Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties.
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.
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden Martin.Augsten@ki.se.
Martin
M
Augsten
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Elin
E
Sjöberg
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Oliver
O
Frings
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Sabine U
SU
Vorrink
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Jeroen
J
Frijhoff
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Eleonor
E
Olsson
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Åke
Å
Borg
Authors' Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Stockholm; Department of Oncology, Lund University, Lund, Sweden.
Arne
A
Östman
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D025521:Tumor Suppressor Proteins; D009569:Nitric Oxide; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I