Research Highlights

Cancer cell signaling: Glypican-1 gathers growth factors

Schematic structure of the three major classes of heparan sulfate proteoglycans. Click here for a larger picture.

Glypicans and syndecans are the main carriers of the glucosaminoglycan heparan sulfate on the mammalian cell surface, and as such they regulate interactions between heparin-binding growth factors (HBGFs) and their receptors. Glypican-1 (GPC1) is overexpressed in pancreatic cancer, both in tumor cells as well as in the cellular microenvironment. In the Journal of Clinical Investigation, Aikawa et al. now describe the consequences of GPC1 suppression for tumor angiogenesis and metastasis.

The authors transfected pancreatic cancer cells (PANC1) with antisense RNA to generate two cell clones (GAS6 and 7) that express less GPC1 than wild-type PANC1 cells. GAS6 and 7 cells exhibited slower doubling and formed fewer colonies than PANC1 cells in soft-agar assays. Furthermore, PANC1 cells treated with the HBGF fibroblast growth factor-2 (FGF-2) developed more colonies than FGF-2-treated GAS cells, suggesting that increased colony formation was connected to GPC1-mediated HBGF signaling.

The authors then examined the effect of GPC1 reduction on mitogenic and angiogenic signaling pathways. Phosphorylated ERK1/2 (extracellular signal-regulated kinases 1 and 2) levels were markedly diminished in GAS-derived tumors, consistent with the hypothesis that MAPKs (mitogen-activated protein kinases) are intracellular transducers of HBGF signals. This finding also suggests that in vivo levels of non-HBGFs, such as the epidermal growth factor (EGF), may be insufficient to sustain normal MAPK signaling in the absence of GPC1.

Pro-angiogenic signaling molecules, such as the Tie-2 receptor, its ligands Ang-1 and -2 (angiopoietin-1 and -2), and their upregulator VEGF-A (vascular endothelial growth factor-A), were strongly reduced in the GAS-derived tumors when compared to PANC1-derived tumors. Aikawa et al. hypothesize that GPC1 ablation in GAS cells diminishes angiopoietin and VEGF-A secretion. The reduced presence of GPC1 in cancer cells attenuates their metastatic potential and the reduction in shed GPC1 may directly downregulate angiogenesis initiated by the tumor environment. Moreover, endothelial cells and fibroblasts in the tumor microenvironment appear also to express GPC1. This may support tumor growth and angiogenesis as PANC1 cells transplanted into GPC1^-/- mice caused fewer tumors and metastasized less efficiently, and endothelial cells from GPC1^-/- mice exhibited decreased proliferation upon exposure to VEGF-A compared to wild-type endothelial cells.

Taken together, these results demonstrate that GPC1 governs the metastatic development of pancreatic cancer by enhancing pro-mitogenic and pro-angiogenic signaling via the MAPK and VEGF-Angiopoietin-Tie2 pathways. Using GPC1 as a paradigmatic molecule, these data also emphasize the role of the tumor environment in pancreatic cancer.

Author: Mirko von Elstermann