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dc.contributor.authorBalliet, R M
dc.contributor.authorCapparelli, C
dc.contributor.authorGuido, C
dc.contributor.authorPestell, T G
dc.contributor.authorMartinez-Outschoorn, U E
dc.contributor.authorLin, Z
dc.contributor.authorWhitaker-Menezes, D
dc.contributor.authorChiavarina, B
dc.contributor.authorPestell, R G
dc.contributor.authorHowell, Anthony
dc.contributor.authorSotgia, Federica
dc.contributor.authorLisanti, Michael P
dc.date.accessioned2012-09-19T16:08:44Z
dc.date.available2012-09-19T16:08:44Z
dc.date.issued2011-12-01
dc.identifier.citationMitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. 2011, 10 (23):4065-73 Cell Cycleen_GB
dc.identifier.issn1551-4005
dc.identifier.pmid22129993
dc.identifier.doi10.4161/cc.10.23.18254
dc.identifier.urihttp://hdl.handle.net/10541/245036
dc.description.abstractIncreasing chronological age is the most significant risk factor for cancer. Recently, we proposed a new paradigm for understanding the role of the aging and the tumor microenvironment in cancer onset. In this model, cancer cells induce oxidative stress in adjacent stromal fibroblasts. This, in turn, causes several changes in the phenotype of the fibroblast including mitochondrial dysfunction, hydrogen peroxide production, and aerobic glycolysis, resulting in high levels of L-lactate production. L-lactate is then transferred from these glycolytic fibroblasts to adjacent epithelial cancer cells and used as "fuel" for oxidative mitochondrial metabolism.  Here, we created a new pre-clinical model system to directly test this hypothesis experimentally. To synthetically generate glycolytic fibroblasts, we genetically-induced mitochondrial dysfunction by knocking down TFAM using an sh-RNA approach.  TFAM is mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of hydrogen peroxide and L-lactate. Thus, TFAM-deficient fibroblasts underwent metabolic reprogramming towards aerobic glycolysis.  Most importantly, TFAM-deficient fibroblasts significantly promoted tumor growth, as assayed using a human breast cancer (MDA-MB-231) xenograft model. These increases in glycolytic fibroblast driven tumor growth were independent of tumor angiogenesis. Mechanistically, TFAM-deficient fibroblasts increased the mitochondrial activity of adjacent epithelial cancer cells in a co-culture system, as seen using MitoTracker. Finally, TFAM-deficient fibroblasts also showed a loss of caveolin-1 (Cav-1), a known breast cancer stromal biomarker. Loss of stromal fibroblast Cav-1 is associated with early tumor recurrence, metastasis, and treatment failure, resulting in poor clinical outcome in breast cancer patients. Thus, this new experimental model system, employing glycolytic fibroblasts, may be highly clinically relevant. These studies also have implications for understanding the role of hydrogen peroxide production in oxidative damage and "host cell aging," in providing a permissive metabolic microenvironment for promoting and sustaining tumor growth.
dc.language.isoenen
dc.rightsArchived with thanks to Cell cycle (Georgetown, Tex.)en_GB
dc.subject.meshAnimals
dc.subject.meshBreast Neoplasms
dc.subject.meshCaveolin 1
dc.subject.meshCell Aging
dc.subject.meshCell Line, Tumor
dc.subject.meshCoculture Techniques
dc.subject.meshDNA-Binding Proteins
dc.subject.meshEpithelial Cells
dc.subject.meshFemale
dc.subject.meshFibroblasts
dc.subject.meshGene Knockdown Techniques
dc.subject.meshGlycolysis
dc.subject.meshHumans
dc.subject.meshHydrogen Peroxide
dc.subject.meshLactic Acid
dc.subject.meshMammary Neoplasms, Experimental
dc.subject.meshMice
dc.subject.meshMice, Nude
dc.subject.meshMitochondria
dc.subject.meshMitochondrial Proteins
dc.subject.meshOxidative Stress
dc.subject.meshTranscription Factors
dc.subject.meshTumor Microenvironment
dc.subject.meshXenograft Model Antitumor Assays
dc.titleMitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection.en
dc.typeArticleen
dc.contributor.departmentThe Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.en_GB
dc.identifier.journalCell Cycleen_GB
html.description.abstractIncreasing chronological age is the most significant risk factor for cancer. Recently, we proposed a new paradigm for understanding the role of the aging and the tumor microenvironment in cancer onset. In this model, cancer cells induce oxidative stress in adjacent stromal fibroblasts. This, in turn, causes several changes in the phenotype of the fibroblast including mitochondrial dysfunction, hydrogen peroxide production, and aerobic glycolysis, resulting in high levels of L-lactate production. L-lactate is then transferred from these glycolytic fibroblasts to adjacent epithelial cancer cells and used as "fuel" for oxidative mitochondrial metabolism.  Here, we created a new pre-clinical model system to directly test this hypothesis experimentally. To synthetically generate glycolytic fibroblasts, we genetically-induced mitochondrial dysfunction by knocking down TFAM using an sh-RNA approach.  TFAM is mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of hydrogen peroxide and L-lactate. Thus, TFAM-deficient fibroblasts underwent metabolic reprogramming towards aerobic glycolysis.  Most importantly, TFAM-deficient fibroblasts significantly promoted tumor growth, as assayed using a human breast cancer (MDA-MB-231) xenograft model. These increases in glycolytic fibroblast driven tumor growth were independent of tumor angiogenesis. Mechanistically, TFAM-deficient fibroblasts increased the mitochondrial activity of adjacent epithelial cancer cells in a co-culture system, as seen using MitoTracker. Finally, TFAM-deficient fibroblasts also showed a loss of caveolin-1 (Cav-1), a known breast cancer stromal biomarker. Loss of stromal fibroblast Cav-1 is associated with early tumor recurrence, metastasis, and treatment failure, resulting in poor clinical outcome in breast cancer patients. Thus, this new experimental model system, employing glycolytic fibroblasts, may be highly clinically relevant. These studies also have implications for understanding the role of hydrogen peroxide production in oxidative damage and "host cell aging," in providing a permissive metabolic microenvironment for promoting and sustaining tumor growth.


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