9P Synergistic potential of vitamin D receptor and cancer stem cells markers expression in ovarian tumors

Ovarian cancer (OC) is the most aggressive gynecological malignancy. Vitamin D actions mediated by its receptor (VDR) showed significant antitumor activity. Cancer stem cells (CSC) that are characterized by specific surface markers CD44 and CD133, are responsible for the tumor resistance to various treatment modalities. This study aimed to analyze the association of CD44, CD133, and VDR expression in epithelial ovarian tumors (EOT). Our cohort comprised 218 patients with EOT of which 131 were OC, 42 atypical proliferative tumors (APT), and 45 benign tumors. A set of histopathology parameters were correlated with CD44, CD133, and VDR immunohistochemical expressions, using the tissue microarray method. We used extensive scoring method (IR score, Remmele's score) as a more validate than basic one. It considered multiplied staining intensity (0- absent, 1- low, 2- moderate, 3- strong) and the percentage of positive cancer cells (0 = 0%, 1 ≤ 10%, 2 = 11–50%, 3 = 51–80%, 4 ≥ 81% of the cells). High expression was defined as IR score >2, while low expression was with IR score 0-2. There was a positive correlation between CD44, CD133, and VDR markers in all groups (p<0.05). CD44 and cytoplasmic VDR expression showed higher levels in OC than in other groups, while CD133 expression was most prominent in the APT (p<0.05). Significant CD44 and VDR expression was evident in high grade serous carcinoma (HGSC) in advanced stages. CD133 marker did not show a correlation with these histopathology parameters. This study indicates very important and complex relationships between CSCs and VDR-mediated calcitriol function, which certainly is one of the very crucial regulation mechanisms in CSC. High VDR expression point to possible effective antitumor (calcitriol) therapy in HGSC ovarian cancer cells. Calcitriol treatment could activate the VDR signaling pathway in CSCs, which further disrupts the CSC's stemness, leading to a reduction of the CSC population. Significant CD44 and cytoplasmic VDR expressions were demonstrated in ovarian CSC in aggressive types as HGSC, at advanced stages. It indicates the possible benefits of target therapy in patients with high expression levels of these markers.