Skip to main content

Advertisement

Log in

Role of simvastatin in tumor lymphangiogenesis and lymph node metastasis

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

GM-CSF:

Granulocyte macrophage colony-stimulating factor

IL-1β:

Interleukin-1β

LEC:

Lymphatic endothelial cell

LN:

Lymph node

LVD:

Lymphatic vessel density

LYVE-1:

Lymphatic endothelial hyaluronan receptor-1

NOD:

Non-obese diabetic

NOS:

Nitric oxide synthase

Prox-1:

Prospero-related homeobox 1

TNF-α:

Tumor necrosis factor-α

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

References

  1. Ji RC (2017) Lymph nodes and cancer metastasis: new perspectives on the role of intranodal lymphatic sinuses. Int J Mol Sci 18:51

    Article  Google Scholar 

  2. Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786

    Article  Google Scholar 

  3. Brown M, Assen FP, Leithner A, Abe J, Schachner H, Asfour G, Bago-Horvath Z, Stein JV, Uhrin P, Sixt M, Kerjaschki D (2018) Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science 359:1408–1411

    Article  CAS  Google Scholar 

  4. Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, Chin SM, Kitahara S, Bouta EM, Chang J, Beech E, Jeong HS, Carroll MC, Taghian AG, Padera TP (2018) Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 359:1403–1407

    Article  CAS  Google Scholar 

  5. Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS (2008) Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer 123:951–957

    Article  CAS  Google Scholar 

  6. Hakamada-Taguchi R, Uehara Y, Kuribayashi K, Numabe A, Saito K, Negoro H, Fujita T, Toyo-oka T, Kato T (2003) Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res 93:948–956

    Article  CAS  Google Scholar 

  7. Kretzer IF, Maria DA, Guido MC, Contente TC, Maranhão RC (2016) Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice. Int J Nanomed 11:885–904

    CAS  Google Scholar 

  8. Ji RC, Eshita Y (2014) Rapamycin inhibition of CFA-induced lymphangiogenesis in PLN is independent of mast cells. Mol Biol Rep 41:2217–2228

    Article  CAS  Google Scholar 

  9. Bryan D, Walker KB, Ferguson M, Thorpe R (2005) Cytokine gene expression in a murine wound healing model. Cytokine 31:429–438

    Article  CAS  Google Scholar 

  10. Chen CY, Peng WH, Tsai KD, Hsu SL (2007) Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci 81:1602–1614

    Article  CAS  Google Scholar 

  11. Ji RC, Eshita Y, Kato S (2007) Investigation of intratumoural and peritumoural lymphatics expressed by podoplanin and LYVE-1 in the hybridoma-induced tumours. Int J Exp Pathol 88:257–270

    Article  CAS  Google Scholar 

  12. Lindenblatt N, Menger MD, Klar E, Vollmar B (2007) Darbepoetin-alpha does not promote microvascular thrombus formation in mice: role of eNOS-dependent protection through platelet and endothelial cell deactivation. Arterioscler Thromb Vasc Biol 27:1191–1198

    Article  CAS  Google Scholar 

  13. Arima H, Natsugoe S, Uenosono Y, Arigami T, Ehi K, Yanagita S, Higashi H, Ishigami S, Hokita S, Aikou T (2006) Area of nodal metastasis and radioisotope uptake in sentinel nodes of upper gastrointestinal cancer. J Surg Res 135:250–254

    Article  CAS  Google Scholar 

  14. Zanfardino M, Spampanato C, De Cicco R, Buommino E, De Filippis A, Baiano S, Barra A, Morelli F (2013) Simvastatin reduces melanoma progression in a murine model. Int J Oncol 43:1763–1770

    Article  CAS  Google Scholar 

  15. Asai J, Takenaka H, Hirakawa S, Sakabe J, Hagura A, Kishimoto S, Maruyama K, Kajiya K, Kinoshita S, Tokura Y, Katoh N (2012) Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am J Pathol 181:2217–2224

    Article  CAS  Google Scholar 

  16. Schulz MM, Reisen F, Zgraggen S, Fischer S, Yuen D, Kang GJ, Chen L, Schneider G, Detmar M (2012) Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis. Proc Natl Acad Sci USA 109:2665–2674

    Article  Google Scholar 

  17. Dicker KT, Gurski LA, Pradhan-Bhatt S, Witt RL, Farach-Carson MC, Jia X (2014) Hyaluronan: a simple polysaccharide with diverse biological functions. Acta Biomater 10:1558–1570

    Article  CAS  Google Scholar 

  18. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S (2006) Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b + macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 209:67–77

    Article  CAS  Google Scholar 

  19. Carreira CM, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 61:8079–8084

    CAS  Google Scholar 

  20. Baluk P, McDonald DM (2008) Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Ann N Y Acad Sci 1131:1–12

    Article  Google Scholar 

  21. Christiansen A, Detmar M (2011) Lymphangiogenesis and cancer. Genes Cancer 2:1146–1158

    Article  Google Scholar 

  22. Ji RC (2012) Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell Mol Life Sci 69:897–914

    Article  CAS  Google Scholar 

  23. Bouta EM, Kuzin I, de Mesy Bentley K, Wood RW, Rahimi H, Ji RC, Ritchlin CT, Bottaro A, Xing L, Schwarz EM (2017) Treatment of TNF-Tg mice with anti-TNF restores lymphatic contraction, repairs lymphatic vessels, and may increase monocyte/macrophage egress. Arthritis Rheumatol 69:1187–1193

    Article  CAS  Google Scholar 

  24. Laufs U, Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273:24266–24271

    Article  CAS  Google Scholar 

  25. Merx MW, Liehn EA, Janssens U, Lütticken R, Schrader J, Hanrath P, Weber C (2004) HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation 109:2560–2565

    Article  CAS  Google Scholar 

  26. Chen Y, Zhang S, Peng G, Yu J, Liu T, Meng R, Li Z, Zhao Y, Wu G (2013) Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: pleiotropic and dose-dependent effect on tumor vascular stabilization. Int J Oncol 42:1325–1336

    Article  CAS  Google Scholar 

  27. Li WC, Zou ZJ, Zhou MG, Chen L, Zhou L, Zheng YK, He ZJ (2015) Effects of simvastatin on the expression of inducible NOS in acute lung injury in septic rats. Int J Clin Exp Pathol 8:15106–15111

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Basraon SK, Menon R, Makhlouf M, Longo M, Hankins GD, Saade GR, Costantine MM (2012) Can statins reduce the inflammatory response associated with preterm birth in an animal model? Am J Obstet Gynecol 207:224-e1

    Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rui-Cheng Ji.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, RC., Eshita, Y., Kobayashi, T. et al. Role of simvastatin in tumor lymphangiogenesis and lymph node metastasis. Clin Exp Metastasis 35, 785–796 (2018). https://doi.org/10.1007/s10585-018-9940-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-018-9940-8

Keywords

Navigation