Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment A new genetically tractable model for human cancer associated fibroblasts

We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells in...

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Vydané v:	Cancer biology & therapy Ročník 11; číslo 4; s. 383 - 394
Hlavní autori:	Trimmer, Casey, Sotgia, Federica, Whitaker-Menezes, Diana, Balliet, Renee M., Eaton, Gregory, Martinez-Outschoorn, Ubaldo E., Pavlides, Stephanos, Howell, Anthony, Iozzo, Renato V., Pestell, Richard G., Scherer, Philipp E., Capozza, Franco, Lisanti, Michael P.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Taylor & Francis 15.02.2011 Landes Bioscience
Predmet:	Animals Binding Biology Bioscience Calcium Cancer Caveolin 1 - genetics Caveolin 1 - metabolism Caveolin 1 - pharmacology Cell Cell Line, Transformed Cell Line, Tumor Cell Proliferation - drug effects Cycle Female Fibroblasts - drug effects Fibroblasts - metabolism Gene Expression Regulation, Neoplastic - genetics Gene Knockdown Techniques Humans Landes Mice Mice, Nude Mitochondria - enzymology Mitochondria - metabolism Models, Biological Neoplasms - genetics Neoplasms - metabolism Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - metabolism Organogenesis Oxidative Stress - drug effects Oxidative Stress - genetics Proteins Proteomics Recombinant Proteins - genetics Recombinant Proteins - metabolism Recombinant Proteins - pharmacology Research Paper RNA, Small Interfering Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase - pharmacology Tumor Microenvironment - drug effects Tumor Microenvironment - genetics Xenograft Model Antitumor Assays
ISSN:	1538-4047, 1555-8576, 1555-8576
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Abstract	We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome.
AbstractList	We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome. We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome.We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome. We have recently proposed a new model for understanding tumor metabolism, termed: “The Autophagic Tumor Stroma Model of Cancer Metabolism”. In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ∼4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified >40 protein biomarkers that were upregulated, most of which were associated with (i) myofibroblast differentiation or (ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant overexpression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancerassociated fibroblasts, in promoting tumor growth, which is consistent with “The Autophagic Tumor Stroma Model of Cancer”. The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic “complementation” approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER-positive breast cancers, which are all associated with a Cav-1 deficient “lethal” tumor microenvironment, driving poor clinical outcome.
Author	Capozza, Franco Pavlides, Stephanos Martinez-Outschoorn, Ubaldo E. Scherer, Philipp E. Howell, Anthony Lisanti, Michael P. Trimmer, Casey Balliet, Renee M. Eaton, Gregory Whitaker-Menezes, Diana Sotgia, Federica Iozzo, Renato V. Pestell, Richard G.
AuthorAffiliation	3 Manchester Breast Centre and 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; Manchester UK 4 Department of Medical Oncology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA 6 Touchstone Diabetes Center; The University of Texas Southwestern Medical Center; Dallas, TX USA 2 Departments of Stem Cell Biology and Regenerative Medicine and/or Cancer Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA 1 The Jefferson Stem Cell Biology and Regenerative Medicine Center; Philadelphia, PA USA 5 Department of Pathology and Cell Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
AuthorAffiliation_xml	– name: 6 Touchstone Diabetes Center; The University of Texas Southwestern Medical Center; Dallas, TX USA – name: 1 The Jefferson Stem Cell Biology and Regenerative Medicine Center; Philadelphia, PA USA – name: 5 Department of Pathology and Cell Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA – name: 3 Manchester Breast Centre and 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; Manchester UK – name: 4 Department of Medical Oncology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA – name: 2 Departments of Stem Cell Biology and Regenerative Medicine and/or Cancer Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
Author_xml	– sequence: 1 givenname: Casey surname: Trimmer fullname: Trimmer, Casey – sequence: 2 givenname: Federica surname: Sotgia fullname: Sotgia, Federica – sequence: 3 givenname: Diana surname: Whitaker-Menezes fullname: Whitaker-Menezes, Diana – sequence: 4 givenname: Renee M. surname: Balliet fullname: Balliet, Renee M. – sequence: 5 givenname: Gregory surname: Eaton fullname: Eaton, Gregory – sequence: 6 givenname: Ubaldo E. surname: Martinez-Outschoorn fullname: Martinez-Outschoorn, Ubaldo E. – sequence: 7 givenname: Stephanos surname: Pavlides fullname: Pavlides, Stephanos – sequence: 8 givenname: Anthony surname: Howell fullname: Howell, Anthony – sequence: 9 givenname: Renato V. surname: Iozzo fullname: Iozzo, Renato V. – sequence: 10 givenname: Richard G. surname: Pestell fullname: Pestell, Richard G. – sequence: 11 givenname: Philipp E. surname: Scherer fullname: Scherer, Philipp E. – sequence: 12 givenname: Franco surname: Capozza fullname: Capozza, Franco – sequence: 13 givenname: Michael P. surname: Lisanti fullname: Lisanti, Michael P. email: mlisanti@KimmelCancerCenter.org
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/21150282$$D View this record in MEDLINE/PubMed
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Snippet	We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new... We have recently proposed a new model for understanding tumor metabolism, termed: “The Autophagic Tumor Stroma Model of Cancer Metabolism”. In this new...
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SubjectTerms	Animals Binding Biology Bioscience Calcium Cancer Caveolin 1 - genetics Caveolin 1 - metabolism Caveolin 1 - pharmacology Cell Cell Line, Transformed Cell Line, Tumor Cell Proliferation - drug effects Cycle Female Fibroblasts - drug effects Fibroblasts - metabolism Gene Expression Regulation, Neoplastic - genetics Gene Knockdown Techniques Humans Landes Mice Mice, Nude Mitochondria - enzymology Mitochondria - metabolism Models, Biological Neoplasms - genetics Neoplasms - metabolism Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - metabolism Organogenesis Oxidative Stress - drug effects Oxidative Stress - genetics Proteins Proteomics Recombinant Proteins - genetics Recombinant Proteins - metabolism Recombinant Proteins - pharmacology Research Paper RNA, Small Interfering Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Superoxide Dismutase - pharmacology Tumor Microenvironment - drug effects Tumor Microenvironment - genetics Xenograft Model Antitumor Assays
Subtitle	A new genetically tractable model for human cancer associated fibroblasts
Title	Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment
URI	https://www.tandfonline.com/doi/abs/10.4161/cbt.11.4.14101 http://www.landesbioscience.com/journals/cbt/article/14101/ https://www.ncbi.nlm.nih.gov/pubmed/21150282 https://www.proquest.com/docview/852903020 https://pubmed.ncbi.nlm.nih.gov/PMC3047109
Volume	11
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