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Cell volume regulation in epithelial physiology and cancer.

Pedersen SF, Hoffmann EK, Novak I - Front Physiol (2013)

Bottom Line: The physiological function of epithelia is transport of ions, nutrients, and fluid either in secretory or absorptive direction.In healthy epithelia, specific ion channels/transporters localize to the luminal and basolateral membranes, contributing to functional epithelial polarity.Furthermore, epithelial architecture and coordinated ion transport function are lost, cell survival/death balance is altered, and new interactions with the stroma arise, all contributing to drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
The physiological function of epithelia is transport of ions, nutrients, and fluid either in secretory or absorptive direction. All of these processes are closely related to cell volume changes, which are thus an integrated part of epithelial function. Transepithelial transport and cell volume regulation both rely on the spatially and temporally coordinated function of ion channels and transporters. In healthy epithelia, specific ion channels/transporters localize to the luminal and basolateral membranes, contributing to functional epithelial polarity. In pathophysiological processes such as cancer, transepithelial and cell volume regulatory ion transport are dys-regulated. Furthermore, epithelial architecture and coordinated ion transport function are lost, cell survival/death balance is altered, and new interactions with the stroma arise, all contributing to drug resistance. Since altered expression of ion transporters and channels is now recognized as one of the hallmarks of cancer, it is timely to consider this especially for epithelia. Epithelial cells are highly proliferative and epithelial cancers, carcinomas, account for about 90% of all cancers. In this review we will focus on ion transporters and channels with key physiological functions in epithelia and known roles in the development of cancer in these tissues. Their roles in cell survival, cell cycle progression, and development of drug resistance in epithelial cancers will be discussed.

No MeSH data available.


Related in: MedlinePlus

The development of epithelial cancer and roles of ion transport and cell volume. (A) Normal secreting epithelium showing net movements of ions and fluid across the basolateral and luminal membranes. Black arrows show the movement of ions and fluid across cell membranes. The insert shows the detailed model of a cell with basic ion channels and transporters that operate, for example, in pancreatic ducts, but are also applicable to other secreting epithelia. The luminal Cl− channels include CFTR and TMEM16A/ANO1, as well as a SLC26 family Cl−/HCO−3 exchanger. The basolateral membrane contains the Na+/K+/2Cl− transporter NKCC1, SLC7 family Na+-HCO−3 cotransporters (NBCs), and the Na+/H+ exchanger NHE1. The epithelium also expresses H+/K+ pumps, as well as several types of K+ channels such as IK-KCa3.1, BK-KCa1.1, KCNQ1 and voltage-activated K+ channels, some of which may be expressed on both luminal and basolateral membranes. The major Ca2+ and cAMP signalling pathways are not elaborated and for simplicity, Ca2+ -channels/transporters and aquaporins are not included. (B) Carcinogenesis and postulated dysregulation of cells volume and secretion. Increased activity of fibroblastic cells, such as cancer associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) (green). (C) The epithelial-to-mesenchymal (EMT) transition showing cells that loose apico-basal polarity and the appearance of some ion transporters from the lumimal membrane in the rear of the cells and some from the basolateral membrane in the leading edge, contributing to driving cell migration. (D) Progression to cancer, showing tumor with extensive fibrosis (gray), fibrogenic cells (green) and immune cells (blue). (Blood vessels are not shown). In the center of the tumor cells may die, while surrounding cells are proliferating and cell volume and corresponding ion transport is up-regulated (see the text).
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Figure 1: The development of epithelial cancer and roles of ion transport and cell volume. (A) Normal secreting epithelium showing net movements of ions and fluid across the basolateral and luminal membranes. Black arrows show the movement of ions and fluid across cell membranes. The insert shows the detailed model of a cell with basic ion channels and transporters that operate, for example, in pancreatic ducts, but are also applicable to other secreting epithelia. The luminal Cl− channels include CFTR and TMEM16A/ANO1, as well as a SLC26 family Cl−/HCO−3 exchanger. The basolateral membrane contains the Na+/K+/2Cl− transporter NKCC1, SLC7 family Na+-HCO−3 cotransporters (NBCs), and the Na+/H+ exchanger NHE1. The epithelium also expresses H+/K+ pumps, as well as several types of K+ channels such as IK-KCa3.1, BK-KCa1.1, KCNQ1 and voltage-activated K+ channels, some of which may be expressed on both luminal and basolateral membranes. The major Ca2+ and cAMP signalling pathways are not elaborated and for simplicity, Ca2+ -channels/transporters and aquaporins are not included. (B) Carcinogenesis and postulated dysregulation of cells volume and secretion. Increased activity of fibroblastic cells, such as cancer associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) (green). (C) The epithelial-to-mesenchymal (EMT) transition showing cells that loose apico-basal polarity and the appearance of some ion transporters from the lumimal membrane in the rear of the cells and some from the basolateral membrane in the leading edge, contributing to driving cell migration. (D) Progression to cancer, showing tumor with extensive fibrosis (gray), fibrogenic cells (green) and immune cells (blue). (Blood vessels are not shown). In the center of the tumor cells may die, while surrounding cells are proliferating and cell volume and corresponding ion transport is up-regulated (see the text).

