Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells

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.

Comparison of Fixation Methods for Preservation of Morphology, RNAs, and Proteins From Paraffin-Embedded Human Cancer Cell-Implanted Mouse Models

“…Recently, this method has been reported as a definitive examination to identify tumor stem cells in various kinds of tumors. It is controversial which fixation is best for analysis; therefore, researchers usually use various fixations (Aikawa et al 2008;Arumugam et al 2005;Sasaki et al 2008). The present study indicated that it is important to select proper fixations and fixation methods for assessment of expression levels of proteins and RNAs.…”

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

“…There are six members of the GPC family. GPC1 is involved in tumorigenesis and angiogenesis, and is frequently overexpressed in different human malignancies including pancreatic carcinoma, breast cancer and glioma (Aikawa et al, 2008;Kleeff et al, 1998;Kleeff et al, 1999;Matsuda et al, 2001;Su et al, 2006). GPC1 has been proposed to act as a co-receptor for FGF that enhances the binding of FGF to its receptor, subsequently promoting FGF-FGFR activation and signaling (Zhang et al, 2001).…”

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

“…Similarly, nerve growth factors from stromal nerve fibers bind and activate their receptors on cancer cells to promote proliferation and invasion of the cells along the neural tissue (Okada et al, 2004). Both the cancer cell-derived and the stromal cell-derived glypican-1, a co-receptor for heparin-binding growth factors, are found to be important for efficient angiogenesis and metastasis of the cancer (Aikawa et al, 2008).…”