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

Casey Trimmer, Federica Sotgia, Diana Whitaker-Menezes, Renee M. Balliet, Gregory Eaton, Ubaldo E. Martinez-Outschoorn, Stephanos Pavlides, Anthony Howell, Renato V. Iozzo, Richard G. Pestell, Philipp E. Scherer, Franco Capozza, Michael P. Lisanti

Research output: Contribution to journalArticle

78 Citations (Scopus)

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 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 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-positive breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor microenvironment, driving poor clinical outcome.

Original languageEnglish (US)
Pages (from-to)383-394
Number of pages12
JournalCancer Biology and Therapy
Volume11
Issue number4
DOIs
StatePublished - Feb 15 2011

Fingerprint

Caveolin 1
Fibroblasts
Neoplasms
Oxidative Stress
Autophagy
superoxide dismutase 2
Cancer-Associated Fibroblasts
Growth
Triple Negative Breast Neoplasms
Breast Neoplasms
Tumor Microenvironment
Myofibroblasts
Tamoxifen
Tumor Burden
Heterografts
Superoxides
Proteomics

Keywords

  • Angiogenesis
  • Cancer associated fibroblast
  • Caveolin-1
  • Collagen 6 (COL6A1, COL6A2)
  • Mitochondria
  • Myofibroblast differentiation
  • Oxidative stress
  • Superoxide disumutase (SOD2)
  • Triple negative breast cancer
  • Tumor stroma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

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

In: Cancer Biology and Therapy, Vol. 11, No. 4, 15.02.2011, p. 383-394.

Research output: Contribution to journalArticle

Trimmer, C, Sotgia, F, Whitaker-Menezes, D, Balliet, RM, Eaton, G, Martinez-Outschoorn, UE, Pavlides, S, Howell, A, Iozzo, RV, Pestell, RG, Scherer, PE, Capozza, F & Lisanti, MP 2011, 'Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: A new genetically tractable model for human cancer associated fibroblasts', Cancer Biology and Therapy, vol. 11, no. 4, pp. 383-394. https://doi.org/10.4161/cbt.11.4.14101
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. / Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment : A new genetically tractable model for human cancer associated fibroblasts. In: Cancer Biology and Therapy. 2011 ; Vol. 11, No. 4. pp. 383-394.
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AU - Whitaker-Menezes, Diana

AU - Balliet, Renee M.

AU - Eaton, Gregory

AU - Martinez-Outschoorn, Ubaldo E.

AU - Pavlides, Stephanos

AU - Howell, Anthony

AU - Iozzo, Renato V.

AU - Pestell, Richard G.

AU - Scherer, Philipp E.

AU - Capozza, Franco

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KW - Triple negative breast cancer

KW - Tumor stroma

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