title: Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts.
abstract: Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Comito
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Coral
authors.initials: C
authors.lastname: Pons Segura
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.affiliation: Department of Urology, University of Florence, Careggi Hospital, Urologic Clinic San Luca, 50100 Florence, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Lanciotti
authors.affiliation: Department of Urology, University of Florence, Careggi Hospital, Urologic Clinic San Luca, 50100 Florence, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Serni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.|Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", 50134 Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D000077211:Zoledronic Acid; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid
keywords: cancer-associated fibroblasts; macrophages; mevalonate pathway; prostate cancer; zoledronic acid