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.
J Gerontol A Biol Sci Med Sci. 2017 Sep 1;72(9):1187-1195. doi: 10.1093/gerona/glw336.
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.
细胞衰老与机体衰老有关，在诱导肿瘤抑制性改变的 DNA 损伤性癌症治疗后观察到，但其特征是分泌因子强烈增加，称为“衰老相关分泌表型”（SASP）。特别是，基质衰老成纤维细胞的 SASP 会产生有利于癌症的微环境，为抗癌干预提供了靶点。在本文中，使用 5µM 白藜芦醇进行慢性治疗（5 周），以调节 MRC5 成纤维细胞与衰老相关的促肿瘤特征，减少 SASP 相关的白细胞介素 IL1α、IL1β、IL6 和 IL8；转化生长因子-β（TGFβ）；基质金属蛋白酶 MMP3 和 MMP2；尿激酶纤溶酶原激活物（uPA）；受体蛋白 uPAR、IL6R、胰岛素生长因子受体-1（IGF-1R）、TGFβ-R2 和 CXCR4。还降低了核因子-κB（NF-κB）蛋白水平，证实了其在诱导 SASP 中的作用。白藜芦醇预处理的 MRC5 成纤维细胞对 TGFβ 的激活具有抗性。白藜芦醇处理衰老的 MRC5 诱导产生条件培养基（CM），该培养基可拮抗衰老 CM 对 A375 和 A375-M6 黑色素瘤细胞增殖和侵袭性的促肿瘤作用，并降低与恶性特征相关的上皮-间充质转化标记物的表达。这种实验方法提出了一种针对衰老基质细胞表型的治疗方法，以诱导抗肿瘤宿主微环境，适用于预防和治疗目的。
