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ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

Stefanie Schmidt1, Neele Schumacher1, Jeanette Schwarz1

  • 1Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany.

The Journal of Experimental Medicine
|February 24, 2018
PubMed

Insights

ADAM17 inhibition significantly reduces colorectal cancer growth by blocking epidermal growth factor receptor (EGF-R) signaling. This pathway involves IL-6 trans-signaling, offering a new therapeutic strategy against EGF-R blockade resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Colorectal cancer (CRC) treatment involves epidermal growth factor receptor (EGF-R) antibodies, but resistance limits efficacy.
  • EGF-R activation by soluble ligands involves ADAM17-mediated cleavage of its precursors.
  • EGF-R signaling on myeloid cells, not epithelial cells, drives intestinal tumorigenesis.

Purpose of the Study:

  • To investigate the role of ADAM17 and IL-6 signaling in colorectal cancer development.
  • To explore a novel therapeutic strategy targeting ADAM17-mediated pathways.

Main Methods:

  • Utilized mouse intestinal cancer models with and without ADAM17.
  • Performed RNA sequencing to analyze gene expression changes.
  • Assessed tumor formation in IL-6 knockout and sgp130Fc transgenic mice.

Main Results:

  • Absence of ADAM17 nearly abolished tumorigenesis and reduced tumor grade in mouse models.
  • RNA sequencing revealed downregulation of STAT3 and Wnt pathway components.
  • Impaired tumor formation was observed in IL-6 deficient and IL-6 trans-signaling blocked mice.
  • ADAM17 mediates EGF-R-induced IL-6 synthesis, crucial for β-catenin-dependent tumorigenesis.

Conclusions:

  • ADAM17-dependent IL-6 trans-signaling is a key driver of colorectal tumorigenesis.
  • Targeting ADAM17 or IL-6 trans-signaling presents a promising therapeutic approach for CRC.
  • This strategy may overcome resistance to current EGF-R blockade therapies.

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