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 3

Pericyte-dependent mechanism of FGF-2–induced macrophage activation.

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Pericyte-dependent mechanism of FGF-2–induced macrophage activation. (A ...
(A and B) qPCR quantification of human and mouse FGFR1, FGFR2, FGFR3, and FGFR4 mRNA levels in various cell types, including 5-8F NPC cell line, hTERT-immortalized dermal fibroblasts, isolated primary pericytes, HUVEC endothelial cells, THP-1 monocyte/macrophage cell line, mouse T241 cell line, mouse MS5 stromal fibroblasts, mouse lung isolated primary pericytes, mouse liver isolated primary endothelial cells, and murine RAW 264.7 monocyte/macrophage cell line. (C and D) Human and mouse tumor cell migration of tumor cells cocultured with various cell types in the presence or absence of FGF-2. Vehicle- or FGF-2–treated tumor cells serve as controls (n = 8 samples per group). (E and F) Human and mouse tumor cell migration of tumor cells cocultured with or without various cell types (n = 8 samples per group). (G and H) Conditioned medium of pericytes or fibroblasts in the presence or absence of FGF-2 was collected. Mouse macrophage migration (n = 8 samples per group) and chemotactic ability (n = 6 samples per group) of macrophages treated with various conditioned medium are shown. (I) Morphological changes of macrophage administrated with vehicle or the conditioned medium of FGF-2–treated pericytes. Quantification of macrophage structural changes (n = 8 random fields per group). (J and K) Human and mouse tumor cell migration of tumor cells cocultured with macrophages, which activated with FGF-2–treated pericyte conditioned medium. Tumor cells receiving the FGF-2–treated pericyte conditioned medium serve as controls (n = 8 samples per group). ***P < 0.001 by unpaired 2-tailed Student’s t test (C, D, and G–K) or 1-way ANOVA with Tukey’s multiple-comparison analysis (A, B, E, and F). Data are presented as mean ± SD.