Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma

SIMPLE SUMMARY: Laryngeal Squamous Cell Carcinoma (LSCC) is a squamous cancer with 2.4% new diagnoses each year, accounting for 25% of head and neck cancers, and has a high mortality rate. A deeper understanding of key mechanisms and knowledge of the putative target molecules of theranostic relevance are required. The receptor for neurotrophins p75NTR has been shown to be highly expressed in cancer stem cells (CSCs) of squamous epithelia, in LSCC as well as in other cancers. However, whether its cleavage product p75ICD expression, known to finely regulate the survival/death balance in neurons, is also a master regulator in cancer and LSCC in particular has not been directly addressed so far. To resolve this question, we performed a preliminary study using a limited number of LSCC specimens and studied p75ICD presence and expression pattern in LSCC specimens, showing that p75ICD may be a promising target in LSCC, requiring further investigation. ABSTRACT: We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.