title: Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection.
abstract: Increasing 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.
authors: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Renee M
authors: RM
authors: Balliet
authors: Claudia
authors: C
authors: Capparelli
authors: Carmela
authors: C
authors: Guido
authors: Timothy G
authors: TG
authors: Pestell
authors: Ubaldo E
authors: UE
authors: Martinez-Outschoorn
authors: Zhao
authors: Z
authors: Lin
authors: Diana
authors: D
authors: Whitaker-Menezes
authors: Barbara
authors: B
authors: Chiavarina
authors: Richard G
authors: RG
authors: Pestell
authors: Anthony
authors: A
authors: Howell
authors: Federica
authors: F
authors: Sotgia
authors: Michael P
authors: MP
authors: Lisanti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; D014157:Transcription Factors; D019344:Lactic Acid; D006861:Hydrogen Peroxide