Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

Keywords: biomarkers; exocrine pancreas; ion channels; pancreatic ductal adenocarcinoma; signaling pathways.

Figure 1

Ion channels in exocrine pancreas. Illustration of the structure of acinar and major ductal segments of secretory glands in pancreas. Acinar cells secrete digestive enzymes (orange circles in acini) and an isotonic NaCl rich fluid which transports the enzymes to the ducts. Fluid secretion in acini cells is regulated by a Cl^- secretion process. Cl^- secretion is activated by [Ca²⁺]_i, from a Ca²⁺ influx through SOCs in the basolateral membrane, where Cl^- channels, Ca²⁺ activated Cl^- channels (CaCC) and different types of K⁺ channels are activated to provide the efflux of their respected ions. K⁺ channels also create a driving force by maintaining a negative membrane potential. The negative charge mediated by a high concentration of Cl^- ions results in transport of Na⁺ through tight junctions to the luminal space. NaCl makes the driving force for water to efflux through aquaporins and a cell shrinkage. This cell shrinkage reduces [Ca²⁺]_i, which inhibits Cl^- and K⁺ efflux through their channels and in parallel activates basolateral transporters and pumps to restore both Cl^- and K⁺. The digestive enzymes are transported in the NaCl isotonic fluid to the ducts, which is low in HCO₃^- concentration in the proximal ducts, but this concentration increases through the transport to the distal duct cells. The ductal fluid becomes rich in HCO₃^-, by a two-step process. The first step takes place in the proximal ducts, where Cl^-/HCO₃^- exchangers secretes HCO₃^- and absorb Cl^- and Cl^- channels recycle Cl^-. As in the acinar cells an osmotic reaction happens, where efflux of negative HCO₃^- and Na⁺ drives water flow through aquaporins. This results in high concentration of HCO₃^- (~100 mM), a low concentration of Cl^- (~25 mM) and a high fraction of water in the pancreatic juice. The second step takes place in the distal part of the ducts, where the specific Cl^- channel CFTR changes selectivity to HCO₃^- and function as a HCO₃^- efflux channel to determine the final concentration of the HCO₃^- rich fluid (~140 mM). K⁺ channels may, as in acini, take part in the secretion of K⁺ and regulation of anion transport by maintaining the membrane potential in both the basolateral and luminal membrane. SOCs ensure the influx of Ca²⁺ which takes part in regulation of ion channels through [Ca²⁺]_i as in acini. Activation or inhibition of P2 receptors by Ca²⁺ signaling also regulate anion secretion through K⁺ and Cl^- channels.

Figure 2

Ion channels in pancreatic ductal adenocarcinoma (PDAC). Illustration of ion channels, which have been shown to have a role in hallmarks of cancer, thereby PDAC development and progression. As cancer cells lose their polarity, the localization of the channels is unknown, and on the illustration, it should be considered that the channels have no particular localization. The aberrant expression in PDAC cells, are shown for; Store-operated channels (SOCs) and transient receptor potential (TRP) channels, K⁺ channels, Cl^- channels, aquaporins (AQP), Na⁺ channels and P2X7R. These channels are known to be involved in PDAC development and progression through proliferation, cell cycle progression, differentiation, migration, invasion, metastasis, and apoptosis. The known pathways and mechanism, which have been shown to be involved in these processes are shown in a grey box next to the channel and are mentioned in Table 2. The channels shown to be expressed in PDAC, but where the role is unknown are also shown in Table 2.

Figure 3

Ion channels can function as biomarkers in pancreatic ductal adenocarcinoma (PDAC). Illustration of ion channels, where the expression has been shown to be correlated with clinical factors. Most of the ion channels show a high expression in PDAC, which correlates with clinical factors (indicated in grey boxes). Some ion channels have shown to be to have a low expression in PDAC, which correlates with other clinical factors. The ion channels are grouped as progression and aggressiveness markers, diagnostic markers or therapeutic targets. Among all ion channels, their expression (except CFTR) have been shown to be correlated with a low overall survival.