Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors.
dc.contributor.author | Martinez-Outschoorn, U E | |
dc.contributor.author | Lin, Z | |
dc.contributor.author | Trimmer, C | |
dc.contributor.author | Flomenberg, N | |
dc.contributor.author | Wang, C | |
dc.contributor.author | Pavlides, S | |
dc.contributor.author | Pestell, R G | |
dc.contributor.author | Howell, Anthony | |
dc.contributor.author | Sotgia, F | |
dc.contributor.author | Lisanti, M P | |
dc.date.accessioned | 2012-06-27T09:06:38Z | |
dc.date.available | 2012-06-27T09:06:38Z | |
dc.date.issued | 2011-08-01 | |
dc.identifier.citation | Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. 2011, 10 (15):2504-20 Cell Cycle | en_GB |
dc.identifier.issn | 1551-4005 | |
dc.identifier.pmid | 21778829 | |
dc.identifier.uri | http://hdl.handle.net/10541/230938 | |
dc.description.abstract | Previously, we proposed that cancer cells behave as metabolic parasites, as they use targeted oxidative stress as a "weapon" to extract recycled nutrients from adjacent stromal cells. Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis, and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the "reverse Warburg effect." To further test the validity of this hypothesis, here we used an in vitro MCF7-fibroblast co-culture system, and quantitatively measured a variety of metabolic parameters by FACS analysis (analogous to laser-capture micro-dissection). Mitochondrial activity, glucose uptake, and ROS production were measured with highly-sensitive fluorescent probes (MitoTracker, NBD-2-deoxy-glucose, and DCF-DA). Interestingly, using this approach, we directly show that cancer cells initially secrete hydrogen peroxide that then triggers oxidative stress in neighboring fibroblasts. Thus, oxidative stress is contagious (spreads like a virus) and is propagated laterally and vectorially from cancer cells to adjacent fibroblasts. Experimentally, we show that oxidative stress in cancer-associated fibroblasts quantitatively reduces mitochondrial activity, and increases glucose uptake, as the fibroblasts become more dependent on aerobic glycolysis. Conversely, co-cultured cancer cells show significant increases in mitochondrial activity, and corresponding reductions in both glucose uptake and GLUT1 expression. Pre-treatment of co-cultures with extracellular catalase (an anti-oxidant enzyme that detoxifies hydrogen peroxide) blocks the onset of oxidative stress, and potently induces the death of cancer cells, likely via starvation. Given that cancer-associated fibroblasts show the largest increases in glucose uptake, we suggest that PET imaging of human tumors, with Fluoro-2-deoxy-D-glucose (F-2-DG), may be specifically detecting the tumor stroma, rather than epithelial cancer cells. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Cell cycle (Georgetown, Tex.) | en_GB |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Breast Neoplasms | |
dc.subject.mesh | Catalase | |
dc.subject.mesh | Cell Line | |
dc.subject.mesh | Coculture Techniques | |
dc.subject.mesh | Female | |
dc.subject.mesh | Fibroblasts | |
dc.subject.mesh | Fluorescent Dyes | |
dc.subject.mesh | Glucose Transporter Type 1 | |
dc.subject.mesh | Glycolysis | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Hydrogen Peroxide | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Oxidative Stress | |
dc.subject.mesh | Positron-Emission Tomography | |
dc.subject.mesh | Reactive Oxygen Species | |
dc.subject.mesh | Tumor Microenvironment | |
dc.title | Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. | en |
dc.type | Article | en |
dc.contributor.department | The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. | en_GB |
dc.identifier.journal | Cell Cycle | en_GB |
html.description.abstract | Previously, we proposed that cancer cells behave as metabolic parasites, as they use targeted oxidative stress as a "weapon" to extract recycled nutrients from adjacent stromal cells. Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis, and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the "reverse Warburg effect." To further test the validity of this hypothesis, here we used an in vitro MCF7-fibroblast co-culture system, and quantitatively measured a variety of metabolic parameters by FACS analysis (analogous to laser-capture micro-dissection). Mitochondrial activity, glucose uptake, and ROS production were measured with highly-sensitive fluorescent probes (MitoTracker, NBD-2-deoxy-glucose, and DCF-DA). Interestingly, using this approach, we directly show that cancer cells initially secrete hydrogen peroxide that then triggers oxidative stress in neighboring fibroblasts. Thus, oxidative stress is contagious (spreads like a virus) and is propagated laterally and vectorially from cancer cells to adjacent fibroblasts. Experimentally, we show that oxidative stress in cancer-associated fibroblasts quantitatively reduces mitochondrial activity, and increases glucose uptake, as the fibroblasts become more dependent on aerobic glycolysis. Conversely, co-cultured cancer cells show significant increases in mitochondrial activity, and corresponding reductions in both glucose uptake and GLUT1 expression. Pre-treatment of co-cultures with extracellular catalase (an anti-oxidant enzyme that detoxifies hydrogen peroxide) blocks the onset of oxidative stress, and potently induces the death of cancer cells, likely via starvation. Given that cancer-associated fibroblasts show the largest increases in glucose uptake, we suggest that PET imaging of human tumors, with Fluoro-2-deoxy-D-glucose (F-2-DG), may be specifically detecting the tumor stroma, rather than epithelial cancer cells. |
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Medical Oncology
Medical Oncology