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.