Epithelial to Stromal Re-Distribution of Primary Cilia during Pancreatic Carcinogenesis

Abstract

BackgroundThe Hedgehog (HH) pathway is a mediator in pancreatic ductal adenocarcinoma (PDAC). Surprisingly, previous studies suggested that primary cilia (PC), the essential organelles for HH signal transduction, were lost in PDAC. The aim of this study was to determine the presence of PC in human normal pancreas, chronic pancreatitis, and during carcinogenesis to PDAC with focus on both epithelia and stroma.MethodsPC were analyzed in paraffin sections from normal pancreas, chronic pancreatitis, intraductal papillary-mucinous neoplasia, and PDAC, as well as in primary human pancreatic stellate cells (PSC) and pancreatic cancer cell lines by double immunofluorescence staining for acetylated α-tubuline and γ-tubuline. Co-staining for the HH receptors PTCH1, PTCH2 and SMO was also performed.ResultsPC are gradually lost during pancreatic carcinogenesis in the epithelium: the fraction of cells with PC gradually and significantly decreased from 32% in ducts of normal pancreas, to 21% in ducts of chronic pancreatitis, to 18% in PanIN1a, 6% in PanIN2, 3% in PanIN3 and to 1.2% in invasive PDAC. However, this loss of PC in the neoplastic epithelium is accompanied by a gain of PC in the surrounding stroma. The fraction of stromal cells with PC significantly increased from 13% around normal ducts to about 30% around PanIN and PDAC. HH-receptors were detected in tumor stroma but not in epithelial cells. PC are also present in PSC and pancreatic cancer cell lines.ConclusionPC are not lost during pancreatic carcinogenesis but re-distributed from the epithelium to the stroma. This redistribution may explain the re-direction of HH signaling towards the stroma during pancreatic carcinogenesis.

CEP164 Deficiency Causes Hyperproliferation of Pancreatic Cancer Cells

“…Based on our data and the results of a previous study (Deng et al, 2018), primary cilia appear to be suppressors of PDAC proliferation. This notion is supported by the fact that PDAC cells gradually lose primary cilia over time (Schimmack et al, 2016;Deng et al, 2018). Conversely, a clinical report showed that the presence of primary cilia correlates with poor prognosis of PDAC patients (Emoto et al, 2014), suggesting the possibility of a promotive role of primary cilia.…”

Ciliary signalling in cancer

“…As another example, in the pancreas , cancer formation commonly goes through set stages in which ductal acini typically convert through pancreatic intraepithelial neoplasia precursor stages (PanIN stages 1–3) to overt pancreatic ductal adenocarcinomas (PDACs). Although normal pancreatic ductal epithelia, islet cells, and centroacinar cells, are highly ciliated, cilia are sharply reduced during formation of PDACs, from the earliest precursor stages 60 , and in cases of the pre-neoplastic condition of pancreatitis 61 . Human PDACs have high levels of intratumoural heterogeneity, with some cancer cells more differentiated and some less so; a study of clinical outcomes showed that residual ciliation of cancer cells segregated to the well-differentiated areas (Figure 4A), and a higher level of cancer cell ciliation was prognostic of improved overall survival 62 .…”

Role of primary cilium in pancreatic ductal adenocarcinoma (Review)

“…Instead, it was more recently demonstrated that primary cilia in the epithelium are gradually lost during pancreatic carcinogenesis, and this loss is accompanied by gain of primary cilia in the surrounding stroma (Table I). Moreover, the BxPc3, Capan1, MiaPaCa2, and PANC-1 PDAC cell lines do not lose primary cilia under conditions of nutrient or oxygen deprivation (27). At the molecular level, these studies demonstrated that, by inhibiting the downstream effectors of the K-Ras pathway, mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K), ciliogenesis was fully restored, suggesting that K-Ras may be involved in the regulation of ciliogenesis in PDAC (15,28).…”