MCP-1/CCL2 Mediated by Autocrine Loop of PDGF-BB Promotes Invasion of Lung Cancer Cell by Recruitment of Macrophages Via CCL2–CCR2 Axis

Abstract

Platelet-derived growth factor-BB (PDGF-BB) is recognized as a potential player in a paracrine manner in tumor stroma development. PDGF-BB has an autocrine growth function in lung cancer cells; however, the mechanism in nonsmall-cell lung cancer is not fully understood. In this study, we report that PDGF-BB increased monocyte chemoattractant protein-1 (MCP-1)-dependent macrophage recruitment and that expression of metastatic genes increased in A549 cells cocultured with RAW 264.7 macrophages. Similar to exogenous PDGF-BB, PDGF-BB might have a self-stimulation in invasion of cancer cells during reciprocal activation of cancer cells and tumor-associated macrophages through secretion of soluble proteins. Also, we found that PDGF-BB upregulates both mRNA and protein level of MCP-1 expression in human A549 cells through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt cell signaling pathways, binding NFκB to MCP-1 promoter site and PDGF-Rβ as critical receptor. These results suggested that MCP-1/chemokine (C-C motif) ligand 2 (CCL2) expression mediated by the autocrine loop of PDGF-BB enhanced recruitment of macrophages through CCL2-CCR2 axis, which could ultimately increase expression of metastatic genes in lung cancer cells, finally promoting invasive potential of cancer cells.