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Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients

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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.

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81071753), the Six Kinds of Outstanding Talent Foundation of Jiangsu Province (06-B-069 and 2009, To Qiang Ding), the Science and Education for Health Foundation of Jiangsu Province (RC2007054), the Natural Science Foundation of Jiangsu Province (BK2008476, BK2009438 and BK2010581), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU (IRT-008), and A project Funded by the Priority Academic Program Development of Jiangsu higher Education Institutions (PAPD).

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Ying-Chun Zhao, Xiao-Jian Ni, Ming-Hai Wang, Xiao-Ming Zha, Yi Zhao & Shui Wang

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  1. Ying-Chun Zhao
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  2. Xiao-Jian Ni
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Correspondence to Shui Wang.

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Ying-Chun Zhao, Xiao-Jian Ni and Ming-Hai Wang contributed equally to this study.

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Zhao, YC., Ni, XJ., Wang, MH. et al. Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients. Med Oncol 29, 2594–2600 (2012). https://doi.org/10.1007/s12032-012-0205-0

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  • DOI: https://doi.org/10.1007/s12032-012-0205-0

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