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Published in: Head & Face Medicine 1/2015

Open Access 01-12-2015 | Research

Analysis of angiogenic markers in oral squamous cell carcinoma-gene and protein expression

Authors: Susanne Jung, Sonja Sielker, Nikolai Purcz, Christoph Sproll, Yahya Acil, Johannes Kleinheinz

Published in: Head & Face Medicine | Issue 1/2015

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Abstract

Purpose

Therapeutic strategies attacking oral squamous cell carcinoma have not essentially succeeded to improve long-term prognosis and overall survival over the last decades. Therefore, in this study, we aimed to illuminate the molecular regulation of angiogenesis in this tumour entity in order to demask novel markers of prognosis or therapeutic approach.

Materials and methods

A panel of significant transcriptional alterations in angiogenic genes of 83 cancer samples was established by comparison to 30 samples of healthy oral mucosa with microarray technique. Immunohistochemistry (IHC) was performed to trace the signalling cascade from gene to protein level.

Results

A distinctive expression profile of VEGFA, EFNB2, PECAM1/CD31, ANGPT1 and ANGPT2 was revealed: VEGFA, EFNB2, and ANGPT2 were found overexpressed in 84 % to 95 % of tumour samples. In contrast, the expression of CD31 and ANGPT1 was downregulated in 80 % to 95 % of tumour samples. IHC confirmed results of the microarray analysis.
Tumours with lymphatic spread showed higher gene expression rates of VEGFA, EFNB2 and ANGPT2 in moderately differentiated tumours and of VEGFA and EFNB2 in small tumours, respectively. The ANGPT1/ ANGPT2 transcription ratio was found decreased in larger tumours and especially in tumours without lymphatic spread.

