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


RESULTS
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. In vitro experiments confirmed the higher expression of the selected genes in tumor-derived endothelium with no expression in tumor cells. In vivo investigation by in situ hybridization established that ADAM23, GPNMB and PRSS3 expression is localized on blood vessels of human cancer specimens.


CONCLUSIONS
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.
Ghilardi
Carmen
C
Laboratory of Biology and Treatment of Metastases, Mario Negri Institute for Pharmacological Research, Milano, Italy. cghilardi@marionegri.it
Chiorino
Giovanna
G
Dossi
Romina
R
Nagy
Zsuzsanna
Z
Giavazzi
Raffaella
R
Bani
MariaRosa
M
D051722:ADAM Proteins / Q000235:genetics; D000311:Adrenal Glands / Q000098:blood supply / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D010450:Endopeptidases; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D018093:Gelatinases; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014357:Trypsin / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
D051722:ADAM Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D014357:Trypsin; D000099167:Fibroblast Activation Protein Alpha; C503042:GPNMB protein, human; C040749:PRSS3 protein, human; C114633:ADAM23 protein, human