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

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

doi:10.1038/ncomms11674

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

Nat Commun. 2016 May 31:7:11674. doi: 10.1038/ncomms11674.

Affiliations

¹ The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
⁴ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Adipocytes / pathology
Adipose Tissue, White / cytology
Adipose Tissue, White / pathology
Adult
Aged
Aged, 80 and over
Animals
Cell Line, Tumor
Cell Movement / physiology*
Chemokine CXCL1 / genetics
Chemokine CXCL1 / metabolism*
Diet, High-Fat / adverse effects
Disease Progression
Endothelial Cells / pathology
Humans
Interleukin-8 / metabolism
Male
Mesenchymal Stem Cells / pathology*
Mice
Mice, Inbred C57BL
Mice, Nude
Middle Aged
Neovascularization, Pathologic / pathology
Obesity / complications
Obesity / metabolism
Obesity / pathology*
Primary Cell Culture
Prostatic Neoplasms / blood supply
Prostatic Neoplasms / complications
Prostatic Neoplasms / pathology*
RNA, Small Interfering / metabolism
Receptors, Interleukin-8A / genetics
Receptors, Interleukin-8A / metabolism
Receptors, Interleukin-8B / genetics
Receptors, Interleukin-8B / metabolism
Tissue Array Analysis
Tumor Microenvironment / physiology*
Xenograft Model Antitumor Assays

Substances

ACTA2 protein, human
Actins
CXCL1 protein, human
CXCL8 protein, human
Chemokine CXCL1
Cxcl1 protein, mouse
Interleukin-8
RNA, Small Interfering
Receptors, Interleukin-8A
Receptors, Interleukin-8B

Grants and funding

P50 CA140388/CA/NCI NIH HHS/United States