VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival

The ability of malignant tumors to metastasize presents a severe challenge in cancer treatment. Lymphatic vessels provide one of the main routes for tumor-metastasis on the way to regional lymph nodes. Increasing evidence suggests that inflammatory cells play an important role in tumor-associated angiogenesis and lymphangiogenesis. Recent data show that a specialized sub fraction of tumor-associated macrophages (TAMs) expressing the lymphoangiogenic growth factors vascular endothelial growth factor-C and -D (VEGF-C/D) at the tumor site, is related to lymphangiogenesis, lymphovascular invasion, and lymph node metastasis. Aim of this study was to clear the role of VEGF-C/D expressing TAMs in invasive breast cancer. One hundred-seven cases of lymph node positive invasive breast cancer were included into the study. Lymphatic microvessel density (LMVD), lymphovascular invasion (LVI), peritumoral inflammatory reaction (PI), and VEGF-C expression in tumors (VEGF-C T) and TAMs (VEGF-C C) were evaluated by immunohistochemistry and in situ hybridization. Significant associations were seen between LMVD and LVI, LMVD and VEGF-C T, and between VEGF-C T and VEGF-C C. Further significant correlations were evaluated between VEGF-C C/VEGF-C T and PI as well as between PI and LVI. LVI remained an independent prognostic factor for disease-free survival and overall survival. Our data provide evidence that the peritumoral inflammatory reaction and VEGF-C expressing TAMs may play an important role in tumor lymphangiogenesis and lymphovascular invasion in invasive breast cancer, implying new potential anti-tumor targets.