Estrogen receptor α promotes lung cancer cell invasion via increase of and cross-talk with infiltrated macrophages through the CCL2/CCR2/MMP9 and CXCL12/CXCR4 signaling pathways

Abstract

Data analysis of clinical samples suggests that higher estrogen receptor alpha (ER alpha) expression could be associated with worse overall survival in some patients with non-small-cell lung cancer (NSCLC). Immunofluorescence results further showed that higher ER alpha expression was linked to larger numbers of infiltrated macrophages in NSCLC tissues. However, the detailed mechanisms underlying this phenomenon remain unclear. Results fromin vitrostudies with multiple cell lines revealed that, in NSCLC cells, ER alpha can activate the CCL2/CCR2 axis to promote macrophage infiltration, M2 polarization, and MMP9 production, which can then increase NSCLC cell invasion. Mechanistic studies using chromatin immunoprecipitation and promoter luciferase assays demonstrated that ER alpha could bind to estrogen response elements (EREs) on the CCL2 promoter to increase CCL2 expression. Furthermore, ER alpha-increased macrophage infiltration can induce a positive feedback mechanism to increase lung cancer cell ER alpha expressionviathe up-regulation of the CXCL12/CXCR4 pathway. Targeting these newly identified pathways, NSCLC ER alpha-increased macrophage infiltration or the macrophage-to-NSCLC CXCL12/CXCR4/ER alpha signal, with anti-estrogens or CCR2/CXCR4 antagonists, may help in the development of new alternative therapies to better treat NSCLC.