Tumor-Associated Macrophage Correlated with Angiogenesis and Progression of Mucoepidermoid Carcinoma of Salivary Glands

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Abstract
There is considerable controversy about whether tumor-associated macrophages (TAMs) promote or inhibit tumor progression. The present study examined the clinicopathologic significance of TAMs and their association with tumor angiogenesis, cell proliferation, and apoptosis in mucoepidermoid carcinoma (MEC). The potential effect of TAMs on cancer cells was also investigated. CD68, CD34, Ki-67, and vascular endothelial growth factor (VEGF)-A immunohistochemical staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) were applied to samples from 41 MEC patients. The biologic effect of macrophages on MEC cancer cells was examined in a co-culture system. The proliferation index (PI) was 11.7 ± 5.9%, and the apoptotic index (AI) was 4.1 ± 2.3% in cancer patients. PI was significantly correlated with tumor grade, and the PI/AI ratio was significantly correlated with tumor size and stage. The distributions of intratumoral TAMs and microvessel density (MVD) were heterogeneous. TAM count associated strongly with tumor size, grading, and MEC staging. A greater intratumoral MVD was observed frequently in patients with large, intermediate/high-grade, and advanced-stage tumors. VEGF-A expression correlated significantly with tumor size and stage. MVD count was closely associated with TAM count and VEGF-A expression. Co-cultured cancer cells with macrophages increased migration and invasion ability of cancer cells. Co-cultured endothelial cells with cancer cells elevated VEGF-A expression, proliferation, and migration, and tube formation of endothelial cells. Our data suggest that TAMs play a tumor-promoting role in MEC. The TAM count, intratumoral MVD, and PI/AI ratio are potentially useful markers of progression in patients with MEC.