The Role of Tumor Cell–Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

Abstract

Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/ CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. [Cancer Res 2009;69(3):775-84]

Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma

“…CTGF has been reported recently to have tumorpromoting activities (23)(24)(25)(26). In this study, using a more specific Ctgf antibody, we found again strong Ctgf staining at the tumorstromal border ( Figure 5A).…”

PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

“…Increased level of the epidermal growth factor receptor 1 and its ligands, epidermal growth factor and transforming growth factor-a, activates the MEK/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase/AKT and signal transducers and activators of transcription signaling pathways to promote survival and progression (Korc et al, 1992;Marshall, 2006). Transforming growth factor-b is upregulated (Friess et al, 1993) and induces the expression of connective tissue growth factor, a metastasis factor known to interact with integrin receptors (Grotendorst et al, 1996;Gao and Brigstock, 2005;Bennewith et al, 2009). In another study, overexpression of neutrophil gelatinaseassociated lipocalin reduces tumor volume and distant metastasis by blocking cell adhesion and invasion (Tong et al, 2008).…”

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…CTGF is a pleiotropic and cysteine-rich matricellular protein that is abundant in many solid malignancies including pancreas, breast, esophageal, glioblastoma, and hepatocellular carcinoma (18)(19)(20)(21)(22)(23). CTGF is expressed in both stromal (23,24) and neoplastic cells (25,26) of the pancreas, and participates in a variety of signaling pathways that influence pancreatic stellate cell (PSC)-mediated fibrogenesis in pancreatitis and pancreatic cancer. Upon activation of profibrogenic molecules such as TGF-β, CTGF is synthesized and regulates integrin α5β1-dependent adhesion, migration, and collagen I synthesis in PSCs (27,28).…”