Abstract B103: Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis

Abstract

Abstract Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrated that CAFs also mediate tumor-enhancing inflammation: CAFs isolated from pre-neoplastic and tumor tissue expressed a pro-inflammatory gene signature and functioned to recruit macrophages and enhance tumor angiogenesis in a mouse model of squamous carcinoma. Moreover, we demonstrated that pro-inflammatory signaling by CAFs is operative also in mouse and human breast carcinogenesis. Although breast cancer is one of the major tumor types where CAFs were shown to be tumor promoting, there is no detailed analysis of CAF characteristics and function in correlation with tumor progression. We therefore set out to characterize the dynamic changes in CAFs during progression of mammary carcinogenesis, in a transgenic mouse model of human breast cancer, the MMTV-PyMT mice. We show that normal mammary fibroblasts can be “educated” by mammary carcinoma cells to become activated, pro-inflammatory CAFs. Furthermore, transcriptome profiling of fibroblasts isolated from normal mammary glands, or from mammary glands of transgenic mice at defined tumorigenic stages (hyperplasia, early carcinoma, invasive adenocarcinoma) revealed distinct CAF gene expression signatures that correspond to different tumor stages, with only partial overlap between the stages, suggesting co-evolution of the microenvironment with tumorigenic progression. Interestingly, the gene signature of fibroblasts isolated from hyperplastic lesions is inverse to that in CAFs from neoplastic stages, and has a putative growth inhibitory phenotype, while CAFs from early and late carcinoma express pro-inflammatory and tumor promoting gene signatures. Elucidating the molecular mechanisms by which CAFs mediate cancer-related inflammation in breast cancer will greatly increase our understanding of stromal pathways that contribute to tumorigenesis, in an effort to identify novel stromal molecular targets for combinatorial therapeutic approaches to combat breast cancer progression. Citation Format: Yoray Sharon, Yael Raz1,2, Lina Alon, Neta Erez. Proinflammatory signaling by cancer-associated fibroblasts co-evolves during mammary carcinogenesis. [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 B103.