Differential role of Hedgehog signaling in human pancreatic (patho-) physiology: An up to date review

Table 1 Summary of the role of Hedgehog signaling in pancreatitis, indicating the protective role in acute pancreatitis vs disease-progressive function in chronic pancreatitis as well the possible association to pancreatic cancerogenesis[32-38,42,43]

	Acute pancreatitis	Chronic pancreatitis
Pathogenetic effect of Hh	Protective	Progressive
Detected members of Hh	↑Shh (Ihh, Dhh), Gli1	↑Ihh (Shh), Ptc, Hip, SMO, Gli1, Gli2
Interactive cells (auto-and paracrine effects)	Acinar/ductal cells with; acute inflammatory cells	Acinar/ductal cells with; PSC
(Immune) mediators of inflammation	IL-10, IL-6, mIL-8, Mcp-1, and M-csf (Csf1)	MT1-MMP, MMP9, TGF-β1, smooth muscle actin, fibronectin 1, type I collagen
Association to cancerogenesis	No	Yes, possibly via ADM and PanIn

Hh: Hedgehog; Shh: Sonic Hh; Ihh: Indian Hh; Dhh: Desert hedgehog; IL: Interleukin; mIL-8: Murine homolog of IL8; Mcp-1: Monocyte chemoattractant protein-1; M-csf: Macrophage colony-stimulating factor; Ptc: Patched; Hip: Hh-interacting protein; SMO: Smoothened; MT1-MMP: Membrane-type 1 matrix metalloproteinase; MMP-9: Matrix metallopeptidase 9; TGF-β: Transforming growth factor beta; ADM: Acino-ductal metaplasia; PanIn: Pancreatic intraductal neoplasia; PSC: Pancreatic stellate cells.

Table 2 Clinical trials of Hedgehog inhibitors for pancreatic cancer (https://clinicaltrials.gov/)

Drug	Combination	Phase	Status	Trial ID
GDC-0449	Gemcitabine	0	N	NCT01713218
		1/2	A	NCT01195415
		2	A	NCT01064622
	Erlotinib, gemcitabine	1	A	NCT00878163
	Gemcitabine, nab-paclitaxel	2	A	NCT01088815
LDE-225	Gemcitabine, nab-paclitaxel	1/2	R	NCT01431794
		1/2	R	NCT02358161
	BKM120	1	C	NCT01576666
IPI-926	Gemcitabine	1/2	C	NCT01130142

A: Active, not recruiting; C: Completed; N: Not yet recruiting; R: Recruiting.