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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma

Authors: Anke Schlüter, Patrick Weller, Oliver Kanaan, Ivonne Nel, Lukas Heusgen, Benedikt Höing, Pia Haßkamp, Sebastian Zander, Magis Mandapathil, Nina Dominas, Judith Arnolds, Boris A. Stuck, Stephan Lang, Agnes Bankfalvi, Sven Brandau

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Patients suffering from squamous cell carcinoma of the larynx (LSCC) with lymphatic metastasis have a relatively poor prognosis and often require radical therapeutic management. The mechanisms which drive metastasis to the lymph nodes are largely unknown but may be promoted by a pro-angiogenic tumor microenvironment. In this study, we examined whether the number of microvessels and the expression level of vascular endothelial growth factor (VEGF) in the primary tumor are correlated with the degree of lymph node metastasis (N-stage), tumor staging (T) and survival time in LSCC patients.

Methods

Tissue-Microarrays of 97 LSCC patients were analyzed using immunohistochemistry. The expression of VEGF was scored as intensity of staining (low vs high) and the number of CD31-positive vessels (median </≥7 vessels per visual field) was counted manually. Scores were correlated with N-stage, T-stage and 5-year overall survival rate.

Results

A high expression of angiogenic biomarkers was not associated with poor overall survival in the overall cohort of patients. Instead high CD31 count was associated with early stage cancer (p = 0.004) and in this subgroup high VEGF expression correlated with poor survival (p = 0.032). Additionally, in early stage cancer a high vessel count was associated with an increased recurrence rate (p = 0.004).

