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sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.
Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie; Behera, Reeti; Ndoye, Abibatou; Kugel, Curtis H; Dang, Vanessa M; Appleton, Jessica; O'Connell, 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; 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.
Afiliação
  • Kaur A; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Webster MR; University of the Sciences, Philadelphia, Pennsylvania 19104, USA.
  • Marchbank K; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Behera R; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Ndoye A; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Kugel CH; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Dang VM; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Appleton J; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • O'Connell MP; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Cheng P; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Valiga AA; Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland.
  • Morissette R; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • McDonnell NB; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Ferrucci L; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Kossenkov AV; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Meeth K; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Tang HY; Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
  • Yin X; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Wood WH; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Lehrmann E; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Becker KG; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Flaherty KT; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
  • Frederick DT; Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
  • Wargo JA; Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
  • Cooper ZA; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Tetzlaff MT; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Hudgens C; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Aird KM; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • Zhang R; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Xu X; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Liu Q; Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Bartlett E; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • Karakousis G; Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Eroglu Z; Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • Lo RS; Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA.
  • Chan M; Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Menzies AM; Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia.
  • Long GV; Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
  • Johnson DB; Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
  • Sosman J; Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
  • Schilling B; Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
  • Schadendorf D; Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
  • Speicher DW; German Cancer Consortium (DKTK), Heidelberg 45127, Germany.
  • Bosenberg M; Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
  • Ribas A; German Cancer Consortium (DKTK), Heidelberg 45127, Germany.
  • Weeraratna AT; The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Nature ; 532(7598): 250-4, 2016 Apr 14.
Article em En | MEDLINE | ID: mdl-27042933
ABSTRACT
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, 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 ß-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Envelhecimento / Resistencia a Medicamentos Antineoplásicos / Microambiente Tumoral / Melanoma / Proteínas de Membrana / Metástase Neoplásica Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Humans / Male / Middle aged Idioma: En Ano de publicação: 2016 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Envelhecimento / Resistencia a Medicamentos Antineoplásicos / Microambiente Tumoral / Melanoma / Proteínas de Membrana / Metástase Neoplásica Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Humans / Male / Middle aged Idioma: En Ano de publicação: 2016 Tipo de documento: Article