Ion channels in control of pancreatic stellate cell migration

Abstract

Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of KCa3.1 channels in PSCs. KCa3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of KCa3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of KCa3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2+ concentration ([Ca2+]i). KCa3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca2+]i and calpain activity. KCa3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of KCa3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology.

Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology

“…Since then it has been shown that PSCs possess Ca 2+ ‐activated K + channels (Storck et al . ) and it is therefore likely that initial Ca 2+ release from intracellular stores would activate such channels, promoting store‐operated Ca 2+ entry due to the more favourable electrochemical gradient provided by the hyperpolarized plasma membrane. Inhibition of excessive Ca 2+ signal generation in PACs and PSCs by partial blockade of CRAC channels is a promising therapeutic avenue in many inflammatory diseases (Parekh, ; Di Capite et al .…”

“…We have previously shown that CRAC channel inhibition markedly reduces the prolonged [Ca 2+ ] i elevation due to the store-operated Ca 2+ entry into the PSCs that follows the initial BK-elicited intracellular Ca 2+ release ). Since then it has been shown that PSCs possess Ca 2+ -activated K + channels (Storck et al 2017) and it is therefore likely that initial Ca 2+ release from intracellular stores would activate such channels, promoting store-operated Ca 2+ entry due to the more favourable electrochemical gradient provided by the hyperpolarized plasma membrane. Inhibition of excessive Ca 2+ signal generation in PACs and PSCs by partial blockade of CRAC channels is a promising therapeutic avenue in many inflammatory diseases (Parekh, 2010;Di Capite et al 2011) including AP (Gerasimenko et al 2013(Gerasimenko et al , 2014Wen et al 2015).…”

“…; Storck et al . ). The role of these cells in normal physiology is unclear, but they have long been suspected of contributing to the fibrosis occurring in chronic pancreatitis as well as pancreatic cancer (Ferdek & Jakubowska, ; Pang et al .…”

“…More recently, Ca 2+ signalling and ion channels have been studied in pancreatic stellate cells (PSCs) (Fels et al 2016;Ferdek et al 2016;Gryshchenko et al 2016;Nielsen et al 2017;Storck et al 2017). The role of these cells in normal physiology is unclear, but they have long been suspected of contributing to the fibrosis occurring in chronic pancreatitis as well as pancreatic cancer (Ferdek & Jakubowska, 2017;Pang et al 2017).…”

The voltage-gated proton channel hHv1 is functionally expressed in human chorion-derived mesenchymal stem cells

“…Moreover, MSCs migrated into the tumor negatively modulate anti-cancer immunity via their interaction with immune cells [87][88][89] . Ion transporters and channels in the plasma membrane participate in the regulation of cell motility [90][91][92][93][94] . There is also evidence for the contribution of hHv1 to cell migration, e.g.…”