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sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

机译：sFRP2在老年微环境中驱动黑色素瘤转移和治疗耐药性

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摘要

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression(1-4), we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in beta-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.
机译：癌症是衰老的疾病。临床上，老年癌症患者的预后往往比年轻患者差。这可能是由于累积的细胞损伤，适应性免疫力下降和慢性炎症引起的。但是，老化的微环境对肿瘤进展的影响尚未得到充分探索。由于真皮成纤维细胞可能对黑素瘤的进展产生深远影响（1-4），因此我们检查了真皮成纤维细胞中与年龄相关的变化是否可以驱动黑素瘤转移和对靶向治疗的反应。在这里，我们发现衰老的成纤维细胞分泌一种Wnt拮抗剂sFRP2，它激活黑色素瘤细胞中的多步信号传导级联反应，从而导致β-catenin和与小眼症相关的转录因子（MITF）减少，并最终导致密钥丢失氧化还原效应器，APE1。 APE1的丢失减弱了黑色素瘤细胞对活性氧引起的DNA损伤的反应，使细胞对靶向治疗（维罗非尼）更具抵抗力。 sFRP2中与年龄相关的增加也促进了黑色素瘤细胞的血管生成和转移。这些数据提供了关于老年微环境中的成纤维细胞如何促进肿瘤进展的综合观点，为老年人的治疗设计提供了新的可能性。

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  • 来源
    《Nature》 |2016年第7598期|250-254|共5页
  • 作者

    Kaur Amanpreet; Webster Marie R.; Marchbank Katie; Behera Reeti; Ndoye Abibatou; Kugel Curtis H. III; Dang Vanessa M.; Appleton Jessica; OConnell Michael P.; Cheng Phil; Valiga Alexander A.; Morissette Rachel; McDonnell Nazli B.; Ferrucci Luigi; Kossenkov Andrew V.; Meeth Katrina; Tang Hsin-Yao; Yin Xiangfan; Wood William H. III; Lehrmann Elin; Becker Kevin G.; Flaherty Keith T.; Frederick Dennie T.; Wargo Jennifer A.; Cooper Zachary A.; Tetzlaff Michael T.; Hudgens Courtney; Aird Katherine M.; Zhang Rugang; Xu Xiaowei; Liu Qin; Bartlett Edmund; Karakousis Giorgos; Eroglu Zeynep; Lo Roger S.; Chan Matthew; Menzies Alexander M.; Long Georgina V.; Johnson Douglas B.; Sosman Jeffrey; Schilling Bastian; Schadendorf Dirk; Speicher David W.; Bosenberg Marcus; Ribas Antoni; Weeraratna Ashani T.;

  • 作者单位

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA|Univ Sci, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Univ Zurich, Dept Dermatol, CH-8006 Zurich, Switzerland;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Yale Univ, Dept Dermatol & Pathol, New Haven, CT 06511 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    NIA, NIH, Baltimore, MD 21224 USA;

    Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut, Boston, MA 02114 USA;

    Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut, Boston, MA 02114 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Univ Penn, Dept Surg, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Dept Pathol, Abramson Canc Ctr, Philadelphia, PA 19104 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Univ Penn, Dept Surg, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Dept Pathol, Abramson Canc Ctr, Philadelphia, PA 19104 USA;

    Univ Penn, Dept Surg, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Dept Pathol, Abramson Canc Ctr, Philadelphia, PA 19104 USA;

    City Hope Med Ctr, Dept Med Oncol, Duarte, CA 91010 USA;

    Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA;

    Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW 2145, Australia;

    Melanoma Inst Australia, Sydney, NSW 2000, Australia|Univ Sydney, Sydney, NSW 2000, Australia;

    Melanoma Inst Australia, Sydney, NSW 2000, Australia|Univ Sydney, Sydney, NSW 2000, Australia;

    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA;

    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA;

    Univ Duesburg Essen, Dept Dermatol, Univ Hosp, West German Canc Ctr, Essen, Germany|German Canc Consortium DKTK, D-45127 Heidelberg, Germany;

    Univ Duesburg Essen, Dept Dermatol, Univ Hosp, West German Canc Ctr, Essen, Germany|German Canc Consortium DKTK, D-45127 Heidelberg, Germany;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Yale Univ, Dept Dermatol & Pathol, New Haven, CT 06511 USA;

    Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA;

    Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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