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

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 1

FGF-2 is distinctively expressed and correlates with TAM infiltration in human NPC.

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FGF-2 is distinctively expressed and correlates with TAM infiltration in...
(A) Cross–data set quantitative heatmap of selected genes of various types of cancer and their adjacent control healthy tissues. Arrow points to distinctively upregulated genes in NPC. Log2 fold changes were used for quantification. (B) Transcriptomic expression levels of FGF2 in human LUAD tissues, BRCA tissues and their adjacent healthy tissues. Sample number: control-LUAD/LUAD/control-BRCA/BRCA=347/483/291/1085. (C) Transcriptomic expression levels of FGF2 in various stages of human NPC tissues and their adjacent healthy tissues. Sample number: control/StageT1/StageT2/StageT3=10/16/11/4. (D) Human normal nasopharyngeal tissues (NNT), rhinitis tissues, and NPC tissues were stained with H&E and an anti–FGF-2 antibody (brown). Sample number: NNT/Rhinitis/NPC=3/10/6. Scale bar in upper panel: 500 μm. Scale bar in middle and lower panels: 50 μm. Quantification of FGF-2+ signals and FGF-2+ signals in stromal and epithelial components (n = 8 random fields per group). (E) NPC cancer cells were sorted by MACS from freshly tissues. qPCR quantification of FGF2 mRNA (n = 3 samples per group). (F) NNT rhinitis tissues and NPC tissues were stained. Sample number: NNT/Rhinitis/NPC=3/10/6. Scale bar in upper and middle panels: 50 μm. Scale bar in lower panel: 100 μm. Quantification of FSP1+ (brown), CD163+ (brown), CD31+ (red), and NG2+ (green) and coverage rate of NG2+ pericytes (n = 8 random fields per group). (G) qPCR quantification of FGF2, CD163, CD31, NG2, and FSP1 mRNA in freshly collected tissues. Sample number: Rhinitis/NPC=5/6. (H) Correlation of FGF2 and CD163 expression of human NPCs and their control healthy tissues. Sample number: Control/NPC=10/31. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired 2-tailed Student’s t test (B, D, E, G, and H) or 1-way ANOVA with Tukey’s multiple-comparison analysis (C, D, and F). Data are presented as mean ± SD.