Extracellular superoxide dismutase inhibits hepatocyte growth factor-mediated breast cancer-fibroblast interactions

Briana Ormsbee Golden, Brandon Griess, Shakeel Mir, Matthew Fitzgerald, Charlotte Kuperwasser, Frederick Domann, Melissa LT Teoh-Fitzgerald

Research output: Contribution to journalArticle

Abstract

We have previously shown tumor suppressive effects of extracellular superoxide dismutase, EcSOD in breast cancer cells. In this study, an RTK signaling array revealed an inhibitory effect of EcSOD on c-Met phosphorylation and its downstream kinase c-Abl in MDA-MB231 cells. Moreover, an extracellular protein array showed that thrombospondin 1 (TSP-1), a scavenger of the c-Met ligand, hepatocyte growth factor (HGF) is significantly up-regulated in EcSOD overexpressing cells (Ec.20). We further determined the effects of EcSOD on HGF/c-Met-mediated cancer-fibroblast interactions by co-culturing normal fibroblasts (RMF) or RMF which overexpresses HGF (RMF-HGF) with MDA-MB231 cells. We observed that while RMF-HGF significantly promoted Matrigel growth of MDA-MB231, overexpression of EcSOD inhibited the HGF-stimulated growth. Similarly, a SOD mimetic, MnTE-2-PyP, inhibited HGF-induced growth and invasion of MDA-MB231. In addition, a long-term heterotypic co-culture study not only showed that Ec.20 cells are resistant to RMF-HGF-induced invasive stimulation but RMF-HGF that were co-cultured with Ec.20 cells showed an attenuated phenotype, suggesting an oxidative-mediated reciprocal interaction between the two cell types. In addition, we demonstrated that RMF-HGF showed an up-regulation of an ROS-generating enzyme, NADPH oxidase 4 (Nox4). Targeting this pro-oxidant significantly suppressed the activated phenotype of RMF-HGF in a collagen contraction assay, suggesting that RMF-HGF contributes to the oxidative tumor microenvironment. We have further shown that scavenging ROS with EcSOD significantly inhibited RMFHGF- stimulated orthotopic tumor growth of MDA-MB231. This study suggests the loss of EcSOD in breast cancer plays a pivotal role in promoting the HGF/c-Met-mediated cancer-fibroblast interactions.

Original languageEnglish (US)
Pages (from-to)107390-107408
Number of pages19
JournalOncotarget
Volume8
Issue number64
DOIs
StatePublished - Jan 1 2017

Fingerprint

Hepatocyte Growth Factor
Superoxide Dismutase
Fibroblasts
Breast Neoplasms
Growth
Neoplasms
Thrombospondin 1
Phenotype
Protein Array Analysis
Tumor Microenvironment
NADPH Oxidase
Coculture Techniques
Reactive Oxygen Species
Phosphotransferases
Up-Regulation
Collagen

Keywords

  • Breast cancer
  • C-Met
  • Cancer-associated fibroblasts
  • EcSOD
  • Tumor-stroma interactions

ASJC Scopus subject areas

  • Oncology

Cite this

Extracellular superoxide dismutase inhibits hepatocyte growth factor-mediated breast cancer-fibroblast interactions. / Golden, Briana Ormsbee; Griess, Brandon; Mir, Shakeel; Fitzgerald, Matthew; Kuperwasser, Charlotte; Domann, Frederick; Teoh-Fitzgerald, Melissa LT.

In: Oncotarget, Vol. 8, No. 64, 01.01.2017, p. 107390-107408.

Research output: Contribution to journalArticle

Golden, Briana Ormsbee ; Griess, Brandon ; Mir, Shakeel ; Fitzgerald, Matthew ; Kuperwasser, Charlotte ; Domann, Frederick ; Teoh-Fitzgerald, Melissa LT. / Extracellular superoxide dismutase inhibits hepatocyte growth factor-mediated breast cancer-fibroblast interactions. In: Oncotarget. 2017 ; Vol. 8, No. 64. pp. 107390-107408.
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AU - Golden, Briana Ormsbee

AU - Griess, Brandon

AU - Mir, Shakeel

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AU - Kuperwasser, Charlotte

AU - Domann, Frederick

AU - Teoh-Fitzgerald, Melissa LT

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AB - We have previously shown tumor suppressive effects of extracellular superoxide dismutase, EcSOD in breast cancer cells. In this study, an RTK signaling array revealed an inhibitory effect of EcSOD on c-Met phosphorylation and its downstream kinase c-Abl in MDA-MB231 cells. Moreover, an extracellular protein array showed that thrombospondin 1 (TSP-1), a scavenger of the c-Met ligand, hepatocyte growth factor (HGF) is significantly up-regulated in EcSOD overexpressing cells (Ec.20). We further determined the effects of EcSOD on HGF/c-Met-mediated cancer-fibroblast interactions by co-culturing normal fibroblasts (RMF) or RMF which overexpresses HGF (RMF-HGF) with MDA-MB231 cells. We observed that while RMF-HGF significantly promoted Matrigel growth of MDA-MB231, overexpression of EcSOD inhibited the HGF-stimulated growth. Similarly, a SOD mimetic, MnTE-2-PyP, inhibited HGF-induced growth and invasion of MDA-MB231. In addition, a long-term heterotypic co-culture study not only showed that Ec.20 cells are resistant to RMF-HGF-induced invasive stimulation but RMF-HGF that were co-cultured with Ec.20 cells showed an attenuated phenotype, suggesting an oxidative-mediated reciprocal interaction between the two cell types. In addition, we demonstrated that RMF-HGF showed an up-regulation of an ROS-generating enzyme, NADPH oxidase 4 (Nox4). Targeting this pro-oxidant significantly suppressed the activated phenotype of RMF-HGF in a collagen contraction assay, suggesting that RMF-HGF contributes to the oxidative tumor microenvironment. We have further shown that scavenging ROS with EcSOD significantly inhibited RMFHGF- stimulated orthotopic tumor growth of MDA-MB231. This study suggests the loss of EcSOD in breast cancer plays a pivotal role in promoting the HGF/c-Met-mediated cancer-fibroblast interactions.

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