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

Hasini Jayatilaka, Pranay Tyle, Jonathan J. Chen, Minsuk Kwak, Julia Ju, Hyun Ji Kim, Jerry S. H. Lee, Pei-Hsun Wu, Daniele M. Gilkes (), Rong Fan () and Denis Wirtz ()
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Hasini Jayatilaka: The Johns Hopkins University
Pranay Tyle: The Johns Hopkins University
Jonathan J. Chen: Yale University
Minsuk Kwak: Yale University
Julia Ju: The Johns Hopkins University
Hyun Ji Kim: The Johns Hopkins University
Jerry S. H. Lee: The Johns Hopkins University
Pei-Hsun Wu: The Johns Hopkins University
Daniele M. Gilkes: The Johns Hopkins University
Rong Fan: Yale University
Denis Wirtz: The Johns Hopkins University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15584

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