Nature Communications
Nature Communications
5 years ago

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

Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration
Julia Ju, Rong Fan, Hasini Jayatilaka, Jonathan J. Chen, Minsuk Kwak, Denis Wirtz, Daniele M. Gilkes, Pranay Tyle, Jerry S. H. Lee, Pei-Hsun Wu, Hyun Ji Kim
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.

Publisher URL: http://www.nature.com/articles/ncomms15584

DOI: 10.1038/ncomms15584

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