Energy transfer in "parasitic" cancer metabolism: mitochondria are the powerhouse and Achilles' heel of tumor cells.
Authors
Martinez-Outschoorn, UPestell, R
Howell, Anthony
Tykocinski, M
Nagajyothi, F
Machado, F
Tanowitz, H
Sotgia, F
Lisanti, M
Affiliation
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA.Issue Date
2011-12-15
Metadata
Show full item recordAbstract
It is now widely recognized that the tumor microenvironment promotes cancer cell growth and metastasis via changes in cytokine secretion and extracellular matrix remodeling. However, the role of tumor stromal cells in providing energy for epithelial cancer cell growth is a newly emerging paradigm. For example, we and others have recently proposed that tumor growth and metastasis is related to an energy imbalance. Host cells produce energy-rich nutrients via catabolism (through autophagy, mitophagy, and aerobic glycolysis), which are then transferred to cancer cells to fuel anabolic tumor growth. Stromal cell-derived L-lactate is taken up by cancer cells and is used for mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP efficiently. However, "parasitic" energy transfer may be a more generalized mechanism in cancer biology than previously appreciated. Two recent papers in Science and Nature Medicine now show that lipolysis in host tissues also fuels tumor growth. These studies demonstrate that free fatty acids produced by host cell lipolysis are re-used via beta-oxidation (beta-OX) in cancer cell mitochondria. Thus, stromal catabolites (such as lactate, ketones, glutamine and free fatty acids) promote tumor growth by acting as high-energy onco-metabolites. As such, host catabolism, via autophagy, mitophagy and lipolysis, may explain the pathogenesis of cancer-associated cachexia and provides exciting new druggable targets for novel therapeutic interventions. Taken together, these findings also suggest that tumor cells promote their own growth and survival by behaving as a "parasitic organism." Hence, we propose the term "Parasitic Cancer Metabolism" to describe this type of metabolic coupling in tumors. Targeting tumor cell mitochondria (OXPHOS and beta-OX) would effectively uncouple tumor cells from their hosts, leading to their acute starvation. In this context, we discuss new evidence that high-energy onco-metabolites (produced by the stroma) can confer drug resistance. Importantly, this metabolic chemo-resistance is reversed by blocking OXPHOS in cancer cell mitochondria with drugs like Metformin, a mitochondrial "poison." In summary, parasitic cancer metabolism is achieved architecturally by dividing tumor tissue into at least two well-defined opposing "metabolic compartments:" catabolic and anabolic.Citation
Energy transfer in "parasitic" cancer metabolism: mitochondria are the powerhouse and Achilles' heel of tumor cells. 2011, 10 (24):4208-16 Cell CycleJournal
Cell CycleDOI
10.4161/cc.10.24.18487PubMed ID
22033146Type
ArticleLanguage
enISSN
1551-4005ae974a485f413a2113503eed53cd6c53
10.4161/cc.10.24.18487
Scopus Count
Collections
Related articles
- Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue.
- Authors: Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Pavlides S, Tsirigos A, Ertel A, Pestell RG, Broda P, Minetti C, Lisanti MP, Sotgia F
- Issue date: 2011 Dec 1
- Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth.
- Authors: Guido C, Whitaker-Menezes D, Lin Z, Pestell RG, Howell A, Zimmers TA, Casimiro MC, Aquila S, Ando' S, Martinez-Outschoorn UE, Sotgia F, Lisanti MP
- Issue date: 2012 Aug
- 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
- Cigarette smoke metabolically promotes cancer, via autophagy and premature aging in the host stromal microenvironment.
- Authors: Salem AF, Al-Zoubi MS, Whitaker-Menezes D, Martinez-Outschoorn UE, Lamb R, Hulit J, Howell A, Gandara R, Sartini M, Galbiati F, Bevilacqua G, Sotgia F, Lisanti MP
- Issue date: 2013 Mar 1
- Oncogenes induce the cancer-associated fibroblast phenotype: metabolic symbiosis and "fibroblast addiction" are new therapeutic targets for drug discovery.
- Authors: Lisanti MP, Martinez-Outschoorn UE, Sotgia F
- Issue date: 2013 Sep 1