Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer

Dirk Bausch, Stefan Fritz, Louisa Bolm, Ulrich F. Wellner, Carlos Fernandez-del-Castillo, Andrew L. Warshaw, Sarah P. Thayer, Andrew S. Liss

Research output: Contribution to journalArticle

Abstract

Introduction: The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis. Methods: Mice bearing three different xenografted human PDAC (n = 5/group) were treated with neutralizing antibodies to SHH. After treatment for 7 days, tumors were evaluated and the expression of 38 pro- and antiangiogenic factors was assessed in the tumor cells and their stroma. The effect of SHH on the regulation of pro- and antiangiogenic factors in fibroblasts and its impact on endothelial cells was then further assessed in in vitro model systems. Results: Inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment of the three cancers. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF. Conclusion: Inhibition of Hh signaling reduces tumor vascularity, suggesting that Hh plays a role in the maintenance or formation of the tumor vasculature. Whether the reduction in tumor growth and viability seen in the epithelium is a direct consequence of Hh pathway inhibition, or indirectly caused by its effect on the stroma and vasculature, remains to be evaluated.

Original languageEnglish (US)
Pages (from-to)479-492
Number of pages14
JournalAngiogenesis
Volume23
Issue number3
DOIs
StatePublished - Aug 1 2020

Keywords

  • Angiogenesis
  • Pancreatic ductal adenocarcinoma
  • SHH
  • TIMP1
  • Thrombospondin 2

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Fingerprint Dive into the research topics of 'Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer'. Together they form a unique fingerprint.

  • Cite this

    Bausch, D., Fritz, S., Bolm, L., Wellner, U. F., Fernandez-del-Castillo, C., Warshaw, A. L., Thayer, S. P., & Liss, A. S. (2020). Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer. Angiogenesis, 23(3), 479-492. https://doi.org/10.1007/s10456-020-09725-x