Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer.
Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, and MMP-1 that culminates in activation of PAR1, a G protein-coupled protease-activated receptor up-regulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation, and metastasis were effectively inhibited by i.p. administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer.
Agarwal
Anika
A
Molecular Oncology Research Institute, Tufts Medical Center, Box 7510, Boston, MA 02111, USA.
Covic
Lidija
L
Sevigny
Leila M
LM
Kaneider
Nicole C
NC
Lazarides
Katherine
K
Azabdaftari
Gissou
G
Sharifi
Sheida
S
Kuliopulos
Athan
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001201:Ascites / Q000201:enzymology*; D001826:Body Fluids / Q000201:enzymology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D000077143:Docetaxel; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010537:Peritoneum / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D010975:Platelet Aggregation Inhibitors
D009842:Oligopeptides; D043823:Taxoids; D000077143:Docetaxel; D045726:Metalloproteases; D010975:Platelet Aggregation Inhibitors
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