ABSTRACT
Prostate specific antigen screening has resulted in a decrease in prostate cancer-related deaths. However, it also has led to over-treatment affecting the quality of life of many patients. New biomarkers are needed to distinguish prostate cancer from benign prostate hyperplasia (BPH) and to predict aggressiveness of the disease. Here, we report that ribonuclease 4 (RNASE4) serves as such a biomarker as well as a therapeutic target. RNASE4 protein level in the plasma is elevated in prostate cancer patients and is positively correlated with disease stage, grade, and Gleason score. Plasma RNASE4 level can be used to predict biopsy outcome and to enhance diagnosis accuracy. RNASE4 protein in prostate cancer tissues is enhanced and can differentiate prostate cancer and BPH. RNASE4 stimulates prostate cancer cell proliferation, induces tumor angiogenesis, and activates receptor tyrosine kinase AXL as well as AKT and S6K. An RNASE4-specific monoclonal antibody inhibits the growth of xenograft human prostate cancer cell tumors in athymic mice.
Subject(s)
Prostatic Hyperplasia , Prostatic Neoplasms , Animals , Humans , Male , Mice , Neoplasm Grading , Prostatic Neoplasms/pathology , Quality of Life , RibonucleasesABSTRACT
BACKGROUND: Angiogenin is a multifunctional secreted ribonuclease that is upregulated in human cancers and downregulated or mutationally inactivated in neurodegenerative diseases. A role for angiogenin in glioblastoma was inferred from the inverse correlation of angiogenin expression with patient survival but had not been experimentally investigated. METHODS: Angiogenin knockout mice were generated and the effect of angiogenin deficiency on glioblastoma progression was examined. Angiogenin and plexin-B2 genes were knocked down in glioblastoma cells and the changes in cell proliferation, invasion and vascular association were examined. Monoclonal antibodies of angiogenin and small molecules were used to assess the therapeutic activity of the angiogenin-plexin-B2 pathway in both genetic and xenograft animal models. RESULTS: Deletion of Ang1 gene prolonged survival of PDGF-induced glioblastoma in mice in the Ink4a/Arf-/-:Pten-/- background, accompanied by decreased invasion, vascular association and proliferation. Angiogenin upregulated MMP9 and CD24 leading to enhanced invasion and vascular association. Inhibition of angiogenin or plexin-B2, either by shRNA, monoclonal antibody or small molecule inhibitor, decreases sphere formation of patient-derived glioma stem cells, reduces glioblastoma proliferation and invasion and inhibits glioblastoma growth in both genetic and xenograft animal models. CONCLUSIONS: Angiogenin and its receptor, plexin-B2, are a pair of novel regulators that mediate invasion, vascular association and proliferation of glioblastoma cells. Inhibitors of the angiogenin-plexin-B2 axis have therapeutic potential against glioblastoma.
Subject(s)
Glioblastoma , Nerve Tissue Proteins , Ribonuclease, Pancreatic , Animals , Cell Line, Tumor , Cell Proliferation , Glioblastoma/drug therapy , Humans , Mice , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolismABSTRACT
Angiogenin (ANG) is a secreted ribonuclease (RNase) with cell-type- and context-specific roles in growth, survival, and regeneration. Although these functions require receptor-mediated endocytosis and appropriate subcellular localization, the identity of the cell surface receptor remains undefined. Here, we show that plexin-B2 (PLXNB2) is the functional receptor for ANG in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells. Mechanistically, PLXNB2 mediates intracellular RNA processing that contribute to cell growth, survival, and regenerative capabilities of ANG. Antibodies generated against the ANG-binding site on PLXNB2 restricts ANG activity in vitro and in vivo, resulting in inhibition of established xenograft tumors, ANG-induced neurogenesis and neuroprotection, levels of pro-self-renewal transcripts in hematopoietic and patient-derived leukemic stem and progenitor cells, and reduced progression of leukemia in vivo. PLXNB2 is therefore required for the physiological and pathological functions of ANG and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases.
Subject(s)
Nerve Tissue Proteins/metabolism , Ribonuclease, Pancreatic/metabolism , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Female , Glioblastoma/metabolism , Glioblastoma/pathology , Hematopoietic Stem Cells/metabolism , Heterografts , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Nerve Tissue Proteins/antagonists & inhibitors , Neurogenesis , Ribonuclease, Pancreatic/chemistryABSTRACT
Angiogenin (ANG), the fifth member of the vertebrate-specific ribonuclease (RNase) A superfamily, is a secreted angiogenic ribonuclease strongly up-regulated in human prostate cancers. ANG is translocated to the nucleus in both prostate cancer epithelial cells and endothelial cells to exert its role in prostate cancer progression by mediating tumor angiogenesis, cancer cell survival and proliferation through rRNA biogenesis. ANG-stimulated rRNA is required not only for prostate intraepithelial neoplasia (PIN) formation, but also for androgen-independent growth of prostate cancer cells. Targeting ANG by various antagonists that inhibit its nuclear translocation, function and/or activity has proven to inhibit prostate cancer growth in animal models. Furthermore, the role of ANG in androgen independence has been firmly established, suggesting a strong rationale for therapeutically targeting ANG in the treatment of castration resistant prostate cancer.
