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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 LU ; Borg, Åke LU and Ostman, Arne (2014) In Cancer Research 74(11). p.2999-3010
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 HIF1 alpha signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
74
issue
11
pages
2999 - 3010
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000337170600010
  • scopus:84902194856
  • pmid:24710408
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-13-2740
language
English
LU publication?
yes
id
914a3af7-86e6-41ff-a4e4-c690a6c35da4 (old id 4544955)
date added to LUP
2016-04-01 14:59:56
date last changed
2022-02-12 06:33:17
@article{914a3af7-86e6-41ff-a4e4-c690a6c35da4,
  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 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.}},
  author       = {{Augsten, Martin and Sjoberg, Elin and Frings, Oliver and Vorrink, Sabine U. and Frijhoff, Jeroen and Olsson, Eleonor and Borg, Åke and Ostman, Arne}},
  issn         = {{1538-7445}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2999--3010}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-13-2740}},
  doi          = {{10.1158/0008-5472.CAN-13-2740}},
  volume       = {{74}},
  year         = {{2014}},
}