Abstract 2811: GPC1 promotes tumor growth and angiogenesis in a KrasG12D- Driven mouse model of pancreatic cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy that is highly therapy-resistant and is the fourth leading cause of cancer-related deaths. The poor prognosis is due, in part, to late diagnosis in conjunction with a high frequency of activating Kras mutations, a loss of the tumor suppressor genes p16INK4A/p14ARF, as well as an over-abundance of heparin-binding growth factors (HBGFs) and their co-receptors. Glypican-1 (GPC1), a co-receptor required for efficient signaling by heparin-binding growth factors, is overexpressed in PDAC and plays a critical role in cell growth, metastasis, and angiogenesis of human and mouse cancer cells. While it is known that the loss of GPC1 results in decreased tumor growth and metastasis in orthotopic mouse models, GPC1's role in pancreatic tumor initiation, development, and progression is unknown. Accordingly, we generated a GPC1 null mouse that combines pancreas-specific Cre-mediated activation of oncogenic Kras (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. Loss of GPC1 resulted in attenuated pancreatic tumor growth and invasiveness, as well as decreased angiogenesis, cancer cell proliferation, and mitogen activated protein kinase (MAPK) activation. These differences were first observed in 30 day old mice and were still highly significant in 65 day old mice. Moreover, pancreatic cancer cells isolated from the tumors of GPC1 null mice were not as invasive in response to fibroblast growth factor 2 (FGF2) as cancer cells isolated from wild-type mice. These data demonstrate in a genetic mouse model of PDAC that GPC1 does not contribute to pancreatic cancer initiation, but that even in the presence of two highly prevalent molecular alterations (oncogenic Kras and loss of p16) endogenous GPC1 contributes to PDAC progression by facilitating tumor growth, angiogenesis, and invasion. Our findings support the concept that GPC1 may be a therapeutic target in PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2011-2811