Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania.
The Wistar Institute, Philadelphia, Pennsylvania.
Cancer Discov. 2019 Jan;9(1):64-81. doi: 10.1158/2159-8290.CD-18-0193. Epub 2018 Oct 2.
Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins, and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3-D skin reconstruction models, and . Intriguingly, aged fibroblast-derived matrices had the opposite effect on the migration of T cells, inhibiting their motility. HAPLN1 treatment of aged fibroblasts restored motility of mononuclear immune cells, while impeding that of polymorphonuclear immune cells, which in turn affected regulatory T-cell recruitment. These data suggest that although age-related physical changes in the ECM can promote tumor cell motility, they may adversely affect the motility of some immune cells, resulting in an overall change in the immune microenvironment. Understanding the physical changes in aging skin may provide avenues for more effective therapy for older patients with melanoma. SIGNIFICANCE: These data shed light on the mechanochemical interactions that occur between aged skin, tumor, and immune cell populations, which may affect tumor metastasis and immune cell infiltration, with implications for the efficacy of current therapies for melanoma...
皮肤的物理变化是衰老最明显的迹象之一。我们发现,年轻的真皮成纤维细胞分泌高水平的细胞外基质 (ECM) 成分,包括糖胺聚糖、糖蛋白和软骨连接蛋白。分泌最多的是 HAPLN1,一种透明质酸和糖胺聚糖连接蛋白。HAPLN1 在衰老的成纤维细胞中丢失,导致 ECM 更有序排列,从而促进黑色素瘤细胞的转移。在衰老的微环境中,在 3-D 皮肤重建模型中,以及在......中,重建 HAPLN1 抑制了转移。有趣的是,衰老的成纤维细胞来源的基质对 T 细胞的迁移有相反的影响,抑制其迁移。HAPLN1 处理衰老的成纤维细胞恢复了单核免疫细胞的迁移能力,同时阻止了多形核免疫细胞的迁移能力,进而影响调节性 T 细胞的募集。这些数据表明,尽管 ECM 中与年龄相关的物理变化可以促进肿瘤细胞的迁移,但它们可能会对某些免疫细胞的迁移产生不利影响,从而导致免疫微环境的整体变化。了解衰老皮肤的物理变化可能为老年黑色素瘤患者提供更有效的治疗途径。意义:这些数据揭示了发生在衰老皮肤、肿瘤和免疫细胞群体之间的机械化学相互作用,这些相互作用可能影响肿瘤转移和免疫细胞浸润,对当前黑色素瘤治疗的疗效有影响。
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