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The significance of lymphatic space invasion and its association with vascular endothelial growth factor-C expression in ovarian cancer

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Abstract

The aim of this study is to investigate the significance of lymphatic space invasion (LSI) and tumor VEGF-C expression in the lymphatic spread of ovarian cancer. By performing immunostaining using human ovarian cancer specimens, we first investigated the association between the extent of LSI and tumor VEGF-C expression, tumor lymphangiogenesis, or the lymphatic metastasis. Moreover, by performing in vitro and in vivo experiments, we elucidated the role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis as well as its role as a therapeutic target in ovarian cancer. The presence of LSI was associated with lymph node metastasis in patients with ovarian cancer. VEGF-C overexpression was significantly associated with the increased LSI and LVD in ovarian cancer. VEGF-C stimulated the lymphangiogenesis in vitro, induced the new lymph vessel formation, and increased the lymph node metastasis in mice models of ovarian cancer. The attenuation of VEGF-C expression by the treatment with mTORC1 inhibitor significantly inhibited lymphangiogenesis, and decreased lymph node metastasis in mice models of ovarian cancer. The presence of LSI is an indicator of nodal metastasis and is associated with higher tumor VEGF-C expression and worse clinical outcome of ovarian cancer patients. VEGF-C plays a crucial role in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer.

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Abbreviations

VEGF-C:

Vascular endothelial growth factor-C

VEGFR-3:

Vascular endothelial growth factor recepotor-3

LVEPCs:

Lymphatic vascular endothelial progenitor cells

LVD:

Lymphatic vessel density

LSI:

Lymphatic space invasion

HMVEC-dLy:

Human dermal lymphatic microvascular endothelial cells

ELISA:

Enzyme-linked immunosorbent assay

LYVE-1:

Lymphatic vessel endothelial hyaluronan receptor 1 cell marker

FACS:

Fluorescence activated cell sorting

mTORC1:

Mammalian target of rapamycin complex 1

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Acknowledgments

We thank Mitsuyo Tone and Takako Sawamura for the immunohistochemical works. We also thank Ayako Okamura for her technical assistance and Yuko Morishita for her secretarial assistance. S. Mabuchi is supported in part by grant-in-aid for General Scientific Research, no. 23592446, from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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    Authors and Affiliations

    1. Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

      Takeshi Hisamatsu, Seiji Mabuchi, Tomoyuki Sasano, Hiromasa Kuroda, Ryoko Takahashi, Yuri Matsumoto, Mahiru Kawano, Katsumi Kozasa, Kei Takahashi, Kenjiro Sawada & Tadashi Kimura

    2. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD 520, Los Angeles, CA, 90031, USA

      Koji Matsuo

    3. Department of Obstetrics and Gynecology, Kyosai Tachikawa Hospital, 4-2-22 Nishikicho, Tachikawa, Tokyo, 190-8531, Japan

      Yutaka Tamada

    4. Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

      Eiichi Morii

    5. Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

      Yasuhiko Kitadai

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    1. Takeshi Hisamatsu
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    Correspondence to Seiji Mabuchi.

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    Takeshi Hisamatsu, Seiji Mabuchi and Tomoyuki Sasano have contributed equally to this work.

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    Hisamatsu, T., Mabuchi, S., Sasano, T. et al. The significance of lymphatic space invasion and its association with vascular endothelial growth factor-C expression in ovarian cancer. Clin Exp Metastasis 32, 789–798 (2015). https://doi.org/10.1007/s10585-015-9751-0

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