ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis

PLoS One. 2012;7(12):e50791. doi: 10.1371/journal.pone.0050791. Epub 2012 Dec 10.

Abstract

ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics*
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Carcinoma / genetics*
  • Carcinoma / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Colon / metabolism
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Cytokines / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism
  • Phosphorylation
  • RNA, Small Interfering
  • Transfection
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Cytokines
  • Neuregulin-1
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • ErbB Receptors
  • ADAM Proteins
  • Matrix Metalloproteinase 9
  • ADAM17 Protein
  • Adam17 protein, mouse

Grants and funding

This work was supported by grant 3144/B/P01/2007/33 from the Ministry of Science and Higher Education, Poland and the Scientific Exchange Program between the New Member States of the EU and Switzerland (Sciex NMS-CH; grant no. 10.085-2 to R.M-K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.