Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment.
AffiliationThe Jefferson Stem Cell Biology and Regenerative Medicine Center, Philadelphia, PA 19107, USA.
MetadataShow full item record
AbstractCancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome.
CitationUnderstanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. 2011, 13 (4):213 Breast Cancer Res.
JournalBreast Cancer Research
- Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment.
- Authors: Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP
- Issue date: 2011 Jul
- Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function.
- Authors: Martinez-Outschoorn U, Sotgia F, Lisanti MP
- Issue date: 2014 Apr
- Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment.
- Authors: Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F
- Issue date: 2010 Sep 1
- Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers.
- Authors: Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, Sneddon S, Martinez-Outschoorn UE, Sotgia F, Lisanti MP
- Issue date: 2012 Mar 15
- Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: implications for preventing chemotherapy resistance.
- Authors: Ko YH, Lin Z, Flomenberg N, Pestell RG, Howell A, Sotgia F, Lisanti MP, Martinez-Outschoorn UE
- Issue date: 2011 Dec 15