Abstract
Simple SummaryUp to 50% of oropharyngeal squamous cell carcinomas (OPSCC) are associated with human papillomavirus type 16 (HPV16), the annual incidence of which is steadily increasing. HPV-positive and -negative OPSCC exhibit a different biology, which is characterized by distinct mutation signatures and expression patterns. It is known that VEGFR2 is commonly overexpressed in HNSCC, but the influence of HPV on VEGFR2 in OPSCC is still unknown, although VEGFR2 has emerged as a promising target in tumor therapy. The aim of our study was to evaluate whether HPV exerts specific effects on VEGFR2 expression in OPSCC and thus possibly on the regulation of vascularization. Interestingly, while HPV-negative carcinoma upregulates VEGFR2 in tumor cells, in HPV-positive carcinoma VEGFR2 is upregulated in tumor-supporting blood vessels. HPV-positive OPSCC with high VEGFR2 expression is associated with poor prognosis, supporting the prognostic significance of deregulated VEGF signaling for OPSCC patients.VEGF signaling regulated by the vascular endothelial growth factor receptor 2 (VEGFR2) plays a decisive role in tumor angiogenesis, initiation and progression in several tumors including HNSCC. However, the impact of HPV-status on the expression of VEGFR2 in OPSCC has not yet been investigated, although HPV oncoproteins E6 and E7 induce VEGF-expression. In a series of 56 OPSCC with known HPV-status, VEGFR2 expression patterns were analyzed both in blood vessels from tumor-free and tumor-containing regions and within tumor cells by immunohistochemistry using densitometry. Differences in subcellular colocalization of VEGFR2 with endothelial, tumor and stem cell markers were determined by double-immunofluorescence imaging. Immunohistochemical results were correlated with clinicopathological data. HPV-infection induces significant downregulation of VEGFR2 in cancer cells compared to HPV-negative tumor cells (p = 0.012). However, with respect to blood vessel supply, the intensity of VEGFR2 staining differed only in HPV-positive OPSCC and was upregulated in the blood vessels of tumor-containing regions (p < 0.0001). These results may suggest different routes of VEGFR2 signaling depending on the HPV-status of the OPSCC. While in HPV-positive OPSCC, VEGFR2 might be associated with increased angiogenesis, in HPV-negative tumors, an autocrine loop might regulate tumor cell survival and invasion.
Highlights
A rising proportion of head and neck squamous cell carcinomas (HNSCC) localized in the oropharynx is associated with human papillomavirus (HPV) infections with HPV16 being the most prevalent type [1].Data from the United States allowed for the projection that OPSCC case numbers would overtake the number of cervical carcinomas in 2020 and data from the Centers for DiseaseControl (CDC) show that this was already the case in 2019 [1,2].Based on their differing risk factors, clinicopathological presentation, biological profiles, mutation patterns and expression signatures, HPV-positive and HPV-negative OPSCC can be regarded as two distinct entities [3]
Since reactive oxygen species (ROS) and oxidative stress (OS) were previously demonstrated to have a strong effect on the expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2), we aimed at characterizing whether differences in the expression pattern of VEGFR2 exist in 56 OPSCC with known HPV-status and OS signatures [13,25]
To prove that the VEGFR2-positive cells are blood vessel lining endothelial cells, we performed double immunofluorescence staining with the endothelial cell marker CD31 together with VEGFR2
Summary
Control (CDC) show that this was already the case in 2019 [1,2] Based on their differing risk factors, clinicopathological presentation, biological profiles, mutation patterns and expression signatures, HPV-positive and HPV-negative OPSCC can be regarded as two distinct entities [3]. The vascular endothelial growth factor receptors (VEGFRs) are expressed on the cell surface and bind to the signaling ligand vascular endothelial growth factor (VEGF). VEGFR2 on endothelial cells is primarily involved in angiogenesis and plays a crucial role in tumor angiogenesis [5]. VEGFR2 is expressed on endothelial cells but can be observed in tumor cells [6]. VEGFR1 is localized on immune and endothelial cells and is considered as a decoy receptor that limits the amount of free available VEGF ligand. Strategies to interact with the vascular supply in a therapeutic approach have been studied over the past decades, and VEGFR2 has emerged as a promising target in tumor therapy [8]
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