The online version of this article (doi:10.1186/1477-7819-10-165) contains supplementary material, which is available to authorized users.
Ying-Chun Zhao, Xiao-Jian Ni contributed equally to this work.
The authors declare that they have no competing of interests.
YCZ, XN and CL designed this study and carried out immnunohistochemistry staining, performed the statistical analysis, collected clinical information and drafted the manuscript. YL, MD, ZY, YYZ participated in immunohistochemistry staining, patient follow up and the statistical analysis. All authors read and approved the final manuscript.
Mounting clinical and experimental data suggest that the migration of tumor cells into lymph nodes is greatly facilitated by lymphangiogenesis. Vascular endothelial growth factor (VEGF)-C and D have been identified as lymphangiogenic growth factors and play an important role in tumor lymphangiogenesis. The purpose of this study was to investigate the location of lymphangiogenesis driven by tumor-derived VEGF-C/D in breast cancer, and to determine the role of intratumoral and peritumoral lymphatic vessel density (LVD) in lymphangiogenesis in breast cancer.
The expression levels of VEGF-C/D were determined by immunohistochemistry, and intratumoral LVD and peritumoral LVD were assessed using immunohistochemistry and the D2-40 antibody in 73 patients with primary breast cancer. The associations of intratumoral LVD and peritumoral LVD with VEGF-C/D expression, clinicopathological features and prognosis were assessed.
VEGF-C and D expression were significantly higher in breast cancer than benign disease (P < 0.01). VEGF-C (P < 0.001) and VEGF-D (P = 0.005) expression were significantly associated with peritumoral LVD, but not intratumoral LVD. Intratumoral LVD was associated with tumor size (P = 0.01). Peritumoral LVD was significantly associated with lymph node metastasis (LNM; P = 0.005), lymphatic vessel invasion (LVI; P = 0.017) and late tumor,node, metastasis (TNM) stage (P = 0.011). Moreover, peritumoral LVD was an independent risk factor for axillary lymph node metastasis, overall survival and disease-free survival in multivariate analysis.
This study suggests that tumor-derived VEGF-C/D induce peritumoral lymphangiogenesis, which may be one mechanism that leads to lymphatic invasion and metastatic spread. Peritumoral LVD has potential as an independent prognostic factor in breast cancer patients.
Pepper MS: Lymphangiogenesis and tumor metastasis: myth or reality?. Clin Cancer Res. 2001, 7: 462-468. PubMed
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS: Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001, 20: 672-682. 10.1093/emboj/20.4.672. PubMedCentralCrossRefPubMed
Van Trappen PO, Steele D, Lowe DG, Baithun S, Beasley N, Thiele W, Weich H, Krishnan J, Shepherd JH, Pepper MS, Jackson DG, Sleeman JP, Jacobs U: Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol. 2003, 201: 544-554. 10.1002/path.1467. CrossRefPubMed
Mohammed RA, Green A, El-Shikh S, Paish EC, Ellis IO, Martin SG: Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer. 2007, 96: 1092-1100. 10.1038/sj.bjc.6603678. PubMedCentralCrossRefPubMed
Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K: Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up. Clin Cancer Res. 2003, 9: 716-721. PubMed
Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, Cox G, Harris AL, Jackson DG: Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 2002, 62: 1315-1320. PubMed
Straume O, Jackson DG, Akslen LA: Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res. 2003, 9: 250-256. PubMed
Pepper MS: Lymphangiogenesis and tumor metastasis: more questions than answers. Lymphology. 2000, 33: 144-147. PubMed
Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M: Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005, 166: 913-921. 10.1016/S0002-9440(10)62311-5. PubMedCentralCrossRefPubMed
Nakazato T, Shingaki S, Kitamura N, Saito C, Kuwano R, Tachibana M: Expression level of vascular endothelial growth factor-C and -A in cultured human oral squamous cell carcinoma correlates respectively with lymphatic metastasis and angiogenesis when transplanted into nude mouse oral cavity. Oncol Rep. 2006, 15: 825-830. PubMed
Hawighorst T, Oura H, Streit M, Janes L, Nguyen L, Brown LF, Oliver G, Jackson DG, Detmar M: Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene. 2002, 21: 7945-7956. 10.1038/sj.onc.1205956. CrossRefPubMed
Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M: Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol. 2003, 162: 1951-1960. 10.1016/S0002-9440(10)64328-3. PubMedCentralCrossRefPubMed
Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO: Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res. 2005, 65: 9789-9798. 10.1158/0008-5472.CAN-05-0901. CrossRefPubMed
Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, Ostoros G, Agocs L, Soltesz I, Dome B: Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res. 2005, 11: 7344-7353. 10.1158/1078-0432.CCR-05-1077. CrossRefPubMed
- Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients
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