Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment

Ubaldo E. Martinez-Outschoorn, Stephanos Pavlides, Anthony Howell, Richard G. Pestell, Herbert B. Tanowitz, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

Cancer cells do not exist as pure homogeneous populations in vivo. Instead they are embedded in "cancer cell nests" that are surrounded by stromal cells, especially cancer associated fibroblasts. Thus, it is not unreasonable to suspect that stromal fibroblasts could influence the metabolism of adjacent cancer cells, and visa versa. In accordance with this idea, we have recently proposed that the Warburg effect in cancer cells may be due to culturing cancer cells by themselves, out of their normal stromal context or tumor microenvironment. In fact, when cancer cells are co-cultured with fibroblasts, then cancer cells increase their mitochondrial mass, while fibroblasts lose their mitochondria. An in depth analysis of this phenomenon reveals that aggressive cancer cells are "parasites" that use oxidative stress as a "weapon" to extract nutrients from surrounding stromal cells. Oxidative stress in fibroblasts induces the autophagic destruction of mitochondria, by mitophagy. Then, stromal cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactate and ketones) to "feed" cancer cells. This mechanism would allow cancer cells to seed anywhere, without blood vessels as a food source, as they could simply induce oxidative stress wherever they go, explaining how cancer cells survive during metastasis. We suggest that stromal catabolism, via autophagy and mitophagy, fuels the anabolic growth of tumor cells, promoting tumor progression and metastasis. We have previously termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Metabolism", or the "Reverse Warburg Effect". We also discuss how glutamine addiction (glutaminolysis) in cancer cells fits well with this new model, by promoting oxidative mitochondrial metabolism in aggressive cancer cells.

Original languageEnglish (US)
Pages (from-to)1045-1051
Number of pages7
JournalInternational Journal of Biochemistry and Cell Biology
Volume43
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • Ammonia
  • Autophagy
  • Cancer
  • Caveolin-1
  • Glutamine addiction
  • Glutaminolysis
  • Metabolic coupling
  • Recycled nutrients
  • Tumor microenvironment
  • Tumor stroma

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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  • Cite this

    Martinez-Outschoorn, U. E., Pavlides, S., Howell, A., Pestell, R. G., Tanowitz, H. B., Sotgia, F., & Lisanti, M. P. (2011). Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment. International Journal of Biochemistry and Cell Biology, 43(7), 1045-1051. https://doi.org/10.1016/j.biocel.2011.01.023