Unknown,Transcriptomics,Genomics,Proteomics

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Identification of a stable molecular signature in breast tumor endothelial cells that persists ex vivo

ABSTRACT: Long-term, in vitro propagation of tumor-specific endothelial cells (TEC) allows for ex vivo functional studies and gene expression profiling of clonally-derived, well-characterized subpopulations. Using a genetically-engineered mouse model (GEMM) of mammary adenocarcinoma (C3-TAg), we have optimized an isolation procedure and defined growth conditions for long-term propagation of breast TEC. Based on expression of EC-selective markers, the isolated TEC maintain their endothelial specification and phenotype in culture. Furthermore, gene expression profiling of multiple TEC subpopulations revealed striking, persistent overexpression of several candidate genes including Irx2 and Zfp503 (transcription factors), Cd166 and Cd133 (cell-surface markers), Ccl12 and neurotensin (angiocrine factors), and Gpr182 and Cnr2 (G protein-coupled receptors). Taken together, we have described an effective method for isolating and culture-expanding breast TEC from a GEMM and we have uncovered several new TEC-selective genes whose overexpression persists even after long-term in vitro culture. These results suggest that stable changes may be induced in vascular endothelial cells in the tumor microenvironment in vivo that are transmittable ex vivo. reference x sample

ORGANISM(S): Mus musculus

SUBMITTER: Charles Perou

PROVIDER: E-GEOD-50555 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Identification of a stable molecular signature in mammary tumor endothelial cells that persists in vitro.

Xiao Lin L Harrell J Chuck JC Perou Charles M CM Dudley Andrew C AC

Angiogenesis 20131121 3

Long-term, in vitro propagation of tumor-specific endothelial cells (TEC) allows for functional studies and genome-wide expression profiling of clonally derived, well-characterized subpopulations. Using a genetically engineered mouse model of mammary adenocarcinoma, we have optimized an isolation procedure and defined growth conditions for long-term propagation of mammary TEC. The isolated TEC maintain their endothelial specification and phenotype in culture. Furthermore, gene expression profili ...[more]

PMID: 24257808

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Project description:Introduction: Over the past several years, we have been interested in understanding the mechanisms by which hormone-dependent (HD) mammary carcinomas grow in the absence of the stimulatory hormone. We have hypothesized that the stromal compartment plays a pivotal role in the acquisition of the hormone-independent (HI) phenotype by providing stimulatory factors that replace the proliferative effects of the hormone. Methods: We used DNA microarrays to compare the gene expression profiles of tumors from the MPA mouse breast cancer model, one hormone-dependent (C4-HD) and one hormone-independent (C4-HI), using whole tumor samples or laser-captured purified stromal and epithelial cells obtained from the same tumors. The expression of selected genes was validated by immunohistochemistry and immunofluorescence assays. Results: We identified 413 genes that were expressed in tumor stroma but not in epithelial cells. Eighty-five percent of these genes were upregulated, whereas the remaining 15% were downregulated in C4-HI tumors relative to their expression in the C4-HD tumor stroma. Several matrix metallopeptidases, including Mmp13, Mmp3, Mmp10 and Mmp9, were overexpressed in the C4-HI tumor microenvironment. On the other hand, 1100 genes were specifically expressed in the tumor parenchyma. Among them, the 29% were upregulated, whereas the remaining 71% were downregulated, in C4-HI relative to C4-HD tumor epithelium. Steap, Pdgfc, Runx2, Cxcl9 and Sdf2 were among the genes with high expression in the C4-HI tumor parenchyma. Interestingly, we found that Fgf2 was one of the few genes upregulated by MPA in C4-HD tumors, confirming its pivotal role in regulating tumor growth in this model. Conclusions: We demonstrate a gene expression profile that distinguishes epithelial from stromal cells in mammary tumors with different hormone dependence. Our results support the hypothesis that the tumor-associated stroma may contribute to hormone-independent tumor growth. The fact that Fgf2 was one of these few stimulatory genes is worth investigating. reference X sample

Dataset Information

Identification of a stable molecular signature in breast tumor endothelial cells that persists ex vivo

Publications

Identification of a stable molecular signature in mammary tumor endothelial cells that persists in vitro.

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