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在老化微环境中的sFRP2驱动黑色素瘤转移和治疗耐药性

Amanpreet Kaur^1,2, Marie R Webster¹, Katie Marchbank¹

¹The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.

|April 5, 2016

概括

老化的皮肤纤维细胞分泌sFRP2,通过影响关键信号通路,促进黑色素瘤转移和对向治疗的抗性. 这突显了老化的微环境.

科学领域:

癌症学
皮肤病学
老龄化研究
癌症微观环境

背景情况:

癌症与衰老密切相关, 老年患者往往预后较差.
细胞损伤,免疫力下降和炎症等因素导致老年癌症患者的治疗结果较差.
老化瘤微环境,特别是皮肤纤维细胞对黑色素瘤进展的影响在很大程度上尚未研究.

研究的目的:

调查皮肤纤维细胞与年龄相关的变化是否影响黑色素瘤转移.
确定皮肤纤维细胞老化对黑色素瘤对向治疗的反应的影响.
阐明老化纤维细胞影响黑色素瘤进展的分子机制.

主要方法:

对皮肤纤维细胞及其分泌因子与年龄相关的变化的分析.
检查受老化纤维细胞影响的黑色素瘤细胞的信号通路,包括Wnt信号,β-catenin,MITF和APE1.
评估黑色素瘤细胞对活性氧物种诱导的DNA损伤和向治疗的反应.
在体内对血管生成和转移的影响的评估.

主要成果:

年龄较大的纤维细胞分泌较高水平的Wnt抗体sFRP2.
在黑色素瘤细胞中,sFRP2触发信号级联,降低β-catenin,MITF和APE1水平.
失去APE1会影响黑色素瘤细胞对DNA损伤的反应,从而增加对维穆拉芬尼的抗药性.
在老年纤维细胞中增加的sFRP2促进黑色素瘤血管生成和转移.

结论:

皮肤纤维细胞与年龄相关的变化,特别是sFRP2分泌量的增加,导致黑色素瘤的进展.
通过改变黑色素瘤细胞信号和氧化还原平衡,老化的微环境有助于治疗耐药性.
这些发现为老年癌症患者提供了针对老年微观环境的新治疗策略.

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