Clinical & Experimental Metastasis

, Volume 35, Issue 8, pp 785–796 | Cite as

Role of simvastatin in tumor lymphangiogenesis and lymph node metastasis

  • Rui-Cheng JiEmail author
  • Yuki Eshita
  • Takashi Kobayashi
  • Shinya Hidano
  • Naganori Kamiyama
  • Yasuhiko Onishi
Research Paper


Lymphangiogenesis plays a crucial role in promoting cancer metastasis to sentinel lymph nodes (LNs) and beyond. Increasing data have shown that simvastatin, a cholesterol-lowering medication for the prevention of cardiovascular diseases, is involved in tumor growth and dissemination, and endothelial functions. This study aimed to investigate the potential effect of simvastatin on lymphatic formation and LN metastasis. Tumor models were established by subcutaneous injection of B16-F10 melanoma cells into mouse hind footpads. Simvastatin was administered (0.2 µg/g, intraperitoneal injection, IP) every other day for a total of eight times. Tissue samples were removed and examined by immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) techniques. The lymphatics of LN, skin, liver, and lung exhibited morphological changes, and LN weight and metastatic area of the tumor group treated with simvastatin was lower than that of the untreated tumor group. Analysis of lymphatic size, area fraction, and lymphatic vessel density showed tissue specificity and variation to melanoma carcinogenesis in the simvastatin-treated group compared with the untreated group. In addition, LNs and cutaneous tissues showed altered expression of lymphangiogenic factors and inflammatory cytokines such as VEGF-A/-C/-D and TNF-α. These findings indicated that simvastatin may modify lymphangiogenesis and tumor progression in malignant melanoma.


Lymphangiogenesis Melanoma Simvastatin VEGF-C/-D TNF-α 



Granulocyte macrophage colony-stimulating factor




Lymphatic endothelial cell


Lymph node


Lymphatic vessel density


Lymphatic endothelial hyaluronan receptor-1


Non-obese diabetic


Nitric oxide synthase


Prospero-related homeobox 1


Tumor necrosis factor-α


Vascular endothelial growth factor


Vascular endothelial growth factor receptor



The study was supported by Grant in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (R.C.Ji, No. 17K01511). This work was partly carried out at the Faculty of Medicine, Oita University.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.


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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Faculty of Welfare and Health ScienceOita UniversityOitaJapan
  2. 2.Hokkaido University Research Center for Zoonosis ControlHokkaidoJapan
  3. 3.Department of Infectious Disease Control, Faculty of MedicineOita UniversityOitaJapan
  4. 4.Ryujyu Science CorporationSetoJapan
  5. 5.Oita University Faculty of MedicineOitaJapan

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