Universität zu Köln

Uzun, Senem ORCID: 0000-0001-5468-1081 (2021). Comprehensive analysis of VEGFR2 expression in HPV-positive and -negative oropharyngeal squamous cell carcinomas. PhD thesis, Universität zu Köln.

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Abstract

A rising proportion of head and neck squamous cell carcinomas (HNSCC) localised in the oropharynx (OPSCC) is associated with human papillomavirus (HPV) infections with HPV16 being the most prevalent type. Based on their differing risk factors, clinicopathological presentation, biological profiles, mutation patterns, expression signatures and presence of HPV DNA, OPSCC are subdivided into HPV-positive and -negative entities. However, modified treatment regimens that take HPV status into account have not yet been implemented in routine clinical practice. Strategies to interact with the vascular supply are promising therapeutic approaches in cancer treatment and have been studied over the past decades. Among the vascular endothelial growth factor receptors (VEGFR), VEGFR2 plays a decisive role in tumour angiogenesis. However, VEGFR2 is not only expressed on endothelial cells but can also be observed in tumour cells. Though it is known that VEGFR2 is commonly overexpressed in HNSCC, the influence of HPV on VEGFR2 in OPSCC is still unknown. The present study addressed the question if differences in VEGFR2 expression in HPV positive and -negative OPSCC exist and aimed to investigate the impact of HPV status on the quantitative and qualitative expression of VEGFR2 in OPSCC. Therefore, a series of 56 OPSCC samples with known HPV status was analysed. VEGFR2 expression patterns both in blood vessels from tumour-free and tumour containing regions and within tumour cells were determined by immunohistochemistry. VEGFR2 signal intensities were quantified by densitometry and compared between HPV-positive and -negative OPSCC. Differences in subcellular colocalisation of VEGFR2 with endothelial (CD31), tumour cell (p16INK4A or p53) and cancer stem cell markers (ALDH1A1) were determined by double-immunofluorescence imaging. The VEGFR2 expression was significantly reduced in HPV-positive tumour cells compared to HPV negative OPSCC. However, with respect to the vascular supply, upregulation in tumour-containing regions was observed only in HPV-positive OPSCC. Furthermore, a strong colocalization of CD31 with VEGFR2 was observed in capillaries of HPV-positive OPSCC. Moreover, colocalization signals of ALDH1A1 with VEGFR2 in cancer stem cells were frequently observed in HPV-positive OPSCC, but sparsely detected in HPV-negative OPSCC. These results may suggest different routes of VEGFR2 signalling depending on HPV status and possibly triggered by hypoxia. While in HPV-positive OPSCC VEGFR2 might be associated with increased angiogenesis, in HPV-negative tumours an autocrine loop might regulate tumour cell survival and invasion. It appears that VEGFR2 expression may play a regulatory role in cancer stem cells of HPV-positive OPSCC. Future studies should clarify the molecular basis of mechanisms involved in the different regulation of VEGFR2 expression in OPSCC.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Uzun, Senem senem.uzun95@gmail.com orcid.org/0000-0001-5468-1081 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-641896
Date:	29 November 2021
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Hals-Nasen-Ohrenheilkunde > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language vascular endothelial growth factor receptor 2 English oropharyngeal squamous cell carcinoma English human papillomavirus English cancer stem cell English
Date of oral exam:	30 August 2022
Referee:	Name Academic Title Klußmann, Jens Peter Universitätsprofessor Dr. med. George, Julie Universitätsprofessorin Dr. rer. nat.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/64189