CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment.

Tao Zhang,John Ward,Marsha L Frazier,Yan Zhang,Christopher Logothetis,Paul G Corn,Elsa M Li-Ning-Tapia,John Davis,Olga Sirin,Curtis Pettaway,Patricia Troncoso,Chieh Tseng,Mikhail G Kolonin

doi:10.1038/ncomms11674

Tao Zhang, John Ward + Show 11 more

Open Access

https://doi.org/10.1038/ncomms11674

Copy DOI

Abstract

White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression.

Highlights

White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers
We detected a significant increase in circulation of cells with the Adipose stromal cells (ASCs) and CPC immunophenotypes
Our recent studies in endometrial and ovarian cancer suggested that CXCL1 and/or CXCL8 secreted by human cancer cells and signalling via their receptors CXCR1 and/or CXCR2 could be implicated in human ASC migration[30]

Summary

Introduction

White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. We show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression. Monocytes/macrophages and other WAT-infiltrating leukocytes, as well as adipocytes and their mesenchymal progenitors termed adipose stromal cells (ASCs), secrete hormones, cytokines and growth factors collectively termed adipokines[28]. Our previous studies showed that human endometrial cancer cells secrete chemokines (C–X–C motif) ligand 1 (CXCL1), known as KC and GROa, as well as a related chemokine CXCL8 ( known as interleukin8)[30] These two chemokines serve as ligands of chemokine receptors CXCR1 and CXCR2, which we reported to be expressed in human ASCs30,37. A recent report demonstrated that CXCL1 expression is increased in high-grade prostate cancer[39], warranting studies on the function of its signalling in disease progression

Methods

Results

Conclusion