Chronic Resveratrol Treatment Inhibits MRC5 Fibroblast SASP-Related Protumoral Effects on Melanoma Cells.
Cellular senescence is related to organismal aging and is observed after DNA damaging cancer therapies, that induce tumor-suppressive modifications, but it is characterized by a strong increase in secreted factors, termed the "senescence-associated secretory phenotype" (SASP). Particularly, SASP from stroma senescent fibroblasts creates a cancer-favoring microenvironment, providing targets for anti-cancer interventions. In the present article, chronic treatment (5 weeks) with 5 µM resveratrol has been used to modulate senescence-related protumoral features of MRC5 fibroblasts, reducing SASP-related interleukins IL1α, IL1β, IL6, and IL8; transforming-growth-factor-β (TGFβ); matrix metallo-proteinases MMP3 and MMP2; urokinase plasminogen activator (uPA); receptor proteins uPAR, IL6R, insulin growth factor receptor-1 (IGF-1R), TGFβ-R2, and CXCR4. The cellular nuclear-factor-kB (NF-kB) protein level was also reduced, confirming its role in the induction of SASP. Resveratrol pretreated MRC5 fibroblasts were resistant to activation by TGFβ. Resveratrol treatment of senescent MRC5 induced the production of conditioned media (CM) which counteracted the protumoral effect of senescent CM on A375 and A375-M6 melanoma cell proliferation and invasiveness, and reduced the expression of epithelial-to-mesenchymal transition markers related to malignant features. This experimental approach proposes a treatment that targets the senescent stromal cell phenotype to induce an anti-tumor hosting microenvironment, which is suitable for both preventive and therapeutic purposes.
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.|Department of Medical Biotechnologies, University of Siena, Italy.
Beatrice
B
Menicacci
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Anna
A
Laurenzana
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Anastasia
A
Chillà
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Francesca
F
Margheri
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Silvia
S
Peppicelli
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Elisabetta
E
Tanganelli
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Gabriella
G
Fibbi
Department NeuroFarBa, Section of Pharmacology and Toxicology, University of Florence, Italy.
Lisa
L
Giovannelli
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Mario
M
Del Rosso
Department of Experimental and Clinical Biomedical Science, Section of Experimental Pathology and Oncology, University of Florence, Italy.
Alessandra
A
Mocali
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D059016:Tumor Microenvironment
D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D007378:Interleukins; D013267:Stilbenes; D000077185:Resveratrol
cancer; cellular senescence; resveratrol