Abstract 1535: Hospicells (MSCs and TAFs relative cells) activate ovarian carcinoma cells and macrophages to secrete IL-6, IL-8 and VEGF and polarize macrophages into a TAM phenotype.

Abstract

Abstract Epithelial Ovarian carcinoma (EOC) is the leading cause of death from gynaecological cancer in the world and is characterized by peritoneal dissemination, ascite development and a high rate of mortality. Late EOC is treated by a cytoreductive surgery and chemotherapy but most of patients experience a recurrence with the apparition of a chemoresistance. The microenvironment could be implied in this recurrence and the resistance to chemotherapies. Rafii et al. isolated a new type of peritoneal cells from ascitic fluid of patients with stage IIIc ovarian cancer, called Hospicells. These cells share homologies with Mesenchymal Stem Cells (MSCs) and Tumor-associated Fibroblasts (TAFs). Ovarian cancer cells (OCCs) xenograft (i.p. or s.c.) associated with Hospicells in Nude mice leads to a dramatic increase of tumour volume, production of ascitic fluid and mortality. In order to understand these effects, we studied the interactions between OCCs and Hospicells. In vitro, Hospicells and OCCs co-culture leads to the enhancement of the secretion of IL-6, IL-8 and VEGF (cytokines implied in several tumoral processes) by the OCCs compared to the culture of each cell line separately. Moreover, the in vivo co-implantation of Hospicells with OCCs into Nude mice leads to an increase quantity of these cytokines compare to the implantation of OCCs alone. These data suggest a specific crosstalk between OCCs and Hospicells. However, while Hospicells always enhance ovarian cancer progression in vivo, only some cell lines can be activated by Hospicells in vitro. We searched for another Hospicells’ cell partner in vivo and showed that they activate macrophages to polarize into a pro-tumoral tumor-associated phenotype (TAM) and to secrete IL-6, IL-8, VEGF, GM-CSF, IL-1 (α and β), MCP-1, etc… To our knowledge, this is the first evidence of macrophage activation by TAF or MSC-like cells. As ovarian cancer enhanced progression could be due to interactions between OCCs, macrophages and Hospicells, we investigated the pathways potentially implied in the activation of OCCs or macrophages by Hospicells. We already know that TNF-α, IL-1α, estrogens, LPA, S1P or NO pathways are not implied in the activation of OCCs or macrophages by Hospicells but Fas-Ligand, IL-1β or CD40 Ligand pathways are still under investigation. However, we showed that the induction of VEGF secretion in OCCs and macrophages by Hospicells is dependant of the COX-2 pathway. This data strengthens the importance of the inflammatory microenvironment in the ovarian cancer and explain a part of the observed effects of Hospicells on the ovarian cancer progression. Targeting interactions between Hospicells and OCCs and macrophages has potential to improve ovarian cancer treatment efficiency. Citation Format: Benoît Thibault, Magali Castells, Eliane Mery, Jean Pierre Delord, Bettina Couderc. Hospicells (MSCs and TAFs relative cells) activate ovarian carcinoma cells and macrophages to secrete IL-6, IL-8 and VEGF and polarize macrophages into a TAM phenotype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1535. doi:10.1158/1538-7445.AM2013-1535