Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

Martin Augsten,Jeroen Frijhoff,Oliver Frings,Eleonor Olsson,Arne Östman,Åke Borg,Sabine U Vorrink,Elin Sjöberg

doi:10.1158/0008-5472.can-13-2740

Martin Augsten, Jeroen Frijhoff + Show 6 more

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https://doi.org/10.1158/0008-5472.can-13-2740

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Abstract

Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1α signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy.

Highlights

CXCL14, designated BRAK, MIP-2g, or BMAC, is an orphan member of the CXC chemokine subfamily
NOS1 expression is enhanced in CXCL14 fibroblasts To further understand the enhanced protumoral effects of
NOS1 seemed as a potential candidate that functionally contributes to the different effects associated with the protumorigenic action of CXCL14-expressing fibroblasts [8]

Summary

Introduction

CXCL14, designated BRAK, MIP-2g, or BMAC, is an orphan member of the CXC chemokine subfamily. Earlier studies have indicated a broad chemotactic activity for various cell types, including immature dendritic cells, monocytes, macrophages, and natural killer cells, but not T cells [1]. Analyses of CXCL14 knockout mice have indicated that CXCL14 is not required for dendritic cell and macrophage function under in vivo inflammatory conditions [2]. The functional roles of CXCL14 in tumor biology have been addressed in a number of studies and indicate context-dependent pro- or antitumoral effects [1]. Some studies, analyzing effects of CXCL14 overexpression in cancer cells, have reported antitumoral and antiangiogenic effects [3,4,5,6]. Protumoral effects of CXCL14 have been suggested based on evidence for upregula-

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