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Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma

Ex Vivo Cancer Pharmacology Centre of Excellence, Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
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Cells 2019, 8(5), 424; https://doi.org/10.3390/cells8050424
Received: 4 April 2019 / Revised: 5 May 2019 / Accepted: 7 May 2019 / Published: 8 May 2019
(This article belongs to the Special Issue Targeting Hedgehog Signaling in Cancer)
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterised by desmoplasia, thought to support progression and chemotherapeutic resistance. The Hedgehog pathway is known to play an important role in this cancer. While the upregulation of Sonic hedgehog (Shh) in the epithelium of PDAC is known, we investigated its expression in the tumour microenvironment in order to find new targets for new chemotherapeutical approaches. Immunohistochemistry was used for the investigation of Shh and Vimentin in primary human pancreatic tissues. Gene (qRT-PCR) and protein (immunofluorescence) expression of Shh, αSMA (a marker of the mesenchymal phenotype) and periostin (a marker of mesenchymal cells within a mixed population) were investigated in in vitro cell models. Shh expression was significantly upregulated in the stromal and epithelial compartments of poorly-differentiated PDAC samples, with a strong correlation with the amount of stroma present. Characterisation of stromal cells showed that there was expression of Shh ligand in a mixed population comprising αSMA+ myofibroblasts and αSMA mesenchymal stem cells. Moreover, we demonstrated the interaction between these cell lines by showing a higher rate of mesenchymal cell proliferation and the upregulation of periostin. Therefore, targeting stromal Shh could affect the equilibrium of the tumour microenvironment and its contribution to tumour growth. View Full-Text
Keywords: pancreatic ductal adenocarcinoma (PDAC); sonic hedgehog (Shh); tumour microenvironment pancreatic ductal adenocarcinoma (PDAC); sonic hedgehog (Shh); tumour microenvironment
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Saini, F.; Argent, R.H.; Grabowska, A.M. Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma. Cells 2019, 8, 424.

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