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HERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

ABSTRACT: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking.hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (?-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled ?-hERG1-MoAb.(i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the ?-hERG1-MoAb could detect PDAC in vivo.hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.

SUBMITTER: Lastraioli E

PROVIDER: S-EPMC4366888 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

Lastraioli E E Perrone G G Sette A A Fiore A A Crociani O O Manoli S S D'Amico M M Masselli M M Iorio J J Callea M M Borzomati D D Nappo G G Bartolozzi F F Santini D D Bencini L L Farsi M M Boni L L Di Costanzo F F Schwab A A Onetti Muda A A Coppola R R Arcangeli A A

British journal of cancer 20150317 6

<h4>Background</h4>hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking.<h4>Methods</h4>hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC prog ...[more]

PMID: 25719829

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Project description:Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

Dataset Information

HERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

Publications

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

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