ABSTRACT
Cells isolated from many types of human cancers express heparin-binding growth factors (HBGFs) that drive tumor growth, metastasis, and angiogenesis. The heparan sulfate proteoglycan glypican-1 (GPC1) is a coreceptor for HBGFs. Here we show that both cancer cell-derived and host-derived GPC1 are crucial for efficient growth, metastasis, and angiogenesis of human and mouse cancer cells. Thus downregulation of GPC1 in the human pancreatic cancer cell line PANC-1, using antisense approaches, resulted in prolonged doubling times and decreased anchorage-independent growth in vitro as well as attenuated tumor growth, angiogenesis, and metastasis when these cells were transplanted into athymic mice. Moreover, athymic mice that lacked GPC1 exhibited decreased tumor angiogenesis and metastasis following intrapancreatic implantation with either PANC-1 or T3M4 human pancreatic cancer cells and fewer pulmonary metastases following intravenous injection of murine B16-F10 melanoma cells. In addition, hepatic endothelial cells isolated from these mice exhibited an attenuated mitogenic response to VEGF-A. These data indicate that cancer cell- and host-derived GPC1 are crucial for full mitogenic, angiogenic, and metastatic potential of cancer cells. Thus targeting GPC1 might provide new avenues for cancer therapy and for the prevention of cancer metastasis.
Subject(s)
Glypicans/metabolism , Lung Neoplasms/metabolism , Melanoma/metabolism , Neovascularization, Pathologic/metabolism , Pancreatic Neoplasms/metabolism , Animals , COS Cells , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Chlorocebus aethiops , Cytokines/genetics , Cytokines/metabolism , Down-Regulation/drug effects , Down-Regulation/genetics , Female , Glypicans/genetics , Lung Neoplasms/genetics , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Melanoma/genetics , Melanoma/pathology , Melanoma/prevention & control , Mice , Mice, Nude , Neoplasm Metastasis , Neoplasm Transplantation , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/prevention & control , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/prevention & control , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-beta1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.