Conclusions

A characteristic expression profile of angiogenic markers was established. The specific overexpression of EFNB2 in small tumours with lymphatic spread and the typical decrease of the ANGPT1/ ANGPT2 ratio in larger tumours give weight to EFNB2 and angiopoietins as prognostic factors and potential therapeutic targets.
Literature
1.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMed
2.
go back to reference Scott S, McGurk M, Grunfeld E. Patient delay for potentially malignant oral symptoms. Eur J Oral Sci. 2008;116:141–7.CrossRefPubMed Scott S, McGurk M, Grunfeld E. Patient delay for potentially malignant oral symptoms. Eur J Oral Sci. 2008;116:141–7.CrossRefPubMed
3.
go back to reference Carlile J, Harada K, Baillie R, Macluskey M, Chisholm DM, Ogden GR, et al. Vascular endothelial growth factor (VEGF) expression in oral tissues: possible relevance to angiogenesis, tumour progression and field cancerisation. J Oral Pathol Med. 2001;30:449–57.CrossRefPubMed Carlile J, Harada K, Baillie R, Macluskey M, Chisholm DM, Ogden GR, et al. Vascular endothelial growth factor (VEGF) expression in oral tissues: possible relevance to angiogenesis, tumour progression and field cancerisation. J Oral Pathol Med. 2001;30:449–57.CrossRefPubMed
4.
go back to reference Walsh JE, Lathers DM, Chi AC, Gillespie MB, Day TA, Young MR. Mechanisms of tumor growth and metastasis in head and neck squamous cell carcinoma. Curr Treat Options Oncol. 2007;8:227–38.CrossRefPubMed Walsh JE, Lathers DM, Chi AC, Gillespie MB, Day TA, Young MR. Mechanisms of tumor growth and metastasis in head and neck squamous cell carcinoma. Curr Treat Options Oncol. 2007;8:227–38.CrossRefPubMed
5.
go back to reference Jung S, Sielker S, Purcz N, Sproll C, Raem AM, Kleinheinz J. Expression profile of angiogenesis related genes in head and neck squamous cell carcinoma. J Biochips. 2013;3:e106. Jung S, Sielker S, Purcz N, Sproll C, Raem AM, Kleinheinz J. Expression profile of angiogenesis related genes in head and neck squamous cell carcinoma. J Biochips. 2013;3:e106.
6.
go back to reference Kämmerer PW, Al-Nawas B, Kalkan S, Liese J, Fruth K, Frerich B, Brieger J. Angiogenesis-related prognosis in patients with oral squamous cell carcinoma-role of the VEGF +936 C/T polymorphism. J Oral Pathol Med. 2014 Sep 12. doi: 10.1111/jop.12254 Kämmerer PW, Al-Nawas B, Kalkan S, Liese J, Fruth K, Frerich B, Brieger J. Angiogenesis-related prognosis in patients with oral squamous cell carcinoma-role of the VEGF +936 C/T polymorphism. J Oral Pathol Med. 2014 Sep 12. doi: 10.1111/jop.12254
7.
go back to reference Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Wey JS, Parikh AA, et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 2003;63:3370–7.PubMed Stoeltzing O, Ahmad SA, Liu W, McCarty MF, Wey JS, Parikh AA, et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 2003;63:3370–7.PubMed
8.
go back to reference Caine GJ, Blann AD, Stonelake PS, Ryan P, Lip GY. Plasma angiopoietin-1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. Eur J Clin Invest. 2003;33:883–90.CrossRefPubMed Caine GJ, Blann AD, Stonelake PS, Ryan P, Lip GY. Plasma angiopoietin-1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. Eur J Clin Invest. 2003;33:883–90.CrossRefPubMed
9.
go back to reference Li C, Sun CJ, Fan JC, Geng N, Li CH, Liao J, et al. Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma. Med Oncol. 2013;30:571.CrossRefPubMed Li C, Sun CJ, Fan JC, Geng N, Li CH, Liao J, et al. Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma. Med Oncol. 2013;30:571.CrossRefPubMed
10.
go back to reference Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165–77.CrossRefPubMed Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165–77.CrossRefPubMed
11.
go back to reference Liu W, Jung YD, Ahmad SA, McCarty MF, Stoeltzing O, Reinmuth N, et al. Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer. Br J Cancer. 2004;90:1620–6.CrossRefPubMedPubMedCentral Liu W, Jung YD, Ahmad SA, McCarty MF, Stoeltzing O, Reinmuth N, et al. Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer. Br J Cancer. 2004;90:1620–6.CrossRefPubMedPubMedCentral
12.
go back to reference Abéngozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M, Olmeda D, et al. Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood. 2012;119:4565–76.CrossRefPubMed Abéngozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M, Olmeda D, et al. Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood. 2012;119:4565–76.CrossRefPubMed
13.
14.
go back to reference Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71:452–6.CrossRefPubMed Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71:452–6.CrossRefPubMed
15.
go back to reference Jang JY, Kim MJ, Ryu G, Choi N, Ko YH, Jeong HS. Prediction of Lymph Node Metastasis by Tumor Dimension versus Tumor Biological Properties in Head and Neck Squamous Cell Carcinomas. Cancer Res Treat. 2015. doi: 10.4143/crt.2014.332. Jang JY, Kim MJ, Ryu G, Choi N, Ko YH, Jeong HS. Prediction of Lymph Node Metastasis by Tumor Dimension versus Tumor Biological Properties in Head and Neck Squamous Cell Carcinomas. Cancer Res Treat. 2015. doi: 10.4143/crt.2014.332.
16.
go back to reference Hanna E, Quick J, Libutti SK. The tumour microenvironment: a novel target for cancer therapy. Oral Dis. 2009;15:8–17.CrossRefPubMed Hanna E, Quick J, Libutti SK. The tumour microenvironment: a novel target for cancer therapy. Oral Dis. 2009;15:8–17.CrossRefPubMed
17.
go back to reference Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, et al. Localization of Ang-1, −2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest. 2006;86:1172–84.PubMed Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, et al. Localization of Ang-1, −2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest. 2006;86:1172–84.PubMed
18.
go back to reference Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, et al. Early vessel destabilization mediated by angiopoietin-2 and subsequent vessel maturation via angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831.CrossRefPubMedPubMedCentral Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, et al. Early vessel destabilization mediated by angiopoietin-2 and subsequent vessel maturation via angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831.CrossRefPubMedPubMedCentral
19.
go back to reference Chien CY, Su CY, Chuang HC, Fang FM, Huang HY, Chen CM, et al. Angiopoietin-1 and −2 expression in recurrent squamous cell carcinoma of the oral cavity. J Surg Oncol. 2008;97:273–7.CrossRefPubMed Chien CY, Su CY, Chuang HC, Fang FM, Huang HY, Chen CM, et al. Angiopoietin-1 and −2 expression in recurrent squamous cell carcinoma of the oral cavity. J Surg Oncol. 2008;97:273–7.CrossRefPubMed
20.
go back to reference Li C, Zhang B, Wang ZH, Chen JC, Li B, Wang SX, et al. Significance of a reversal expression of the angiopoietin-1 and 2 in oral squamous cell carcinoma. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009;44:412–8.PubMed Li C, Zhang B, Wang ZH, Chen JC, Li B, Wang SX, et al. Significance of a reversal expression of the angiopoietin-1 and 2 in oral squamous cell carcinoma. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009;44:412–8.PubMed
21.
go back to reference Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19:512–26.CrossRefPubMed Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19:512–26.CrossRefPubMed
22.
go back to reference Rigamonti N, De Palma M. A role for angiopoietin-2 in organ-specific metastasis. Cell Rep. 2013;4:621–3.CrossRefPubMed Rigamonti N, De Palma M. A role for angiopoietin-2 in organ-specific metastasis. Cell Rep. 2013;4:621–3.CrossRefPubMed
23.
go back to reference Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res. 2013;3:649–1657. Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res. 2013;3:649–1657.
Metadata
Title
Analysis of angiogenic markers in oral squamous cell carcinoma-gene and protein expression
Authors
Susanne Jung
Sonja Sielker
Nikolai Purcz
Christoph Sproll
Yahya Acil
Johannes Kleinheinz
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Head & Face Medicine / Issue 1/2015
Electronic ISSN: 1746-160X
DOI
https://doi.org/10.1186/s13005-015-0076-7

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