sFRP2 in the Aged Microenvironment Drives Melanoma Metastasis and Therapy Resistance

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aging / metabolism*
  • Animals
  • Cell Line, Tumor
  • Culture Media, Conditioned / pharmacology
  • DNA Damage
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • Fibroblasts / metabolism
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Male
  • Melanoma / blood supply
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology*
  • Membrane Proteins / metabolism*
  • Mice
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasm Metastasis*
  • Neovascularization, Pathologic
  • Oxidative Stress
  • Phenotype
  • Reactive Oxygen Species / metabolism
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Tumor Microenvironment*
  • Vemurafenib
  • Wnt Signaling Pathway
  • Wnt1 Protein / antagonists & inhibitors
  • beta Catenin / metabolism

Substances

  • Culture Media, Conditioned
  • Indoles
  • Membrane Proteins
  • Microphthalmia-Associated Transcription Factor
  • Reactive Oxygen Species
  • SFRP2 protein, human
  • Sulfonamides
  • Wnt1 Protein
  • beta Catenin
  • Vemurafenib
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase

Associated data

  • GEO/GSE57445