479683 Synergistic IL6/8 Paracrine Signaling Pathway Infers New Strategy to Prevent Cancer Metastasis through Inhibition of Cell Migration

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Fatima Umanzor1, Hasini Jayatilaka2 and Denis Wirtz2, (1)Johns Hopkins University, Baltimore, MD, (2)Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD

Following uncontrolled proliferation, primary tumor cells invade neighboring tissues by acquiring phenotypic changes that enhance migration. Tumor cell proliferation and migration have been previously shown to be mutually exclusive of each other. This study demonstrates that as tumor cells proliferate, past a threshold cell density, migration is enhanced in metastatic human sarcoma and carcinoma cells - but not in normal cells or non-metastatic cancer cells-, through a synergistic paracrine signaling via Interleukin 6 (IL-6) and Interleukin 8 (IL-8). Transcriptome sequencing reveals that the functional phenotype of high-density cells emerged due cell proliferation resembles that of low-density cells treated with a combination of IL-6 and IL-8. Mechanistic study with cell models indicates that the productive, paracrine IL-6/8 signaling pathway is only activated in 3D collagen matrices via Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), Wiskott-Aldrich syndrome protein family member 3 (WASF3), and the Arp2/3 complex which induces enhanced protrusion activity and significantly increases cell migration. Combined inhibition of IL-6 and IL-8 receptors significantly decreases the expression of Arp2/3 in a mouse xenograft model and consequently reduces metastasis. This study reveals previously unobserved direct coupling between proliferation and migration through a synergistic paracrine IL-6/8 signaling pathway, which could be a therapeutically target for preventing or treating metastatic cancers.

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