TY - JOUR
T1 - Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer
AU - Bausch, Dirk
AU - Fritz, Stefan
AU - Bolm, Louisa
AU - Wellner, Ulrich F.
AU - Fernandez-del-Castillo, Carlos
AU - Warshaw, Andrew L.
AU - Thayer, Sarah P.
AU - Liss, Andrew S.
N1 - Funding Information:
S.P. Thayer: National Institutes of Health (NIH) P01 5P01CA117969, 1P50CA127003; D. Bausch, S. Fritz: Karin Grunebaum Cancer Research Foundation; L. Bolm: German Research Foundation, Research Grant.
Publisher Copyright:
© 2020, Springer Nature B.V.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085284414&partnerID=8YFLogxK
U2 - 10.1007/s10456-020-09725-x
DO - 10.1007/s10456-020-09725-x
M3 - Journal articles
C2 - 32444947
AN - SCOPUS:85085284414
SN - 0969-6970
VL - 23
SP - 479
EP - 492
JO - Angiogenesis
JF - Angiogenesis
IS - 3
ER -