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

Hasini Jayatilaka,Daniele M Gilkes,Pranay Tyle,Julia Ju,Jerry S H Lee,Pei-Hsun Wu,Jonathan J Chen,Rong Fan,Minsuk Kwak,Hyun Ji Kim,Denis Wirtz

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.

Highlights

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 suggests that as cancer cells proliferate and local cell density increases the secretion profile of cancer cells in the tumour microenvironment (TME) may be dynamically altered and this may play an important role in metastasis
Increased local cell density directly enhances cell migration in metastatic cells embedded in 3D matrices by increasing interleukin 6 (IL-6) and Interleukin 8 (IL-8) levels

Summary

Introduction

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. We find that metastatic human sarcoma and carcinoma cells exhibit enhanced migration as a consequence of cell proliferation, which causes increased cell density in 3D collagen matrices This increase in cell density causes significant enhancement in cell migration due to an increase in the secretion of specific soluble proteins. This study reveals a synergistic paracrine signalling pathway that when inhibited has the potential to decrease the metastatic capacity of cancer cells and thereby improve patient outcomes

Methods

Results

Conclusion