Conclusion

Only in the early stage subgroup a high expression of angiogenic biomarkers was associated with reduced survival and an increased rate of recurrence. Thus, biomarkers of angiogenesis may be useful to identify high risk patients specifically in early stage LSCC.
Literature
1.
go back to reference Boffeta P, Merletti F, Faggiano F, Migliaretti G, Ferro G, Zanetti R, Terracini B. Prognostic factors and survival of laryngeal cancer patients from Turin, Italy. A population-based study. Am J Epidemiol. 1997;145:1100–5.CrossRef Boffeta P, Merletti F, Faggiano F, Migliaretti G, Ferro G, Zanetti R, Terracini B. Prognostic factors and survival of laryngeal cancer patients from Turin, Italy. A population-based study. Am J Epidemiol. 1997;145:1100–5.CrossRef
2.
go back to reference Bolzoni Villaret A, Barbieri D, Peretti G, et al. Angiogenesis and lymphangiogenesis in early-stage laryngeal carcinoma: prognostic implications. Head Neck. 2013;35:1132–7.CrossRefPubMed Bolzoni Villaret A, Barbieri D, Peretti G, et al. Angiogenesis and lymphangiogenesis in early-stage laryngeal carcinoma: prognostic implications. Head Neck. 2013;35:1132–7.CrossRefPubMed
3.
go back to reference Lionello M, Staffieri A, Marioni G. Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma. Acta Otolaryngol. 2012;132:574–82.CrossRefPubMed Lionello M, Staffieri A, Marioni G. Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma. Acta Otolaryngol. 2012;132:574–82.CrossRefPubMed
4.
go back to reference Beatrice F, Cammarota R, Giordano C, et al. Angiogenesis: prognostic significance in laryngeal cancer. Anticancer Res. 1998;18:4737–40.PubMed Beatrice F, Cammarota R, Giordano C, et al. Angiogenesis: prognostic significance in laryngeal cancer. Anticancer Res. 1998;18:4737–40.PubMed
5.
go back to reference Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991;64:327–36.CrossRefPubMed Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991;64:327–36.CrossRefPubMed
6.
go back to reference Krecicki T, Dus D, Kozlak J, et al. Quantitative evaluation of angiogenesis in laryngeal cancer by digital image measurement of the vessel density. Auris Nasus Larynx. 2002;29:271–6.CrossRefPubMed Krecicki T, Dus D, Kozlak J, et al. Quantitative evaluation of angiogenesis in laryngeal cancer by digital image measurement of the vessel density. Auris Nasus Larynx. 2002;29:271–6.CrossRefPubMed
7.
go back to reference Lentsch EJ, Goudy S, Sosnowski J, Major S, Bumpous JM. Microvessel density in head and neck squamous cell carcinoma primary tumors and its correlation with clinical staging parameters. Laryngoscope. 2006;116:397–400.CrossRefPubMed Lentsch EJ, Goudy S, Sosnowski J, Major S, Bumpous JM. Microvessel density in head and neck squamous cell carcinoma primary tumors and its correlation with clinical staging parameters. Laryngoscope. 2006;116:397–400.CrossRefPubMed
8.
go back to reference Burian M, Quint C, Neuchrist C. Angiogenic factors in laryngeal carcinomas: do they have prognostic relevance? Acta Otolaryngol. 1999;119:289–92.CrossRefPubMed Burian M, Quint C, Neuchrist C. Angiogenic factors in laryngeal carcinomas: do they have prognostic relevance? Acta Otolaryngol. 1999;119:289–92.CrossRefPubMed
9.
go back to reference Teppo H, Soini Y, Melkko J, Koivunen P, Alho O. Prognostic factors in laryngeal carcinoma: the role of apoptosis, p53, proliferation (Ki-67) and angiogenesis. APMIS. 2003;111:451–7.CrossRefPubMed Teppo H, Soini Y, Melkko J, Koivunen P, Alho O. Prognostic factors in laryngeal carcinoma: the role of apoptosis, p53, proliferation (Ki-67) and angiogenesis. APMIS. 2003;111:451–7.CrossRefPubMed
10.
go back to reference Rodrigo JP, Cabanillas R, Chiara MD, Garcia Pedrero J, Astudillo A, Suarez Nieto C. Prognostic significance of angiogenesis in surgically treated supraglottic squamous cell carcinomas of the larynx. Acta Otorrinolaringol Esp. 2009;60:272–7.CrossRefPubMed Rodrigo JP, Cabanillas R, Chiara MD, Garcia Pedrero J, Astudillo A, Suarez Nieto C. Prognostic significance of angiogenesis in surgically treated supraglottic squamous cell carcinomas of the larynx. Acta Otorrinolaringol Esp. 2009;60:272–7.CrossRefPubMed
