Abstract LB-301: Potential role of prostate cancer-associated fibroblasts in inducing stem cell-like properties to the malignant epithelial cells of the prostate

Abstract

Abstract Epithelial-mesenchymal transdifferentiation (EMT) is a well recognized mechanism for initiating metastasis of epithelial cancers. Shared attributes between EMT and cancer stem cells (CSCs) are being uncovered and extracellular signals from the microenvironment which regulate EMT are being investigated to define their role in a potential Cancer Cell-EMT-CSC lineage. Recently we have described epithelial cell lines (Hormones & Cancer. 1: 44–54, 2010), primary cultures of cancer-associated fibroblasts (CAFs) (Cancer Res. 68: 198–205, 2008) and CSC subpopulation (Cancer Res. 70: 7294–303, 2010), all derived from the cPten-/-L mouse model of prostate adenocarcinoma (Cancer Res. 67: 7525–33, 2007) that could be used to evaluate and characterize factors that can support or accelerate EMT induction to epithelial cancer cells, and further define putative factors that may facilitate de-differentiation to CSC phenotypes and biology. Here we report that a malignant epithelial cell line (cE1) derived from the androgen depletion-independent recurrent tumor of the model can be further fractionated into three different subpopulations based on the levels of cell surface expressions of SCA-1(S) and CD49f (C) antigens: SC− (low expression of S and C), SChi (high expression of S and C), and SCme (medium expression of S and C). Of these fractions, SCme population is relatively more sensitive to undergo EMT-like changes when exposed to TGF-β1 than the other fractions. SChi fraction displays increased ability to form spheroids in 3-D cultures akin to the CSCs isolated from the prostate tumors of the model. SC− cells appear to represent bulk of the cells with reduced propensity for EMT or spheroid formation. SCme cells were treated with conditioned medium (CM) from either CAF cultures or NPF (normal prostate fibroblast) cultures, and the morphological changes were monitored over a period of 14 days. It is remarkable that extensive EMT-like changes were induced by CM from CAFs and much less by that from NPFs. Furthermore, following EMT induction, these transformed cells appear to be more similar to the SChi group based on expression of S and C and statistically significant upregulation of Oct4 (p<0.05), Sox2 (p<0.001) and Nanog (p<0.0001). While the factors that are secreted by CAFs and responsible for the observed shift towards CSC phenotype remain to be defined, our preliminary results from mass spectrometric analyses indicate excess production of members of the Annexin family of proteins by CAFs. We believe the study system we described could be explored for this and other cues on the intersections of signaling networks regulating EMT of the cancer epithelial cells and then potentially to further de-differentiation to CSC-like phenotypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2011-LB-301