Abstract B102: Fibroblast-dependent modulation of drug sensitivity, stemcellness, and tumor cell dormancy

Abstract

Abstract Solid tumors are composed of tumor cells and different cell types making up the tumor stroma — endothelial cell, pericytes, immune cells and cancer associated fibroblasts. We focus on the impact of cancer associated fibroblasts on the stem cell properties of tumor cells, including drug sensitivity, anchorage independent growth and tumor initiating capacities. Previous work in our group showed that expression of platelet derived growth factor receptor β (PFGFRβ) in the tumor stroma is associated with worse prognosis in breast cancer. Furthermore, two experimental approaches were used to explore PDGFR-dependent paracrine signaling: (1) primary human breast fibroblasts isolated from normal as well as cancer tissue co-cultured with human breast cancer cell lines and (2) tumor cells, cancer associated fibroblasts and normal breast tissue fibroblasts derived from a genetic breast cancer mouse model. When looking at PFGFRβ expression in tumors from a randomized tamoxifen study we found that tumors with high expression in the tumor stroma did not seem to respond to the treatment. Ongoing in vitro studies are analyzing the impact of co-cultured fibroblasts on breast cancer cell tamoxifen sensitivity in vitro. Specifically we want to investigate how PDGF receptors, expressed by the tumor stroma, play a role in the sensitivity to tamoxifen by the tumor cells. We have also investigated the impact of fibroblasts on stemness properties of tumor cells derived from tumors of the MMTV polyoma middle T antigen driven mouse breast cancer model. Conditioned medium of tumor associated fibroblasts but also from normal mouse breast tissue fibroblasts increased the anchorage independent sphere forming capacity of the tumor cells in vitro. Conditioned media from the tumor cells themselves had similar effects. Tumor-supporting effects of fibroblasts were confirmed after orthotopic coinjection of tumor cells together with fibroblasts in syngeneic mice. The presence of fibroblasts resulted in a significant increase in the tumor take rate. Together these studies identify fibroblast-mediated modulation of “stemness” of breast cancer cells and a PDGFR-dependent modulation by fibroblasts of tamoxifen-sensitivity. Citation Format: Janna Paulsson, Carina Strell, Pernilla Roswall, Helena Rannikmae, Anne Weiland, Lisa Rydén, Arne Östman. Fibroblast-dependent modulation of drug sensitivity, stemcellness, and tumor cell dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B102.