Abstract
Background
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.
Methods
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.
Results
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).
Conclusions
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.
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References
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677.
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.
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. https://doi.org/10.1002/hsr2.40.
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.
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.
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. https://doi.org/10.1371/journal.pone.0096932.
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. https://doi.org/10.15761/GIMCI.1000131.
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.
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.
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.
Acknowledgements
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.
Funding
The present study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant no. 17K10609).
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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.
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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). https://doi.org/10.1007/s10388-020-00719-8
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DOI: https://doi.org/10.1007/s10388-020-00719-8