ABSTRACT
Glioma is a devastating cancer with a dismal prognosis and there is an urgent need to discover novel glioma-specific antigens for glioma therapy. Previous studies have identified CD163-positive tumour cells in certain solid tumours, but CD163 expression in glioma remains unknown. In this study, via an analysis of public datasets, we demonstrated that CD163 overexpression in glioma specimens correlated with an unfavourable patient prognosis. CD163 expression was increased in glioma cells, especially primary glioma cells. The loss of CD163 expression inhibited both cell cycle progression and the proliferation of glioblastoma multiforme (GBM) cell lines and primary glioma cells. CD163 interacted directly with casein kinase 2 (CK2) and CD163 silencing reduced AKT/GSK3ß/ß-catenin/cyclin D1 pathway activity via CK2. Moreover, CD163 was upregulated in CD133-positive glioma stem cells (GSCs), and CD163 downregulation decreased the expression of GSC markers, including CD133, ALDH1A1, NANOG and OCT4. The knockdown of CD163 impaired GSC stemness by inhibiting the CK2/AKT/GSK3ß/ß-catenin pathway. Finally, a CD163 antibody successfully induced complement-dependent cytotoxicity against glioma cells. Our findings indicate that CD163 contributes to gliomagenesis via CK2 and provides preclinical evidence that CD163 and the CD163 pathway might serve as a therapeutic target for glioma.
Subject(s)
Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Casein Kinase II/genetics , Glioblastoma/genetics , Molecular Targeted Therapy , Receptors, Cell Surface/genetics , Animals , Antigens, CD/therapeutic use , Antigens, Differentiation, Myelomonocytic/therapeutic use , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glioblastoma/pathology , Glycogen Synthase Kinase 3 beta/genetics , Humans , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Prognosis , Receptors, Cell Surface/therapeutic use , Signal Transduction , beta Catenin/geneticsABSTRACT
MAb have become an important treatment modality in cancer therapy.Genetically engineered chimeric and humanized Ab have demonstrated activity against a variety of tumors. While the humanized anti-CD33MAb lintuzumab has only modest single-agent activity against overt AML, it can eliminate minimal residual disease detectable by reverse transcription-PCR in acute promyelocytic leukemia. Targeted chemotherapy with the anti−CD33−calicheamicin construct gemtuzumab ozogamicin has produced remissions in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, CD/therapeutic use , Antigens, Differentiation, Myelomonocytic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/therapy , Aminoglycosides/administration & dosage , Aminoglycosides/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, CD/administration & dosage , Antigens, Differentiation, Myelomonocytic/administration & dosage , Gemtuzumab , Humans , Immunotherapy/methods , Leukemia, Myeloid, Acute/immunology , Sialic Acid Binding Ig-like Lectin 3Subject(s)
Aminoglycosides , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Immunotoxins/therapeutic use , Leukemia, Myeloid/therapy , Antibodies, Monoclonal, Humanized , Antigens, CD/immunology , Antigens, CD/therapeutic use , Antigens, Differentiation, Myelomonocytic/immunology , Antigens, Differentiation, Myelomonocytic/therapeutic use , Gemtuzumab , Humans , Immunotoxins/administration & dosage , Sialic Acid Binding Ig-like Lectin 3 , United States , United States Food and Drug AdministrationABSTRACT
Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to bacterial LPS/endotoxin. Activation of monocytes and neutrophils by the binding of LPS to the membrane receptor, CD14, plays a key role in this response. Furthermore, a soluble form of the CD14 receptor enhances the endothelial cell response to LPS. We show here that despite the agonist effects of soluble CD14 on the endothelial cell response to LPS, recombinant soluble CD14 is able to protect mice from LPS-induced lethality. This protection appears to be associated with the inhibition of TNF-alpha release. These results suggest that the soluble CD14 receptor may represent a new form of therapy for endotoxic shock in humans.
