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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.

SUBMITTER: Agarwal A

PROVIDER: S-EPMC2917243 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy.

Agarwal Anika A Tressel Sarah L SL Kaimal Rajani R Balla Marianthi M Lam Francis H FH Covic Lidija L Kuliopulos Athan A

Cancer research 20100622 14

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 an ...[more]

PMID: 20570895

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Project description:Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.

Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.

Dataset Information

Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy.

Publications

Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy.

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