11.
go back to reference Hagedorn HG, Nerlich AG. Microvessel density and endothelial basement membrane composition in laryngeal squamous cell carcinomas. Acta Otolaryngol. 2000;120:891–8.CrossRefPubMed Hagedorn HG, Nerlich AG. Microvessel density and endothelial basement membrane composition in laryngeal squamous cell carcinomas. Acta Otolaryngol. 2000;120:891–8.CrossRefPubMed
12.
go back to reference Gumina RJ, Kirschbaum NE, Rao PN, vanTuinen P, Newman PJ. The human PECAM1 gene maps to 17q23. Genomics. 1996;34:229–32.CrossRefPubMed Gumina RJ, Kirschbaum NE, Rao PN, vanTuinen P, Newman PJ. The human PECAM1 gene maps to 17q23. Genomics. 1996;34:229–32.CrossRefPubMed
13.
go back to reference Jong JS. De, van Diest PJ, Baak JP. Heterogeneity and reproducibility of microvessel counts in breast cancer. Lab Investig. 1995;73:922–6.PubMed Jong JS. De, van Diest PJ, Baak JP. Heterogeneity and reproducibility of microvessel counts in breast cancer. Lab Investig. 1995;73:922–6.PubMed
14.
go back to reference Rubio L, Burgos JS, Morera C, Vera-Sempere FJ. Morphometric study of tumor angiogenesis as a new prognostic factor in nasopharyngeal carcinoma patients. Pathol Oncol Res. 2000;6:210–6.CrossRefPubMed Rubio L, Burgos JS, Morera C, Vera-Sempere FJ. Morphometric study of tumor angiogenesis as a new prognostic factor in nasopharyngeal carcinoma patients. Pathol Oncol Res. 2000;6:210–6.CrossRefPubMed
15.
go back to reference Sion-Vardy N, Fliss DM, Prinsloo I, Shoham-Vardi I, Benharroch D. Neoangiogenesis in squamous cell carcinoma of the larynx - biological and prognostic associations. Pathol Res Pract. 2001;197:1–5.CrossRefPubMed Sion-Vardy N, Fliss DM, Prinsloo I, Shoham-Vardi I, Benharroch D. Neoangiogenesis in squamous cell carcinoma of the larynx - biological and prognostic associations. Pathol Res Pract. 2001;197:1–5.CrossRefPubMed
16.
go back to reference Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ. Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131:624–30.CrossRefPubMed Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ. Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131:624–30.CrossRefPubMed
17.
go back to reference Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol. 2007;49:1015–26.CrossRefPubMed Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol. 2007;49:1015–26.CrossRefPubMed
18.
go back to reference Sawatsubashi M, Yamada T, Fukushima N, Mizokami H, Tokunaga O, Shin T. Association of vascular endothelial growth factor and mast cells with angiogenesis in laryngeal squamous cell carcinoma. Virchows Arch. 2000;436:243–8.CrossRefPubMed Sawatsubashi M, Yamada T, Fukushima N, Mizokami H, Tokunaga O, Shin T. Association of vascular endothelial growth factor and mast cells with angiogenesis in laryngeal squamous cell carcinoma. Virchows Arch. 2000;436:243–8.CrossRefPubMed
19.
go back to reference Chen G, Liu Y, Wang J, et al. Expression of vascular endothelial growth factor and cyclooxygenase-2 in laryngeal squamous cell carcinoma and its significance. J Huazhong Univ Sci Technolog Med Sci. 2006;26:105–7.CrossRefPubMed Chen G, Liu Y, Wang J, et al. Expression of vascular endothelial growth factor and cyclooxygenase-2 in laryngeal squamous cell carcinoma and its significance. J Huazhong Univ Sci Technolog Med Sci. 2006;26:105–7.CrossRefPubMed
20.
go back to reference Denhart BC, Guidi AJ, Tognazzi K, Dvorak HF, Brown LF. Vascular permeability factor/vascular endothelial growth factor and its receptors in oral and laryngeal squamous cell carcinoma and dysplasia. Lab Investig. 1997;77:659–64.PubMed Denhart BC, Guidi AJ, Tognazzi K, Dvorak HF, Brown LF. Vascular permeability factor/vascular endothelial growth factor and its receptors in oral and laryngeal squamous cell carcinoma and dysplasia. Lab Investig. 1997;77:659–64.PubMed
21.
