Paracrine signaling by VEGF-C promotes non-small cell lung cancer cell metastasis via recruitment of tumor-associated macrophages
Authors: Zhicheng Yang
Qipeng Wu
Yang Yang
Bei Yao
Yanchao Deng
Luyong Zhang
Bing Liu
Lei Ma
Journal: Experimental cell research (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Macrophage; Metastasis; NSCLC; VEGF-C.
Affiliations: Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China., Guangzhou key laboratory of construction and application of new drug screening model systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: ., Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangzhou key laboratory of construction and application of new drug screening model systems, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: .

Abstract:  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. 

Retracted: Yes

PubPeer comments:
 An image in figure 1B (top) and an image in figure 2B (bottom) appear to overlap. If I understand correctly, this should not be the case. Could the authors please check? Brought to my attention by another reader. *** ![file] , 
  Fig. 3. Tumoral VEGF-C promotes macrophage migration via VEGFR-3 axis. Macrophage cell (1 u00d7 105 cells well) were treated with Flt-4 Fc (100 ng mL) or SAR131675 (1 u00b5M) in the CM of NSCLC cells. Macrophage migration was detected by migration assay. ![file] , 
 July 31, 2020 This article has been retracted: please see Elsevier Policy on Article Withdrawal (http: www.elsevier.com locate withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. Image analyses strongly suggested inappropriate image manipulations duplications in Figures. Upon request, the authors did not provide a satisfactory explanation. Manipulating images in any part of a publication is ethically not acceptable. The authors sincerely thank the readers who pointed out the mistakes and appreciate the rigorous scientific attitude of the editors. ,