Connective tissue growth factor associated with oncogenic activities and drug resistance in glioblastoma multiforme

Connective tissue growth factor (CTGF or CCN2) is a secreted protein that belongs to the CCN [cysteine-rich CYR61/connective tissue growth factor/nephroblastoma overexpressed gene] family. These proteins have been implicated in various biological processes, including stimulation of cell proliferation, migration, angiogenesis and tumorigenesis. In a previous study, we found that CTGF mRNA was elevated in primary gliomas and a significant correlation existed between CTGF mRNA levels versus tumor grade, histology, and patient survival. In the present study, the role of CTGF in glioma tumorigenesis was explored. Forced expression of CTGF in glioblastoma multiforme (GBM) cells accelerated their growth in liquid culture and soft agar, stimulated cells migration in Boyden chamber assays and significantly increased their ability to form large, vascularized tumors in nude mice. CTGF induced the expression of the anti-apoptotic proteins, Bcl-xl, Survivin, and Flip. Over-expression of CTGF caused the U343 GBM cells to survive for longer than 40 days in serum-free medium and resist anti-tumor drugs including tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), VELCADE (Bortezomib, Proteasome Inhibitor), and Temozolomide. Our data suggest that CTGF plays an important role in glioma progression, by supporting tumor cells survival and drug resistance.