Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.586599
Keywords
pancreatic ductal adenocarcinoma; ion channels; therapy; immune cells; fibrosis
Categories
Funding
- Marie Sklodowska-Curie Innovative Training Network (ITN) [813834]
- Deutsche Forschungsgemeinschaft (DFG) [SCHW 407/17-1, SCHW 407/22-1, GRK 2515/1]
- IZKF Munster [Schw2/020/18]
- National Research, Development, and Innovation Office, Hungary [OTKA K119417]
- Ministry of Human Capacities, Hungary [EFOP-3.6.2-16-2017-00006]
- Ministry of Finance, Hungary [GINOP-2.3.2-15-2016-00015]
- European Union
- European Regional Development Fund
- AIRC [IG 15627, IG 21510]
- PRIN Italian Ministry of University and Research (MIUR) Leveraging basic knowledge of ion channel network in cancer for innovative therapeutic strategies (LIONESS) [20174TB8KW]
- Marie Curie Actions (MSCA) [813834] Funding Source: Marie Curie Actions (MSCA)
Ask authors/readers for more resources
Ion channels play a critical role in the development of pancreatic ductal adenocarcinoma, by sensing and modifying the tumor microenvironment to promote cancer progression. However, the underlying mechanisms are still unclear.
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, K(Ca)3.1, 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 channeltargeting 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available