Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells.
Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively "glues" cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our results describe a new role for Dex as a suppressor of GBM dispersal and growth.
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Stephen
S
Shannon
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Connan
C
Vaca
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Dongxuan
D
Jia
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Ildiko
I
Entersz
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Andrew
A
Schaer
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Jonathan
J
Carcione
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Michael
M
Weaver
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Yoav
Y
Avidar
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Ryan
R
Pettit
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Mohan
M
Nair
Department of Radiation Oncology, Cancer Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Atif
A
Khan
Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Ramsey A
RA
Foty
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology*; D002449:Cell Aggregation / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D005353:Fibronectins; D039081:Integrin alpha5beta1; D012333:RNA, Messenger; D003907:Dexamethasone