Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium

<p>Abstract</p> <p>Background</p> <p>Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibition of tumor growth and dissemination. Evidence suggests that tumor vasculature expresses unique markers that distinguish it from normal vasculature. Our efforts focused on the molecular characterization of endothelial cells (EC) in the search for selective markers of tumor vasculature that might be helpful for the development of effective therapeutic approaches.</p> <p>Results</p> <p>We investigated by microarray analysis the gene expression profiles of EC purified and cultured from tumor (ovarian carcinoma [HOC-EC]) and normal (human adrenal gland [HA-EC]) tissue specimens. We found distinct transcriptional features characterizing the EC of different origin, and identified 158 transcripts highly expressed by HOC-EC. We analyzed four of these genes, ADAM23, FAP, GPNMB and PRSS3, which were not previously known to be expressed by endothelium. <it>In vitro </it>experiments confirmed the higher expression of the selected genes in tumor-derived endothelium with no expression in tumor cells. <it>In vivo </it>investigation by <it>in situ </it>hybridization established that ADAM23, GPNMB and PRSS3 expression is localized on blood vessels of human cancer specimens.</p> <p>Conclusion</p> <p>These findings elucidate some of the molecular features of the tumor endothelium. Comparative transcriptomic analysis allowed us to determine molecular differences of tumor and normal tissue-derived endothelium and to identify novel markers that might be exploited to selectively target tumor vasculature.</p

Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic microenvironment

We previously identified regulator of G-protein signaling 5 (RGS5) among several genes expressed by tumor-derived endothelial cells (EC). In this study, we provide the first in vivo/ex vivo evidence of RGS5 protein in the vasculature of ovarian carcinoma clinical specimens and its absence in human ovaries. Consistent with this, we show higher amounts of Rgs5 transcript in EC isolated from human cancers (as opposed to normal tissues) and demonstrate that expression is sustained by a milieu of factors typical of the proangiogenic tumor environment, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature. RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA). To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues. RGS5 expression by the cancer vasculature triggered and retained by the proangiogenic microenvironment supports its exploitation as a novel biomarker and opens the path to explore new possibilities of therapeutic intervention aimed at targeting tumor blood vessels

Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium-1

smooth muscle cells (USMAC) as well as in tumor cell lines (1A9, SKOV3, HT29 and MDA-MB-231). Gene expression of each target gene was normalized to 18s rRNA for each cell type (ΔCt = Ct- Ct). Average of ΔCt of the target gene from tumor derived ECs (Figure 1) was assumed as reference (ΔCt). Fold differences for each cell type were calculated according to the comparative ΔΔCt method (Fold difference = 2) and expressed as percentage relative to tumor-derived EC (100%).<p><b>Copyright information:</b></p><p>Taken from "Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium"</p><p>http://www.biomedcentral.com/1471-2164/9/201</p><p>BMC Genomics 2008;9():201-201.</p><p>Published online 30 Apr 2008</p><p>PMCID:PMC2410137.</p><p></p