Peritumor mucosa in advanced laryngeal carcinoma exhibits an aberrant proangiogenic signature distinctive from the expression pattern in adjacent tumor tissue

Abstract

Abstract Field cancerization theory is an important paradigm in head and neck carcinoma as its oncological repercussions affect treatment outcomes in diverse ways. The aim of this study is to assess the possible interconnection between peritumor mucosa and the process of tumor neoangiogenesis. Sixty patients with advanced laryngeal carcinoma were enrolled in the study. The majority of patients express a canonical HIF-upregulated proangiogenic signature with almost complete predominancy of HIF-1α overexpression and normal expression levels of the HIF-2α isoform. Remarkably, more than 60% of the whole cohort exhibit a HIF-upregulated proangiogenic signature also in peritumoral benign mucosa. Additionally, the latter subgroup has a distinctly shifted phenotype towards HIF-2α upregulation compared to the one in tumor tissue, i.e., a tendency towards a HIF-switch is observed in contrast to the dominated by HIF-1α tumor phenotype. ETS-1 displays stable and identical significant overexpression in both proangiogenic phenotypes present in tumor and peritumoral mucosa. In the current study, we report for the first time the existence of an abnormal proangiogenic expression profile present in the peritumoral mucosa in advanced laryngeal carcinoma when compared to paired distant laryngeal mucosa. Moreover, we describe a specific phenotype of this proangiogenic signature that is significantly different from the one present in tumor tissue as we delineate both phenotypes, quantitively and qualitatively. This finding is per se cancer heterogeneity that extends beyond the “classical” borders of the malignancy and is proof of a strong interconnection between field cancerization and one of the classical hallmarks of cancer – the process of tumor neoangiogenesis.