Microenvironmental autophagy promotes tumour growth

Nature. 2017 Jan 19;541(7637):417-420. doi: 10.1038/nature20815. Epub 2017 Jan 11.

Abstract

As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

Publication types

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

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Autophagy* / drug effects
  • Autophagy* / genetics
  • Biological Transport
  • Cell Proliferation
  • Disease Models, Animal
  • Drosophila Proteins / deficiency
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / metabolism
  • Female
  • Interleukin-6 / metabolism
  • Membrane Proteins
  • Models, Biological*
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tumor Microenvironment*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics

Substances

  • Amino Acids
  • Drosophila Proteins
  • Interleukin-6
  • Membrane Proteins
  • Reactive Oxygen Species
  • Scrib protein, Drosophila
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins