Serum Endostatin Levels in Oral Squamous Cell Carcinoma

Document Type: Original


1 Oral and Dental Disease Research Center, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Department of Oral and Maxillofacial Pathology, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.

3 Department of Otolaryngology, Khalili Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.

4 Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran.

5 Undergraduate Student, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran.


Endostatin is a C-­terminal proteolytic fragment of collagen XVIII and, as with angiostatin and thrombospondin, is known as an anti­angiogenic agent. The aim of this study was to assess the level of serum endostatin in patients with oral squamous cell carcinoma (SCC), and its association with the clinicopathological characteristics of the tumor.
Materials and Methods:
 Using an enzyme-linked immunosorbent assay (ELISA) kit, we investigated the circulating levels of endostatin in the blood serum of 45 patients with oral SCC and 45 healthy controls.
The mean level of serum endostatin in patients was significantly lower (68.8±85 ng/ml) than in healthy controls (175.6±73 ng/ml) (P<0.001). Serum endostatin levels were significantly lower in patients with lymph node metastasis compared with patients without lymph node metastasis (P<0.001). In addition, serum endostatin level was associated with higher histological grade (P<0.001). There were no apparent correlations between serum endostatin concentration and clinicopathological features such as age, gender, and tumor stage (P>0.05).
Findings of the present study suggest the prognostic and anti-metastatic role of endostatin, and this may be used as a tool for monitoring tumor progression.


Main Subjects

1. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009; 45: 309–16.

2. Wang ZH, Zhu ZT, Xiao XY, Sun J. Correlation of Serum Levels of Endostatin with Tumor Stage in Gastric Cancer: A Systematic Review and Meta-Analysis Biomed Res Int. 2015;2015:623939.

3. ZhuwW, Che Y, Song X, Luo Y. Endostatin specifically targets both tumor blood vessels and lymphatic vessels. Front Med. 2011;5:336–40.

4. O'Reilly MS, Boehm T, ShingY, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.

5. Taddei L, Chiarugi P, Brogelli L, Cirri P, Magnelli L, Raugei G, et al. Inhibitory effect of full-length human endostatin on in vitro angiogenesis. Biochem Biophys Res Commun. 1999; 263:340–5.

6. Dhanabal M, Ramchandran R, Waterman MJF, Lu H, Knebelmann B, Segal M, et al. Endostatin induces endothelial cell apoptosis. J Biol Chem. 1999;274:11721–6.

7. Jiang WG, Lu XA, Shang BY, Fu Y, Zhang SH, Zhou D, et al. Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis. BMC: Cancer. 2013;13: 479.

8. Wan YY, Tian GY, Guo HS, Kang YM, Yao ZH, Li XL, et al. Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats. Respir Res. 2013;14:56.

9. Zhuo W, Luo C, Wang X, Song X, Fu Y, Luo Y. Endostatin inhibits tumour lymphangiogenesis and lymphatic metastasis via cell surface nucleolin on lymphangiogenic endothelial cells. J Pathol. 2010;222:249–60.

10. Bai YJ, Huang LZ, Zhou AY, Zhao M, Yu WZ, Li XX. Antiangiogenesis effects of endostatin in retinal neovascularization. J Ocul Pharmacol Ther. 2013;29:619–26.

11. Feldman AL, Alexander HR Jr, Bartlett DL, Kranda KC, Miller MS, Costouros NG, et al. A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases. Ann Surg Oncol. 2001;8:741–5.

12. Feldman AL, Alexander HR Jr, Yang JC, Linehan WM, Eyler RA, Miller MS, et al. Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma. Cancer. 2002;95:1637–43.

13. Hata K, Dhar DK, Kanasaki H, Nakayama K, Fujiwaki R, Katabuchi H, et al. Serum endostatin levels in patients with epithelial ovarian cancer. Anticancer Res. 2003;23:1907–12.

14. Bono P, Teerenhovi L, Joensuu H. Elevated serum endostatin is associated with poor outcome in patients with non-Hodgkin lymphoma. Cancer. 2003;97:2767–75.

15. Suzuki M, Izasa T, Ko E, Baba M, Saitoh Y, Shibuya K, et al. Serum endostatin correlates with progression and prognosis of non-small cell lung cancer. Lung Cancer. 2002;35:29–34.

16. Mo HY, Luo DH, Qiu HZ, Liu H, Chen QY, Tang LQ. Elevated serum endostatin levels are associated with poor survival in patients with advanced-stage nasopharyngeal carcinoma. Clin Oncol. 2013;25(5):308–17.

17. Kantola T, Väyrynen JP, Klintrup K, Mäkelä J, Karppinen SM, Pihlajaniemi T, et al. Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers. Br J Cancer. 2014; 111: 1605–13.

18. Szarvas T, László V, VomDorp F, Reis H, Szendröi A, Romics I, et al. Serum endostatin levels correlate with enhanced extracellular matrix degradation and poor patients' prognosis in bladder cancer. Int J Cancer. 2012;130:2922–9.

19. Greene FL, Compton CC, Fritz AG, Shah JP, Winchester DP. Lip and oral cavity. In: AJCC cancer staging atlas. 6th ed. New York: Springer; 2006.19–26.

20. Sharma BK, Srinivasan R, Kapil S, Singla B, Saini N, Chawla YK, et al. Serum levels of angiogenic and anti-angiogenic factors: their prognostic relevance in locally advanced hepatocellular carcinoma. Mol Cell Biochem. 2013; 383:103–12.

21. O'Byrne KJ, Dalgleish AG, Browning MJ, Steward WP, Harris AL. The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. Eur J Cancer. 2000;36:151–69.

22. Homer JJ, Greenman J, Stafford ND. Circulating angiogenic cytokines as tumour markers and prognostic factors in head and neck squamous cell carcinoma. Clin Otolaryngol Allied Sci. 2002;27:32–37.

23. Nikitakis NG, Rivera H, Lopes MA, Siavash H, Reynolds MA, Ord RA, et al.Immunohistochemical Expression of Angiogenesis-Related Markers in oral squamous cell carcinomas with multiple metastatic lymph nodes. Am J Clin Pathol. 2003;119:574–86.

24. Fukumoto S, Morifuji M, Katakura Y, Ohishi M, Nakamura S. Endostatin inhibits lymph node metastasis by a down-regulation of the vascular endothelial growth factor C expression in tumor cells. Clin Exp Metastasis. 2005;22:31–8.

25. Onogawa S, Kitadai Y, Tanaka S, Kuwai T, Kimura S, Chayama K, et al. Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma. Cancer Sci. 2004; 95: 32–9.

26. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, et al. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eu J Cancer. 2002;38:1413–9.

27. Neuchrist C, Erovic BM, Handisurya A, Fischer MB, Steiner GE, Hollemann D, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck. 2003;25:464–74.

28. Kitadai Y, Amioka T, Haruma K, Tanaka S, Yoshihara M, Sumii K, et al. Clinicopathological significance of vasucular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer. 2001;93:662–6.

29. Shao XJ, Xie FM. Influence of angiogenesis inhibitors, endostatin and PF-4, on lymphangiogenesis. Lymphology. 2005;38:1–8.

30. Sund M, Hamano Y, Sugimoto H, Sudhakar A, Soubasakos M, Yerramalla U, et al. Function of endogenous inhibitors of angiogenesis as endothelium specific tumor suppressors. Proc Natl Acad Sci USA. 2005;102:2934–9.

31. Li C, Harris MB, Venema VJ, Venema RC. Endostatin induces acute endothelial nitric oxide and prostacyclin release. Biochem Biophys Res Commun. 2005;329:873–8.

32. Celik I, Sürücü O, Dietz C, Heymach JV, Force J, Höschele I, et al. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve. Cancer Res. 2005;65:11044–50.

33. Tjin Tham Sjin RM, Naspinski J, Birsner AE, Li C, Chan R, Lo K-M, et al. Endostatin therapy reveals a U-shaped curve for antitumor activity. Cancer Gene Ther. 2006;13:619–27.

34. Nyberg P, Heikkilä P, Sorsa T, Luostarinen J, Heljasvaara R, Stenman UH, et al. Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13. J Biol Chem. 2003; 278: 22404–11.

35. Kim YM, Jang JW, Lee OH, Yeon J, Choi EY, Kim KW,et al. Endostatin Inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase 2. Cancer Res. 2000;60:5410–3.

36. Lee SJ, Jang JW, Kim YM, Lee HI, Jeon JY, Kwon YG, et al. Endostatin binds to the catalytic domain of matrix metalloproteinase-2. FEBS Lett. 2002;519:147–52.

37. Gao SR, Li LM, Xia HP, Wang GM, Xu HY, Wang AR. Clinical observation on recombinant human endostatin combined with chemotherapy for advanced gastrointestinal cancer. Asian Pac J Cancer Prev. 2015;16:4037–40.