title: Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients.
abstract: Breast cancer usually initially metastases to the sentinel lymph nodes (SLNs). Recent studies have demonstrated that tumor cells induce SLN lymphangiogenesis before metastasis in several malignancies. In addition, tumor-derived VEGF-C or VEGF-D may induce lymphangiogenesis and promote lymph node metastasis. To explore the mechanisms of lymph node metastasis in breast cancer, we investigated whether primary tumors induce SLN lymphangiogenesis before metastasis and determined the function of tumor-derived VEGF-C and VEGF-D in SLN lymphangiogenesis. Expression of VEGF-C and VEGF-D was examined using immunohistochemistry in 63 primary breast tumors. No significant relationships between VEGF-C and VEGF-D (P=0.420), and VEGF-C or VEGF-D expression and clinical parameters (age, tumor size, grade, hormonal receptor status, her-2 status) were observed (P>0.05). Expression of the lymphatic-specific markers VEGFR-3, Prox-1 and LYVE-1 was measured using quantitative real-time RT-PCR in uninvolved SLNs from 63 patients and compared to control lymph nodes from patients with benign breast disease. Expression of Prox-1 and LYVE-1 mRNA was significantly higher in uninvolved SLNs from breast cancer patients than that in control lymph nodes (P<0.01). Interestingly, expression of VEGFR-3, Prox-1 and LYVE-1 was significantly higher in SLNs from patients with high VEGF-C-expressing tumors than low VEGF-C-expressing tumors (P<0.05), but not VEGF-D-high-expressing tumors (P>0.05). This study demonstrates that primary breast tumors induce SLN lymphangiogenesis before metastasis occurs and that tumor-derived VEGF-C, but not VEGF-D, plays an important role in SLN lymphangiogenesis in breast cancer.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Zhao
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Ni
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Zha
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shui
authors.initials: S
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008875:Middle Aged; D021701:Sentinel Lymph Node Biopsy; D025521:Tumor Suppressor Proteins / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis / Q000502:physiology*; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; C119248:LYVE1 protein, human; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D033921:Vesicular Transport Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3