title: Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy.
abstract: Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies that block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown that matrix metalloprotease-1 (MMP1) activation of the G protein-coupled receptor protease-activated receptor-1 (PAR1) is an important stimulator of angiogenesis and metastasis in peritoneal mouse models of ovarian cancer. In the present study, we tested the hypothesis that MMP1-PAR1 promotes angiogenesis through its paracrine control of angiogenic chemokine receptors. We found that MMP1-PAR1 activation induces the secretion of several angiogenic factors from ovarian carcinoma cells, most prominently interleukin (IL)-8, growth-regulated oncogene-alpha (GRO-alpha), and monocyte chemoattractant protein-1. The secreted IL-8 and GRO-alpha acts on endothelial CXCR1/2 receptors in a paracrine manner to cause robust endothelial cell proliferation, tube formation, and migration. A cell-penetrating pepducin, X1/2pal-i3, which targets the conserved third intracellular loop of both CXCR1 and CXCR2 receptors, significantly inhibited endothelial cell proliferation, tube formation, angiogenesis, and ovarian tumor growth in mice. Matrigel plugs mixed with MMP1-stimulated, OVCAR-4-conditioned media showed a dramatic 33-fold increase in blood vessel formation in mice. The X1/2pal-i3 pepducin completely inhibited MMP1-dependent angiogenesis compared with a negative control pepducin or vehicle. Conversely, a vascular endothelial growth factor-directed antibody, Avastin, suppressed angiogenesis in mice but, as expected, was unable to inhibit IL-8 and GRO-alpha-dependent endothelial tube formation in vitro. These studies identify a critical MMP1-PAR1-CXCR1/2 paracrine pathway that might be therapeutically targeted for ovarian cancer treatment.
authors.affiliation: Department of Medicine, Tufts Medical Center, Molecular Oncology Research Institute, Tufts University Medical School, Boston, Massachusetts 02111, USA.
authors.forename: Anika
authors.initials: A
authors.lastname: Agarwal
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Tressel
authors.forename: Rajani
authors.initials: R
authors.lastname: Kaimal
authors.forename: Marianthi
authors.initials: M
authors.lastname: Balla
authors.forename: Francis H
authors.initials: FH
authors.lastname: Lam
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D054360:Chemokine CXCL1; D016209:Interleukin-8; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1