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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Veröffentlicht in:Cell cycle (Georgetown, Tex.) Jg. 11; H. 16; S. 3019 - 3035
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Taylor & Francis 15.08.2012
Landes Bioscience
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ISSN:1538-4101, 1551-4005, 1551-4005
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Abstract 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.
AbstractList 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.
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.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.
Author Capparelli, Claudia
Whitaker-Menezes, Diana
Andò, Sebastiano
Balliet, Renee
Sotgia, Federica
Pestell, Richard G.
Martinez-Outschoorn, Ubaldo
Howell, Anthony
Aquila, Saveria
Lin, Zhao
Guido, Carmela
Lisanti, Michael P.
AuthorAffiliation Manchester Breast Centre & Breakthrough Breast Cancer Research Unit; Paterson Institute for Cancer Research; School of Cancer, Enabling Sciences and Technology; Manchester Academic Health Science Centre; University of Manchester; UK
Department of Pharmaco-Biology, and Faculty of Pharmacy; University of Calabria; Arcavacata di Rende, Cosenza, Italy
Department of Medical Oncology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
The Jefferson Stem Cell Biology and Regenerative Medicine Center; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
Departments of Stem Cell Biology & Regenerative Medicine, and Cancer Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
AuthorAffiliation_xml – name: Departments of Stem Cell Biology & Regenerative Medicine, and Cancer Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
– name: Manchester Breast Centre & Breakthrough Breast Cancer Research Unit; Paterson Institute for Cancer Research; School of Cancer, Enabling Sciences and Technology; Manchester Academic Health Science Centre; University of Manchester; UK
– name: The Jefferson Stem Cell Biology and Regenerative Medicine Center; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
– name: Department of Pharmaco-Biology, and Faculty of Pharmacy; University of Calabria; Arcavacata di Rende, Cosenza, Italy
– name: Department of Medical Oncology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
Author_xml – sequence: 1
  givenname: Carmela
  surname: Guido
  fullname: Guido, Carmela
– sequence: 2
  givenname: Diana
  surname: Whitaker-Menezes
  fullname: Whitaker-Menezes, Diana
– sequence: 3
  givenname: Claudia
  surname: Capparelli
  fullname: Capparelli, Claudia
– sequence: 4
  givenname: Renee
  surname: Balliet
  fullname: Balliet, Renee
– sequence: 5
  givenname: Zhao
  surname: Lin
  fullname: Lin, Zhao
– sequence: 6
  givenname: Richard G.
  surname: Pestell
  fullname: Pestell, Richard G.
– sequence: 7
  givenname: Anthony
  surname: Howell
  fullname: Howell, Anthony
– sequence: 8
  givenname: Saveria
  surname: Aquila
  fullname: Aquila, Saveria
– sequence: 9
  givenname: Sebastiano
  surname: Andò
  fullname: Andò, Sebastiano
– sequence: 10
  givenname: Ubaldo
  surname: Martinez-Outschoorn
  fullname: Martinez-Outschoorn, Ubaldo
– sequence: 11
  givenname: Federica
  surname: Sotgia
  fullname: Sotgia, Federica
  email: federica.sotgia@jefferson.edu
– sequence: 12
  givenname: Michael P.
  surname: Lisanti
  fullname: Lisanti, Michael P.
  email: mlisanti@KimmelCancerCenter.org
BackLink https://www.ncbi.nlm.nih.gov/pubmed/22874531$$D View this record in MEDLINE/PubMed
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Snippet 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...
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SubjectTerms "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
Title 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
URI https://www.tandfonline.com/doi/abs/10.4161/cc.21384
http://www.landesbioscience.com/journals/cc/article/21384/
https://www.ncbi.nlm.nih.gov/pubmed/22874531
https://www.proquest.com/docview/1036880917
https://pubmed.ncbi.nlm.nih.gov/PMC3442913
Volume 11
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