Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility.
Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility.
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DOI：
10.1158/2159-8290.cd-18-0193
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发表时间：
2019-01
期刊：
影响因子：
28.2
通讯作者：
Weeraratna AT
中科院分区：
文献类型：
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作者：
Kaur A;Ecker BL;Douglass SM;Kugel CH 3rd;Webster MR;Almeida FV;Somasundaram R;Hayden J;Ban E;Ahmadzadeh H;Franco-Barraza J;Shah N;Mellis IA;Keeney F;Kossenkov A;Tang HY;Yin X;Liu Q;Xu X;Fane M;Brafford P;Herlyn M;Speicher DW;Wargo JA;Tetzlaff MT;Haydu LE;Raj A;Shenoy V;Cukierman E;Weeraratna AT
皮肤的生理变化是衰老的最明显迹象之一。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，包括蛋白多糖、糖蛋白和软骨连接蛋白。分泌最丰富的是HAPLN1，一种透明质酸和蛋白多糖连接蛋白。HAPLN1在老化的成纤维细胞中丢失，导致更具排列的ECM促进黑色素瘤细胞的转移。在老年微环境、3D皮肤重建模型和体内，重组HAPLN1可抑制肿瘤转移。有趣的是，老化的成纤维细胞来源的基质对T细胞的迁移有相反的影响，抑制了它们的运动。HAPLN1处理老化的成纤维细胞，恢复了单核免疫细胞的活力，同时阻碍了多形核免疫细胞的活力，这反过来又影响了Treg的招募。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运动，但它们可能会对某些免疫细胞的运动产生不利影响，导致免疫微环境的整体变化。了解老化皮肤的生理变化可能为老年黑色素瘤患者提供更有效的治疗途径。
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 3D skin reconstruction models, and in vivo. Intriguingly, aged fibroblast-derived matrices had the opposite effects 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 Treg recruitment. These data suggest while age-related physical changes in the ECM can promote tumor cell motility, they may adversely impact 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 melanoma patients.