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.