Connective Tissue Growth Factor and the Parallels Between Brain Injury and Brain Tumors

JNCI | Editorials 1141 Glioblastoma is the most common primary brain tumor, comprising 52% of all primary brain tumors. Despite advances in treatment, glioblastoma remains virtually incurable, with a median survival of approximately 15 months. A chief cause of the high mortality of glioblastoma is the invasive nature of the tumor, which renders full resection of tumor cells practically impossible. Thus, understanding the mechanisms that underlie glioblastoma invasion is crucial for developing new treatment approaches for this devastating disease. In this issue of the Journal, Edwards et al. (1) identify connective tissue growth factor (CTGF) as a secreted factor that stimulates the migration and invasion of glioblastoma cells. They show that CTGF, which is produced at high levels by reactive astrocytes bordering the tumor, binds a complex comprising tyrosine kinase receptor type A (TrkA) and integrin B1 on glioma cells, which leads to the activation of nuclear factor kappa B (NF-kB) signaling. NF-kB signaling activates the zinc finger E-box-binding homeobox 1 (ZEB-1) transcription factor, which transcriptionally represses E-cadherin, thereby enhancing invasion and migration. CTGF is a potent modulator of intercellular signaling and extracellular matrix function. It has chemotactic and mitogenic activity for fibroblasts and other cells. CTGF expression is induced by many growth factors, and CTGF itself binds directly to bone morphogenetic proteins, transforming growth factor B, and vascular endothelial growth factor (VEGF) and modulates their activities. It stimulates the production of extracellular matrix components such as collagen and fibronectin as well as integrins. CTGF also binds integrins and various matrix components, including heparin, fibronectin, and matrix metalloproteinases, and this binding alters the activities of both extracellular matrix components and CTGF itself (2,3). CTGF expression is most frequently linked to pathologies associated with inflammation and fibrosis throughout the body. For example, CTGF expression has been implicated in fibrosis of the kidney, liver, lung, pancreas, and skin; in atherosclerosis; and in inflammatory bowel syndromes. Strikingly, CTGF is overexpressed in many cancers that have a substantial fibrotic component, including pancreatic cancer, breast cancer, and melanoma. CTGF expression is also high in sarcomas and chondrosarcomas, which like fibroblasts are of the mesodermal lineage (3,4). In the brain, elevated CTGF expression has been observed in various cell types, primarily during injury response, inflammation, and reactive gliosis. For example, increased CTGF expression is seen in spinal cord injury, amyotrophic lateral sclerosis, cerebral infarction, brain trauma, and models of excitotoxic brain damage (5,6). Elevated expression of CTGF is well characterized in reactive astrocytes, and CTGF is also expressed in pathological contexts by microglia, fibroblasts, smooth muscle cells, endothelial cells, and neurons (5,7). Not surprisingly, then, altered CTGF expression has been observed in brain tumors as well. Indeed, CTGF is overexpressed in 58% of primary gliomas, and expression is correlated with tumor grade and patient survival independent Connective Tissue Growth Factor and the Parallels Between Brain Injury and Brain Tumors