Plasma vasohibin-1 and vasohibin-2 are useful biomarkers in patients with esophageal squamous cell carcinoma



Vasohibins (VASH), which are angiogenesis regulators, consist of Vasohibin-1 (VASH1) and Vasohibin-2 (VASH2). VASH1 is an angiogenesis inhibitor, while VASH2 is a proangiogenic factor. Patients with esophageal squamous cell carcinoma (ESCC) with high tumor expression levels of VASH1 and VASH2 have been reported to show a poor prognosis. The clinical significance of VASH concentrations in the blood of patients with ESCC has not yet been investigated.


Plasma samples from 89 patients with ESCC were analyzed, and the relationships between the plasma VASH concentrations and the clinicopathological factors of the patients were evaluated. Immunohistochemical examination (IHC) of the resected tumor specimens for VASH was performed in 56 patients, and the correlation between the plasma VASH concentrations and tumor expression levels of VASH was analyzed.


The patient group with high plasma concentrations of VASH1 showed a higher frequency of lymph node metastasis (P = 0.01) and an invasive growth pattern (P = 0.05). Furthermore, poorly differentiated cancer occurred at a higher frequency in the patient group with high plasma concentrations of VASH2 (P < 0.01). High tumor expression levels of VASH1 were encountered more frequently in the patient group with high plasma concentrations of VASH1 (P = 0.03), and high tumor expression levels of VASH2 were encountered more frequently in the patient group with high plasma concentrations of VASH2 (P = 0.04).


In patients with ESCC, high plasma concentrations were associated with poor clinical outcomes for both VASH1 and VASH2. We propose that results indicate that plasma VASH1 and VASH2 are useful biomarkers in patients with ESCC.

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

Fig. 1


  1. 1.

    Watanabe K, Hasegawa Y, Yamashita H, et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest. 2004;114:898–907.

    CAS  Article  Google Scholar 

  2. 2.

    Shibuya T, Watanabe K, Yamashita H, et al. Isolation and characterization of vasohibin-2 as a homologue of VEGF-inducible endothelium-derived angiogenesis inhibitor vasohibin. Arterioscler Thromb Vasc Biol. 2006;26:1051–7.

    CAS  Article  Google Scholar 

  3. 3.

    Tamaki K, Moriya T, Sato Y, et al. Vasohibin-1 in human breast carcinoma: a potential negative feedback regulator of angiogenesis. Cancer Sci. 2009;100:88–94.

    CAS  Article  Google Scholar 

  4. 4.

    Murakami K, Kasajima A, Kawagishi N, et al. The prognostic significance of vasohibin 1-associated angiogenesis in patients with hepatocellular carcinoma. Hum Pathol. 2014;45:589–97.

    CAS  Article  Google Scholar 

  5. 5.

    Takahashi Y, Koyanagi T, Suzuki Y, et al. Vasohibin-2 expressed in human serous ovarian adenocarcinoma accelerates tumor growth by promoting angiogenesis. Mol Cancer Res. 2012;10:1135–46.

    CAS  Article  Google Scholar 

  6. 6.

    Kim JC, Kim KT, Park JT, et al. Expression of vasohibin-2 in pancreatic ductal adenocarcinoma promotes tumor progression and is associated with a poor clinical outcome. Hepatogastroenterology. 2015;62:251–6.

    CAS  PubMed  Google Scholar 

  7. 7.

    Ninomiya Y, Ozawa S, Oguma J, et al. Expression of vasohibin-1 and-2 predicts poor prognosis among patients with squamous cell carcinoma of the esophagus. Oncol lett. 2018;16:5265–74.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Sonoda H, Ohta H, Watanabe K, et al. Multiple processing forms and their biological activities of a novel angiogenesis inhibitor vasohibin. Biochem Biophys Res Commun. 2006;342:640–6.

    CAS  Article  Google Scholar 

  9. 9.

    Heishi T, Hosaka T, Suzuki Y, et al. Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenic activity and suppresses lymph node metastasis. Am J Pathol. 2010;176:1950–8.

    CAS  Article  Google Scholar 

  10. 10.

    Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677.

    CAS  Article  Google Scholar 

  11. 11.

    Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.

    CAS  Article  Google Scholar 

  12. 12.

    Watanabe T, Hosaka T, Ohmori-Matsuda K, et al. High preoperative plasma vasohibin-1 concentration predicts better prognosis in patients with non-small cell lung carcinoma. Health sci rep. 2018.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Suzuki Y, Kobayashi M, Miyashita H, Ohta H, Sonoda H, Sato Y. Isolation of a small vasohibin-binding protein (SVBP) and its role in vasohibin secretion. J Cell Sci. 2010;123:3094–101.

    CAS  Article  Google Scholar 

  14. 14.

    Saito M, Suzuki Y, Yano S, Miyazaki T, Sato Y, et al. Proteolytic inactivation of anti-angiogenic vasohibin-1 by cancer cells. J Biochem. 2016;160:227–32.

    CAS  Article  Google Scholar 

  15. 15.

    Hinamoto N, Maeshima Y, Saito D, Yamasaki H, Tanabe K, Nasu T, et al. Urinary and plasma levels of vasohibin-1 can predict renal functional deterioration in patients with renal disorders. PLoS One. 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Suzuki Y, Ito O, Kohzuki M, et al. Persistent physical exercise raises the plasma concentration of vasohibin-1 in patients with peripheral vascular disease. Gen Int Med Clin Innov. 2016.

    Article  Google Scholar 

  17. 17.

    Kimura H, Miyashita H, Suzuki Y, Kobayashi M, Watanabe K, Sonoda H, et al. Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis. Blood. 2009;113:4810–8.

    CAS  Article  Google Scholar 

  18. 18.

    Norita R, Suzuki Y, Furutani Y, et al. Vasohibin-2 is required for epithelial–mesenchymal transition of ovarian cancer cells by modulating transforming growth factor-β signaling. Cancer Sci. 2017;108:419–26.

    CAS  Article  Google Scholar 

  19. 19.

    Suzuki Y, Kitahara S, Suematsu T, et al. Requisite role of vasohibin-2 in spontaneous gastric cancer formation and accumulation of cancer-associated fibroblasts. Cancer Sci. 2017;108:2342–51.

    CAS  Article  Google Scholar 

Download references


For this research, the anti-vasohibin antibodies were provided by the Institute of Development, Aging and Cancer, Tohoku University, and we are grateful to Dr. Yasuhiro Suzuki and Professor Yasufumi Sato for their discussions about vasohibin. This research was supported by the Support Center for Medical Research and Education of Tokai University School of Medicine. We thank Mr. Hideo Tsukamoto (Japan Medical Device Technology), Mr. Noboru Kawabe and Ms. Yoko Kameyama for there suppport with research. We thank Ms. Izu Inada and Ms. Izumi Tsuchiya (Department of Gastroenterological Surgery, Tokai University School of Medicine) for their support with the data analysis.


The present study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant no. 17K10609).

Author information



Corresponding author

Correspondence to Soji Ozawa.

Ethics declarations

Ethical Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.

Conflict of interest

The authors declare that have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yamamoto, M., Ozawa, S., Ninomiya, Y. et al. Plasma vasohibin-1 and vasohibin-2 are useful biomarkers in patients with esophageal squamous cell carcinoma. Esophagus 17, 289–297 (2020).

Download citation


  • Esophageal cancer
  • Vasohibin-1
  • Vasohibin-2
  • Plasma concentration
  • Biomarker