Abstract 5296: Studies on the potential role of S100A6 in growth and metastasis of ovarian cancer

Abstract

Abstract Epithelial ovarian cancer (OVCA) accounts for 90% of all ovarian cancers and is the most lethal gynecological cancer. The vast majorities of OVCA cases are diagnosed at advanced stage and have pelvic involvement extending to the abdomen and/or lymph nodes (stage III), or distal organs such as liver, lungs and spleen (stage IV). The five-year survival rate for late stage disease is less than 25%. Although peritoneal dissemination and correlative parenchymal metastases frequently occur, little is known about the properties of OVCA cells contributing to this malignant biology. Further understanding of OVCA metastasis may shed light on disease prevention and treatment. We previously documented a significant correlation between peritoneal OVCA tumor burden and serum S100A6 concentration in an animal model of OVCA carcinomatosis. This was further substantiated by evidence of prominent S100A6 expression in patient OVCA tissues, as well as increased S100A6 in sera from a separate late stage OVCA patient cohort. Yet, the biological function of S100A6 is not well defined. Immunofluorescent labeling (IF) of S100A6 in SKOV3 epithelial OVCA cells revealed a diffuse expression in various sub-cellular compartments, including nuclei, nuclear envelop, cytoplasm, and interestingly, phyllopodia; among which, the nuclear and phyllopodia localization were most prominent. The presence of S100A6 at phyllopodia suggested a role for S100A6 in cell motility. To test an association of S100A6 in cell mobility and tumor growth, S100A6 expression was knocked down in SKOV3 cells (stable, KD), using siRNA expressing vector pSuper (Oligoengine). These KD cells showed diminished S100A6 overall by IF, yet the subcellular distribution of S100A6 was not altered; conspicuous nuclear and phyllopodial localization remained. S100A6 KD cells exhibited decreased cell mobility in a wound healing assay in vitro. KD cells were less mobile when evaluated in a migration assay, both under unstimulated culture conditions and in response to EGF chemotaxis. To test the effect of altered S100A6 expression on tumor malignancy and growth, S100A6 KD cells expressing luciferase were compared to parental SKOV cells and SKOV cells expressing control non-targeting siRNA (control), for up to 4 weeks in vivo following intraperitoneal injection. When photon flux from luciferase activity was quantified twice a week from xenografts, growth of control and parental SKOV3 cells was comparable, in contrast to KD cells, which grew significantly slower. Necropsy at 4 weeks after cell inoculation revealed reduced or grossly unapparent tumor burden in mice receiving KD cells, as compared to controls, thereby corroborating the imaging findings. In summary, elevated S100A6 may augment ability of OVCA cells to colonize and spread in the peritoneum, contributing to malignancy of OVCA cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5296.