Paracrine signaling by VEGF-C promotes non-small cell lung cancer cell metastasis via recruitment of tumor-associated macrophages

Journal Article · Thu Mar 15 04:00:00 EDT 2018 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2018.02.005· OSTI ID:23082426

Deng, Yanchao; Yang, Yang; Yao, Bei; Ma, Lei; Wu, Qipeng; Yang, Zhicheng ^[1]; Zhang, Luyong ^[2]; Liu, Bing ^[1]

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1. Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006 (China)
2. Guangzhou key laboratory of construction and application of new drug screening model systems, Guangdong Pharmaceutical University, Guangzhou 510006 (China)

Highlights: • VEGF-C exerts a novel function that induces macrophage migration and recruitment. • Tumoral VEGF-C induces macrophage migration via VEGFR/Src/p38 axis in macrophages. • Paracrine VEGF-C-mediated macrophage infiltration promotes NSCLC cell metastasis. High expression of tumoral vascular endothelial growth factor C (VEGF-C) is correlated with clinical non-small cell lung cancer (NSCLC) metastasis and patient survival. Nevertheless, the comprehensive mechanisms accounting for VEGF-C-mediated cancer progression remain largely unclear. The present study found that VEGF-C expression was upregulated in various NSCLC cell lines. By utilizing transwell migration assay, we found that both recombinant VEGF-C protein and overexpression of VEGF-C in NSCLC cells (A549 and H441 cell lines) could efficiently enhance RAW264.7 cell (murine macrophages) migration. However, recombinant VEGF-C treatment had no effects on both CD206 (an M2 macrophage marker) expression and M1/M2 cytokine profiles of macrophages. Furthermore, additional treatment of recombinant Flt-4/Fc, the specific VEGFR-3 inhibitor or the specific VEGFR-2 inhibitor significantly suppressed macrophage migration compared with A549-CM (conditioned medium) or H441-CM alone group, confirming that NSCLC cells-derived VEGF-C is sufficient to promote macrophage migration. Interestingly, VEGF-C could stimulate the Src/p38 signaling via VEGFR-2/3 axis in macrophages, and inhibition of Src/p38 signaling obviously reversed the enhancement effect of VEGF-C on macrophage migration. Finally, the functional importance of macrophage infiltration induced by tumoral VEGF-C in promoting metastasis was established in a mouse model. In conclusion, our results highlight a novel function of tumoral VEGF-C that paracrinely induces macrophage recruitment, and resultantly promotes NSCLC cell metastasis. Therefore, VEGF-C/VEGFR-2/3 axis may be a promising microenvironmental target against progression of NSCLC.

• OSTI ID: 23082426
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 364; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
LUNGS
LYMPHOKINES
MACROPHAGES
METASTASES
MICE
NEOPLASMS
PATIENTS