoids impair CAF activation and migration, crucial for tumor progression.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Cancer progression involves interactions between tumor cells and the tumor microenvironment, including cancer-associated fibroblasts (CAFs).
- Cannabinoids are investigated for anti-cancer properties, but their effect on stromal cells is less understood.
Purpose of the Study:
- To investigate the effect of cannabinoid treatment on cancer-associated fibroblasts (CAFs) in prostate cancer.
- To determine if cannabinoids can impair CAF activation, migration, and their contribution to cancer cell invasiveness.
Main Methods:
- Prostate cancer-derived CAFs were treated with WIN 55-212.2 mesylate, a synthetic cannabinoid agonist.
- Expression of α-smooth muscle actin and matrix metalloprotease-2 was analyzed.
- CAF migration and CAF-mediated cancer cell invasiveness were assessed.
- Selective cannabinoid receptor antagonists (CB1 and CB2) were used to identify the mediating receptor.
Main Results:
- WIN 55-212.2 mesylate downregulated α-smooth muscle actin and matrix metalloprotease-2 expression in CAFs.
- Cannabinoid treatment inhibited CAF migration and CAF-mediated cancer cell invasiveness.
- The anti-CAF effects were primarily mediated by the CB2 receptor.
- Evidence suggests an endocannabinoid autocrine loop sustaining both tumor cells and CAFs.
Conclusions:
- Cannabinoids, particularly via CB2 receptor activation, effectively impair prostate cancer-associated fibroblasts.
- This dual action on cancer and stromal cells supports the potential of cannabinoids as anti-cancer agents in prostate cancer therapy.
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07:25A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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