Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration

  • Nat Commun. 2017 May 26;8:15584. doi: 10.1038/ncomms15584.
Hasini Jayatilaka  1 ,  Pranay Tyle  1 ,  Jonathan J Chen  2 ,  Minsuk Kwak  2 ,  Julia Ju  1 ,  Hyun Ji Kim  1 ,  Jerry S H Lee  1  3 ,  Pei-Hsun Wu  1  4 ,  Daniele M Gilkes  1  5 ,  Rong Fan  2 ,  Denis Wirtz  1  4  5
Affiliations
  • 1. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
  • 2. Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, USA.
  • 3. Center for Strategic Scientific Initiatives, National Cancer Institute, Bethesda, Maryland 20850, USA.
  • 4. Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
  • 5. Department of Oncology and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
PMID: 28548090 DOI: 10.1038/ncomms15584
Abstract

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells- but not in normal or non-metastatic Cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells.

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