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Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors

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Abstract

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.

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Acknowledgments

Special thanks go to Prof. Dr. med. Dr. h. c. mult. M. Samii from the International Neuroscience Institute Hannover/Germany, Department of Neurosurgery, for providing us with a large amount of data on chordoma patients due to his excellent experience in skull base surgery.

Conflict of interest

I, Dr. Reza Akhavan-Sigari, declare that none of the authors of the above manuscript has declared any conflict of interest within the last 3 years which may arise from being named as an author on the manuscript.

Funding statement

I, Dr. Reza Akhavan-Sigari, declare that I have no proprietary, financial, professional, or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of, the manuscript mentioned above.

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Authors and Affiliations

  1. Department of Neurosurgery, University Medical Center Göttingen, Georg-August-University Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    R. Akhavan-Sigari, V. Rohde & K. von Eckardstein

  2. Department of Neurosurgery, Nordstadt Medical Center, Klinikum Hannover, Haltenhoffstr. 41, 30167, Hannover, Germany

    M. R. Gaab

  3. Department of Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    A. Brandis

  4. Department of Urology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    H. Tezval

  5. Department of Neurosurgery, Razavi Hospital, Imam Reza University, Shahid Kalantari Avenue, after Ghaem Bridge, Mashhad, Iran

    M. Abili

  6. Department of Pathology, Nordstadt Medical Center, Klinikum Hannover, Haltenhoffstr. 41, 30167, Hannover, Germany

    H. Ostertag

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  1. R. Akhavan-Sigari
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Correspondence to R. Akhavan-Sigari.

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Comments

Takahiko Naka, Kitakyushu, Japan

Tumor growth or progression correlates with angiogenesis in many human malignant neoplasms. Chordoma grows slowly; however, it generally shows locally aggressive behavior and frequently recurs after excision. Vascular formation is poor in chordoid lobules and abundant in intralesional fibrous septum, particularly on the surface, suggesting induction of tumor vessels by chordoma cells [1]. As a consequence, it seems interesting to study angiogenesis in chordoma; however, there were few papers in this field [2, 3]. In the current study, Akhavan-Sigari and colleagues reported the expression of angiogenic factors using tissue microarray in a large series of chordoma and investigated the relationship between the immunoprofile and clinicopathologic parameters. They found a higher VEGF-R positivity in recurrent lesions than in primary lesions. In addition, they revealed that patients with higher VEGF-R expression showed poorer prognosis. It is very significant to show the relationship between angiogenesis and aggressive clinical course of chordoma because angiogenic process is a potential therapeutic target for chordomas.

1. Naka T, Boltze C, Kuester D, Samii A, Herold C, Ostertag H, Iwamoto Y, Oda Y, Tsuneyoshi M, Roessner A (2005) Intralesional fibrous septum in chordoma: a clinicopathologic and immunohistochemical study of 122 lesions. Am J Clin Pathol 124(2):288–294.

2. Chen KW, Yang HL, Lu J, Wang GL, Ji YM, Wu GZ, Zhu LF, Liu JY, Chen XQ, Gu YP (2011) Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma. J Neurooncol 101(3):357–363

3. Li X, Ji Z, Ma Y, Qiu X, Fan Q, Ma B (2012) Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas. Oncol Lett 3(6):1268–1274.

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Akhavan-Sigari, R., Gaab, M.R., Rohde, V. et al. Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors. Neurosurg Rev 37, 79–88 (2014). https://doi.org/10.1007/s10143-013-0495-5

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