Journal Article

Modulation of invasive properties of human glioblastoma cells stably expressing amino-terminal fragment of urokinase-type plasminogen activator

Dinh, Dzung H, Khawar, Siddique, Mirza, Faiz, Olivero, William C, Mohanam, Sanjeeva, Yanamandra, Niranjan, Rao, Jasti S, Chandrasekar, Nirmala

2002

Overview

The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of tumor cells is involved in the activation of proteolytic cascades responsible for the invasiveness of those cells. The diffuse, extensive infiltration of glioblastomas into the surrounding normal brain tissue is believed to rely on modifications of the proteolysis of extracellular matrix components; blocking the interaction between uPA and uPAR might be a suitable approach for inhibiting glioma tumorigenesis. We assessed how expression of an amino-terminal fragment (ATF) of uPA that contains binding site to uPAR affects the invasiveness of SNB19 human glioblastoma cells. SNB19 cells were transfected with an expression plasmid (pcDNA3-ATF) containing a cDNA sequence of ATF-uPA. The resulting ATF-uPA-expressing clones showed markedly less cell adhesion, spreading, and clonogenicity than did control cells. Endogenous ATF expression also significantly decreased the invasive capacity of transfected glioblastoma cells in Matrigel and spheroid-rat brain cell aggregate models. ATF-uPA transfectants were also markedly less invasive than parental SNB19 cells after injection into the brains of nude mice, suggesting that competitive inhibition of the uPA-uPAR interaction on SNB19 cells by means of transfection with ATF cDNA could be a useful therapeutic strategy for inhibiting tumor progression.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Actins - metabolism / Animal models / Animals / Binding Sites / Biological and medical sciences / Biology / Brain cancer / Brain Neoplasms - enzymology / Brain Neoplasms - pathology / Brain Neoplasms - therapy / Brain tumors / Breast cancer / Cell Adhesion / Cell Aggregation / Cell culture / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Clone Cells - pathology / Collagen / Cytoskeleton - ultrastructure / Development and progression / DNA, Complementary - genetics / Drug Combinations / Extracellular matrix / Fundamental and applied biological sciences. Psychology / Genetic Therapy / Glioblastoma / Glioblastoma - enzymology / Glioblastoma - pathology / Glioblastoma - therapy / Glioblastoma cells / Glioblastoma multiforme / Glioma / Humans / Invasiveness / Laminin / Metastases / Metastasis / Mice / Mice, Nude / Molecular and cellular biology / Neoplasm Invasiveness - physiopathology / Neoplasm Proteins - chemistry / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Peptides / Physiological aspects / Protein Structure, Tertiary / Proteoglycans / Proteolysis / Rats / Receptors, Cell Surface - metabolism / Receptors, Urokinase Plasminogen Activator / Recombinant Fusion Proteins - physiology / Risk factors / Spheroids, Cellular - pathology / Structure-Activity Relationship / Thrombolytic drugs / Transfection / Tumor cells / Tumor Cells, Cultured - pathology / Tumor Stem Cell Assay / Tumorigenesis / U-Plasminogen activator / Urokinase / Urokinase-Type Plasminogen Activator - chemistry / Urokinase-Type Plasminogen Activator - genetics / Urokinase-Type Plasminogen Activator - physiology / Xenograft Model Antitumor Assays