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FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
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Research Article Immunology Oncology

FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis

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Abstract

Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here, we report that an elevation of FGF-2 signaling in samples from patients with nasopharyngeal carcinoma (NPC) and xenograft mouse models promoted NPC metastasis. Mechanistically, tumor cell–derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1/AHR signaling. Gain- and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization toward an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposome treatment resulted in a reduction of FGF-2–induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2/FGFR1/pericyte/CXCL14/TAM stromal communication axis in NPC and propose an effective antimetastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2hi tumors.

Authors

Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie

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Figure 5

CXCL14 recruits, activates, and polarizes TAMs.

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CXCL14 recruits, activates, and polarizes TAMs.
(A and B) Mouse macropha...
(A and B) Mouse macrophage migration (n = 8 samples per group) and chemotactic ability (n = 6 samples per group) of macrophage treated with or without CXCL14. (C) Quantification of CD45+ cells in xenograft shScrambled- and shFGF2-transfected NPC tumors (n = 5 samples per group). (D) Pie charts of percentage of various inflammatory cells in xenograft shScrambled- and shFGF2-transfected NPC tumors (n = 5 samples per group). CD45+CD11b+F4/80+ macrophage population, CD45+MHCII+CD11b+CD11c+ DC population, CD45+CD11b+Ly6GhiLy6Cint granulocytic subsets of myeloid-derived suppressor cell population, CD45+CD11b+Ly6G–Ly6C+ monocytic subsets of myeloid-derived suppressor cell population, CD45+B220+ B cell population, and CD45+CD11b–CD49b+ NK cell population were analyzed. (E and F) Quantification of CD45+CD11b+F4/80+ TAM population, CD45+CD11b+ F4/80+CD206+ M2-like TAM population, and CD45+CD11b+F4/80+CD86+ M1-like TAM population (n = 5 sample per group). (G) qPCR quantification of CD206 and CD86 mRNA levels in F4/80+ TAMs isolated from xenograft shScrambled- and shFGF2-transfected NPC tumors (n = 3 samples per group). (H) Tumor tissues were stained with an anti-CD206 antibody (brown). Scale bar: 50 μm. Quantification of CD206+ signals (n = 8 random fields per group). (I and J) qPCR quantification of CD206 and CD86 mRNA levels in macrophages that were activated with FGF-2–treated pericyte conditioned medium or CXCL14. Vehicle- and FGF-2–stimulated macrophages serve as controls (n = 3 samples per group). (K) CXCL14- or FGF-2–treated pericyte conditioned medium–induced CD206 upregulation and CD86 downregulation in macrophages. β-Actin marks the loading level in each lane. These experiments were repeated twice. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired 2-tailed Student’s t test (A–C and E–J). Data are presented as mean ± SD.

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