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

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Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties. / Augsten, Martin; Sjoberg, Elin; Frings, Oliver; Vorrink, Sabine U.; Frijhoff, Jeroen; Olsson, Eleonor; Borg, Åke; Ostman, Arne.

I: Cancer Research, Vol. 74, Nr. 11, 2014, s. 2999-3010.

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Augsten, Martin ; Sjoberg, Elin ; Frings, Oliver ; Vorrink, Sabine U. ; Frijhoff, Jeroen ; Olsson, Eleonor ; Borg, Åke ; Ostman, Arne. / Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties. I: Cancer Research. 2014 ; Vol. 74, Nr. 11. s. 2999-3010.

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TY - JOUR

T1 - Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

AU - Augsten, Martin

AU - Sjoberg, Elin

AU - Frings, Oliver

AU - Vorrink, Sabine U.

AU - Frijhoff, Jeroen

AU - Olsson, Eleonor

AU - Borg, Åke

AU - Ostman, Arne

PY - 2014

Y1 - 2014

N2 - 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 HIF1 alpha 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. (C) 2014 AACR.

AB - 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 HIF1 alpha 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. (C) 2014 AACR.

U2 - 10.1158/0008-5472.CAN-13-2740

DO - 10.1158/0008-5472.CAN-13-2740

M3 - Article

VL - 74

SP - 2999

EP - 3010

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 11

ER -