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

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.

The synergy of Helicobacter pylori and lipid metabolic disorders in induction of Th17-related cytokines in human gastric cancer

“…Thus, the production of CXCL1 and GM-CSF may be critical members of the cytokine milieu, as these have been reported to promote the recruitment and function of MDSCs, respectively. [38] In agreement with previous observations, we found that both GM-CSF and CXCL1 were greatly increased in H. pylori positive tumors [ Figure 3A and C] and their upregulation was coincident with elevated IL-17A [ Figure 3B and D]. In addition, it has been shown that inflamed adipose and stomach tissues induced by H. felis/HFD can enhance IL-6 and leptin production to stimulate Th17 differentiation and stabilization.…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…In a murine model, CXCL1 signalling was a rate-limiting step for both obesity-associated ASC recruitment and ASC effects on tumour vascularity. Corroborating evidence for this pathway are the findings that, in human prostate cancers, obese patients show both increased epithelial CXCL1 expression and CXCL1 receptor-positive cells in the stroma [81].…”

Cytokine signaling regulating adipose stromal cell trafficking

“…9 In a recent report, using animal models and human tissue samples, we demonstrated that adipose stromal cell recruitment to prostate tumors is mediated by CXCL1 secreted from cancer cells and acting on ASC via CXCR1. 39 This study also showed that CXCL1 signaling is a determinant of a-smooth muscle actin (aSMA) expression and pro-angiogenic properties of ASC in tumors.…”

“…39 In that study, multiplex analysis of mouse plasma identified IL-22 as the only cytokine (in the panel of 50 cytokines) circulation of which in peripheral blood was dramatically (50 times) higher in obese tumor-bearing mice compared to lean tumor-bearing mice. Because IL-22 signaling through the IL-22 receptor (IL-22R) has been previously identified as a pathway inducing the expression of CXCL1 in the epithelium, [40][41][42][43] we set out to test if the pattern of IL-22 / IL-22R expression is consistent with its potential role in obesity-associated CXCL1 induction.…”