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

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 HIF1a 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. Cancer Res; 74(11); 2999-3010. Ó2014 AACR.

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…However, L-NMMA may also inhibit eNOS and nNOS activity. eNOS gene polymorphisms are related with the development of breast cancer (64), and nNOS is related to the increase of cancer-associated fibroblasts in breast cancer (65). Using a pan-NOS inhibitor may help to overcome NO-related carcinogenic effects.…”

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…Of note, nitric oxide synthase (NOS1) has increased expression in CAF and, with CXCL14, stimulates CAFs. NOS1 can speed up tumor growth with the assistance of CXCL14-expressing CAFs [61]. Furthermore, lower miR-29b expression in CAFs can accelerate metastasis by activating the p38-STAT1 pathway in breast cancer cells and up-regulating CXCL14 and CCL11 in CAFs.…”

FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling

“…Although CCL2-derived from tumor cells was also reported to mediate T-cell migration (28,38), including regulatory T cells, another important immunosuppressive cells, coinjection of FAP þ CAFs or fibroblastic knockdown of CCL2 had no effect on tumor-infiltrating regulatory T cells (data not shown), and even caused decreased IFNg þ T cell infiltration. Given that tyrosine nitrated CCL2 attracted myeloid cells but not T cells and tyrosine nitration was reported in protumorigenic fibroblasts (39,40), this could explain why CCL2 derived from FAP þ CAFs was effective in attracting MDSCs, but not T cells, to tumor sites. CXCL1/2 was reported to be important for the recruitment of MDSCs to sites of inflammation or cancer (41,42).…”