go back to reference Neuchrist C, Quint C, Pammer A, Burian M. Vascular endothelial growth factor (VEGF) and microvessel density in squamous cell carcinomas of the larynx: an immunohistochemical study. Acta Otolaryngol. 1999;119:732–8.CrossRefPubMed Neuchrist C, Quint C, Pammer A, Burian M. Vascular endothelial growth factor (VEGF) and microvessel density in squamous cell carcinomas of the larynx: an immunohistochemical study. Acta Otolaryngol. 1999;119:732–8.CrossRefPubMed
22.
go back to reference Unal ZN, Unal M, Bagdatoglu OT, Polat G, Atik U. Genetic polymorphism of VEGF-1154 (a/G) in laryngeal squamous cell carcinoma. Arch Med Res. 2008;39:209–11.CrossRefPubMed Unal ZN, Unal M, Bagdatoglu OT, Polat G, Atik U. Genetic polymorphism of VEGF-1154 (a/G) in laryngeal squamous cell carcinoma. Arch Med Res. 2008;39:209–11.CrossRefPubMed
23.
go back to reference Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5:1369–79.PubMed Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5:1369–79.PubMed
24.
go back to reference Bernier J. Head and neck Cancer: multimodality management. New York: Springer; 2011.CrossRef Bernier J. Head and neck Cancer: multimodality management. New York: Springer; 2011.CrossRef
25.
go back to reference Kupisz K, Chibowski D, Klatka J, Klonowski S, Stepulak A. Tumor angiogenesis in patients with laryngeal cancer. Eur Arch Otorhinolaryngol. 1999;256:303–5.CrossRefPubMed Kupisz K, Chibowski D, Klatka J, Klonowski S, Stepulak A. Tumor angiogenesis in patients with laryngeal cancer. Eur Arch Otorhinolaryngol. 1999;256:303–5.CrossRefPubMed
26.
go back to reference Teknos TN, Cox C, Barrios MA, et al. Tumor angiogenesis as a predictive marker for organ preservation in patients with advanced laryngeal carcinoma. Laryngoscope. 2002;112:844–51.CrossRefPubMed Teknos TN, Cox C, Barrios MA, et al. Tumor angiogenesis as a predictive marker for organ preservation in patients with advanced laryngeal carcinoma. Laryngoscope. 2002;112:844–51.CrossRefPubMed
27.
go back to reference Wang Z, Chen Y, Li X, et al. Expression of VEGF-C/VEGFR-3 in human laryngeal squamous cell carcinomas and its significance for lymphatic metastasis. Asian Pac J Cancer Prev. 2012;13:27–31.CrossRefPubMed Wang Z, Chen Y, Li X, et al. Expression of VEGF-C/VEGFR-3 in human laryngeal squamous cell carcinomas and its significance for lymphatic metastasis. Asian Pac J Cancer Prev. 2012;13:27–31.CrossRefPubMed
28.
go back to reference Bonhin RG, Rocha VBC, De Carvalho GM, et al. Correlation between vascular endothelial growth factor expression and presence of lymph node metastasis in advanced squamous cell carcinoma of the larynx. Braz J Otorhinolaryngol. 2015;81:58–62.CrossRefPubMed Bonhin RG, Rocha VBC, De Carvalho GM, et al. Correlation between vascular endothelial growth factor expression and presence of lymph node metastasis in advanced squamous cell carcinoma of the larynx. Braz J Otorhinolaryngol. 2015;81:58–62.CrossRefPubMed
29.
go back to reference Pignataro L, Carboni N, Midolo V, et al. Clinical relevance of microvessel density in laryngeal squamous cell carcinomas. Int J Cancer. 2001;92:666–70.CrossRefPubMed Pignataro L, Carboni N, Midolo V, et al. Clinical relevance of microvessel density in laryngeal squamous cell carcinomas. Int J Cancer. 2001;92:666–70.CrossRefPubMed
30.
go back to reference Gleich LL, Biddinger PW, Duperier FD, Gluckman JL. Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation. Head Neck. 1997;19:276–80.CrossRefPubMed Gleich LL, Biddinger PW, Duperier FD, Gluckman JL. Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation. Head Neck. 1997;19:276–80.CrossRefPubMed
31.
go back to reference Chaudhury TK, Lerner MP, Nordquist RE. Angiogenesis by human melanoma and breast cancer cells. Cancer Lett. 1980;11:43–9.CrossRefPubMed Chaudhury TK, Lerner MP, Nordquist RE. Angiogenesis by human melanoma and breast cancer cells. Cancer Lett. 1980;11:43–9.CrossRefPubMed
32.
go back to reference Frank R, Saclarides TJ, Leurgans S, Speziale NJ, Drab EA, Rubin DB. Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative Colon Cancer. Ann Surg. 1995;222(6):695–9.CrossRefPubMedPubMedCentral Frank R, Saclarides TJ, Leurgans S, Speziale NJ, Drab EA, Rubin DB. Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative Colon Cancer. Ann Surg. 1995;222(6):695–9.CrossRefPubMedPubMedCentral
