The effect of vascular endothelial growth factor C expression in tumor-associated macrophages on lymphangiogenesis and lymphatic metastasis in breast cancer.

The aim of this study was to investigate the effect of vascular endothelial growth factor-C (VEGF-C) expression in tumor-associated macrophages (TAMs) on lymphatic microvessel density (LMVD) and lymphatic endothelial cell proliferation (LECP) and to determine the role of VEGF-C expression in lymphangiogenesis in patients with breast cancer. Breast cancer tissue specimens confirmed by pathological analysis were obtained from 75 patients. Samples were observed by microscopy analysis after immunohistochemical double‑staining. The total number of TAMs and the number of VEGF-C-positive TAMs were determined. LMVD and LECP were calculated for the intratumoral and peritumoral areas. Correlation analysis was performed among these indexes, lymph vessel invasion (LVI) and lymph node metastasis in the peritumoral regions. Immunohistochemical double-staining demonstrated that VEGF-C was markedly expressed in TAMs. The number of TAMs, LMVD and LECP in the peritumoral areas was significantly higher than that in the intratumoral areas (P<0.001). We observed positive correlations between the following parameters: the number of TAMs and the peritumoral LMVD (P<0.001), the percentage of TAMs expressing VEGF-C and the peritumoral LMVD (P<0.001), the number of TAMs and the peritumoral LECP (P<0.001), and the percentage of TAMs expressing VEGF-C and the peritumoral LECP (P<0.001). Furthermore, the total number of TAMs and VEGF-C-positive TAMs, LMVD and LECP in cases with lymph node metastasis or LVI were significantly higher compared to those in cases without lymph node metastasis or LVI (P<0.01 or P<0.05). Our findings suggest that TAMs play a critical role in tumor-induced lymphangiogenesis through upregulating VEGF-C, which may contribute to lymphatic invasion in breast cancer.