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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Vydáno v:	Cancer biology & therapy Ročník 11; číslo 4; s. 383 - 394
Hlavní autoři:	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:	angličtina
Vydáno:	United States Taylor & Francis 15.02.2011 Landes Bioscience
Témata:	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
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-4047 1555-8576 1555-8576
DOI:	10.4161/cbt.11.4.14101