Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: Connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production

We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav...

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Vydáno v:	Cell cycle (Georgetown, Tex.) Ročník 11; číslo 16; s. 3019 - 3035
Hlavní autoři:	Guido, Carmela, Whitaker-Menezes, Diana, Capparelli, Claudia, Balliet, Renee, Lin, Zhao, Pestell, Richard G., Howell, Anthony, Aquila, Saveria, Andò, Sebastiano, Martinez-Outschoorn, Ubaldo, Sotgia, Federica, Lisanti, Michael P.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Taylor & Francis 15.08.2012 Landes Bioscience
Témata:	"Pied-Piper of Hamelin" aerobic glycolysis Animals Autocrine Communication autocrine signaling Autophagy Binding Biology Bioscience Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Calcium Cancer cancer associated fibroblast cancer metabolism Caveolin 1 - genetics Caveolin 1 - metabolism Cell Cell Line, Tumor Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cellular Reprogramming Coculture Techniques Cycle Female Fibroblasts - metabolism Fibroblasts - pathology Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Glycolysis Humans Immunohistochemistry Lactic Acid - metabolism Landes Ligands Mice Mice, Nude Mitochondria - genetics Mitochondria - metabolism Mitochondria - pathology mitophagy myofibroblast Neovascularization, Pathologic - metabolism Organogenesis Oxidative Phosphorylation Oxidative Stress Paracrine Communication paracrine signaling Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proteins Receptors, Transforming Growth Factor beta - genetics Receptors, Transforming Growth Factor beta - metabolism Stromal Cells - metabolism Stromal Cells - pathology TGF beta the field effect Transforming Growth Factor beta - genetics Transforming Growth Factor beta - metabolism Tumor Microenvironment tumor stroma Xenograft Model Antitumor Assays
ISSN:	1538-4101, 1551-4005, 1551-4005
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Shrnutí:	We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive TGF-β signaling. However, it remains unknown whether hyperactivation of the TGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. To address these issues, we overexpressed TGF-β ligands and the TGF-β receptor I (TGFβ-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of TGF-β in tumorigenesis is compartment-specific, and that TGF-β promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumor-promoting effects of TGF-β are independent of the cell type generating TGF-β. Thus, stromal-derived TGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that TGF-β-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the TGF-β pathway in cancer cells does not influence tumor growth, but cancer cell-derived-TGF-β ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cell-autonomous activation of the TGF-β pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. These metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. Our data provide novel insights into the role of the TGF-β pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of TGF-β signaling and the metabolic reprogramming of the tumor microenvironment.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-4101 1551-4005 1551-4005
DOI:	10.4161/cc.21384