33.
go back to reference Gleich LL, Biddinger PW, Pavelic ZP, Gluckman JL. Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: role in predicting tumor aggressiveness. Head Neck. 1996;18:343–6.CrossRefPubMed Gleich LL, Biddinger PW, Pavelic ZP, Gluckman JL. Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: role in predicting tumor aggressiveness. Head Neck. 1996;18:343–6.CrossRefPubMed
34.
go back to reference Laitakari J, Nayha V, Stenback F. Size, shape, structure, and direction of angiogenesis in laryngeal tumour development. J Clin Pathol. 2004;57:394–401.CrossRefPubMedPubMedCentral Laitakari J, Nayha V, Stenback F. Size, shape, structure, and direction of angiogenesis in laryngeal tumour development. J Clin Pathol. 2004;57:394–401.CrossRefPubMedPubMedCentral
35.
go back to reference Akdeniz O, Akduman D, Haksever M, Ozkarakas H, Muezzinoglu B. Relationships between clinical behavior of laryngeal squamous cell carcinomas and expression of VEGF, MMP-9 and E-cadherin. Asian Pac J Cancer Prev. 2013;14:5301–10.CrossRefPubMed Akdeniz O, Akduman D, Haksever M, Ozkarakas H, Muezzinoglu B. Relationships between clinical behavior of laryngeal squamous cell carcinomas and expression of VEGF, MMP-9 and E-cadherin. Asian Pac J Cancer Prev. 2013;14:5301–10.CrossRefPubMed
36.
go back to reference Baek S, Jung K, Lee S, et al. Prognostic significance of vascular endothelial growth factor-C expression and lymphatic vessel density in supraglottic squamous cell carcinoma. Laryngoscope. 2009;119:1325–30.CrossRefPubMed Baek S, Jung K, Lee S, et al. Prognostic significance of vascular endothelial growth factor-C expression and lymphatic vessel density in supraglottic squamous cell carcinoma. Laryngoscope. 2009;119:1325–30.CrossRefPubMed
37.
go back to reference Sullu Y, Gun S, Atmaca S, Karagoz F, Kandemir B. Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx. Diagn Pathol. 2010;5:35.CrossRefPubMedPubMedCentral Sullu Y, Gun S, Atmaca S, Karagoz F, Kandemir B. Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx. Diagn Pathol. 2010;5:35.CrossRefPubMedPubMedCentral
38.
go back to reference Hinojar-Gutierrez A, Fernandez-Contreras M, Gonzalez-Gonzalez R, et al. Intratumoral lymphatic vessels and VEGF-C expression are predictive factors of lymph node relapse in T1-T4 N0 laryngopharyngeal squamous cell carcinoma. Ann Surg Oncol. 2007;14:248–57.CrossRefPubMed Hinojar-Gutierrez A, Fernandez-Contreras M, Gonzalez-Gonzalez R, et al. Intratumoral lymphatic vessels and VEGF-C expression are predictive factors of lymph node relapse in T1-T4 N0 laryngopharyngeal squamous cell carcinoma. Ann Surg Oncol. 2007;14:248–57.CrossRefPubMed
39.
go back to reference Williams JK, Carlson GW, Cohen C, DeRose PB, Hunter S, Jurkiewicz MJ. Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am J Surg. 1994;168:373–80.CrossRefPubMed Williams JK, Carlson GW, Cohen C, DeRose PB, Hunter S, Jurkiewicz MJ. Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am J Surg. 1994;168:373–80.CrossRefPubMed
40.
go back to reference Murray JD, Carlson GW, McLaughlin K, et al. Tumor angiogenesis as a prognostic factor in laryngeal cancer. Am J Surg. 1997;174:523–6.CrossRefPubMed Murray JD, Carlson GW, McLaughlin K, et al. Tumor angiogenesis as a prognostic factor in laryngeal cancer. Am J Surg. 1997;174:523–6.CrossRefPubMed
41.
go back to reference Rajeev S, Shevde LA. Recent advances in anti-Angiogenic therapy of Cancer. Oncotarget. 2011;2(3):122–34. Rajeev S, Shevde LA. Recent advances in anti-Angiogenic therapy of Cancer. Oncotarget. 2011;2(3):122–34.
Metadata
Title
CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma
Authors
Anke Schlüter
Patrick Weller
Oliver Kanaan
Ivonne Nel
Lukas Heusgen
Benedikt Höing
Pia Haßkamp
Sebastian Zander
Magis Mandapathil
Nina Dominas
Judith Arnolds
Boris A. Stuck
Stephan Lang
Agnes Bankfalvi
Sven Brandau
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4180-5

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