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

Nature 2016 Apr 4;532(7598):250-4. Epub 2016 Apr 4.

The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature17392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833579PMC
April 2016
68 Reads

Publication Analysis

Top Keywords

aged microenvironment
12
melanoma cells
12
tumour progression
8
targeted therapy
8
melanoma metastasis
8
dermal fibroblasts
8
melanoma
6
therapy find
4
find aged
4
augment angiogenesis
4
aged fibroblasts
4
response targeted
4
metastasis response
4
sfrp2 augment
4
antagonist sfrp2
4
loss ape1
4
wnt antagonist
4
secrete wnt
4
drive melanoma
4
fibroblasts secrete
4

References

(Supplied by CrossRef)

D Ruiter et al.
Lancet Oncol. 2002

G Li et al.
Crit. Rev. Oral Biol. Med. 2002

MY Hsu et al.
Differentiation 2002

T Bogenrieder et al.
Crit. Rev. Oncol. Hematol. 2002

D Dankort et al.
Nature Genet. 2009

KS Hoek et al.
Pigment Cell Melanoma Res. 2011

KS Hoek et al.
Cancer Res. 2008

MR Webster et al.
Biochim. Biophys. Acta 1856

MP O’Connell et al.
Cancer Discov. 2013

EH Flach et al.
Mol. Pharm. 2011

J Campisi et al.
J. Investig. Dermatol. Symp. Proc. 1998

Similar Publications