Format

Send to

Choose Destination
Nature. 2016 Apr 14;532(7598):250-4. doi: 10.1038/nature17392. Epub 2016 Apr 4.

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

Author information

1
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
2
University of the Sciences, Philadelphia, Pennsylvania 19104, USA.
3
Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland.
4
The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
5
Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA.
6
Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA.
7
Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
8
Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
9
Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA.
10
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
11
Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia.
12
Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia.
13
Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA.
14
Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
15
German Cancer Consortium (DKTK), Heidelberg 45127, Germany.

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 β-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.

PMID:
27042933
PMCID:
PMC4833579
DOI:
10.1038/nature17392
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center