Identification of a Metalloprotease-Chemokine Signaling System in the Ovarian Cancer Microenvironment: Implications for Antiangiogenic Therapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-07, Vol.70 (14), p.5880-5890
• Main Authors: AGARWAL, Anika, TRESSEL, Sarah L, KAIMAL, Rajani, BALLA, Marianthi, LAM, Francis H, COVIC, Lidija, KULIOPULOS, Athan
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cell Communication - physiology; Cell Line, Tumor; Chemokine CXCL1 - metabolism; Chemokine CXCL1 - secretion; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Interleukin-8 - metabolism; Interleukin-8 - secretion; Matrix Metalloproteinase 1 - metabolism; Medical sciences; Mice; Mice, Nude; Molecular Sequence Data; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Receptor, PAR-1 - metabolism; Receptors, Interleukin-8A - metabolism; Receptors, Interleukin-8B - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-4341

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.