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A KrasG12D-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis

Abstract

Pancreatic ductal adenocarcinomas (PDACs) exhibit multiple molecular alterations and overexpress heparin-binding growth factors (HBGFs) and glypican-1 (GPC1), a heparan sulfate proteoglycan that promotes efficient signaling by HBGFs. It is not known, however, whether GPC1 has a role in genetic mouse models of PDAC. Therefore, we generated a GPC1 null mouse that combines pancreas-specific Cre-mediated activation of oncogenic Kras (KrasG12D) with deletion of a conditional INK4A/Arf allele (Pdx1-Cre;LSL-KrasG12D;INK4A/Arflox/lox;GPC1−/− mice). By comparison with Pdx1-Cre;LSL-KrasG12D;INK4A/Arflox/lox mice that were wild type for GPC1, the Pdx1-Cre;LSL-KrasG12D;INK4A/Arflox/lox;GPC1−/− mice exhibited attenuated pancreatic tumor growth and invasiveness, decreased cancer cell proliferation and mitogen-activated protein kinase activation. These mice also exhibited suppressed angiogenesis in conjunction with decreased expression of messenger RNAs encoding several pro-angiogenic factors and molecules, including vascular endothelial growth factor-A (VEGF-A), SRY-box containing gene (SOX17), chemokine C-X3-C motif ligand 1 (CX3CL1) and integrin β3 (ITGB3). Moreover, pancreatic cancer cells isolated from the tumors of GPC1−/− mice were not as invasive in response to fibroblast growth factor-2 (FGF-2) as cancer cells isolated from wild-type mice, and formed smaller tumors that exhibited an attenuated metastatic potential. Similarly, VEGF-A and FGF-2 did not enhance the migration of hepatic endothelial cells and immortalized murine embryonic fibroblasts isolated from GPC1 null mice. These data demonstrate in an oncogenic Kras-driven genetic mouse model of PDAC that tumor growth, angiogenesis and invasion are enhanced by GPC1, and suggest that suppression of GPC1 may be an important component of therapeutic strategies in PDAC.

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Acknowledgements

We thank Dr Daniel Longnecker (Dartmouth Medical School) for his expert assistance in the evaluation of pancreatic tumor pathology. This work was supported by two US Public Health Service Grant (CA-R37-075059) awarded to MK. CAW was supported by a Ruth L Kirschstein National Research Service Award, F32 CA-144579 from the National Cancer Institute.

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Correspondence to M Korc.

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Whipple, C., Young, A. & Korc, M. A KrasG12D-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis. Oncogene 31, 2535–2544 (2012). https://doi.org/10.1038/onc.2011.430

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Keywords

  • pancreatic cancer
  • glypican-1
  • proliferation
  • angiogenesis
  • tumor microenvironment

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