Mentions: Here, we will focus on secretory epithelia such as pancreas, salivary glands, colorectum, stomach, mammary glands, and prostate, which, as will be discussed below, might not fully regulate their cell volume during stimulated secretion. Notably, several of these epithelia are among the tissues in the body that are most commonly afflicted by cancer (Siegel et al., 2013). One of the most common mechanisms for initiating fluid secretion by agonists or hormones is opening of luminal Cl− channels and luminal and basolateral K+ channels, and this also leads to a cell volume decrease. A number of transport mechanisms on the basolateral membrane are activated to provide ions for luminal exit and thus secretion, and this will potentially lead to regain of cell volume. Concurrently, the cells need to regulate their intracellular pH (pHi), and for cells exhibiting net secretion of H+ or HCO−3 (stomach, pancreatic ducts), this is a particular challenge. Figure 1A shows the basic model for ion transport across secretory cells such as pancreatic duct cell. As seen, this model includes a toolbox of ion channels and transporters (Novak et al., 2011; Frizzell and Hanrahan, 2012; Wilschanski and Novak, 2013), some of which are dys-regulated in cancer, as will be described below. The ion channels include: the cystic fibrosis transmembrane conductace regulator (CFTR) and Ca2+-activated Cl− channels (ANO1/TMEM16A), intermediate and large conductance K+ channels (IK—KCa3.1; BK—KCa1.1), volume sensitive KCNQ1 channels, and possibly voltage-regulated channels (HERG—Kv11.1; EAG2—Kv10.2) (Hayashi et al., 2012; Wang et al., 2013). The ion transporters include Na+-K+-2Cl− cotransporters (NKCC1), Na+/H+ exchangers (NHEs), Cl−/HCO−3 exchangers (SLC26A3,6 and SCL4A family), Na+-HCO−3 transporters (NBCs) and H+/K+-pumps. Another mechanism of achieving secretion, which is beyond the scope of this review, is that driven at least in part by exocytosis, such as in mammary epithelial cells secreting milk, or, for example, parietal cell secreting hydrochloric acid following exocytotic recruitment of the H+/K+ pump from tubulovesicles to the apical membrane (Forte and Zhu, 2010).


Cell volume regulation in epithelial physiology and cancer.

Pedersen SF, Hoffmann EK, Novak I - Front Physiol (2013)

The development of epithelial cancer and roles of ion transport and cell volume. (A) Normal secreting epithelium showing net movements of ions and fluid across the basolateral and luminal membranes. Black arrows show the movement of ions and fluid across cell membranes. The insert shows the detailed model of a cell with basic ion channels and transporters that operate, for example, in pancreatic ducts, but are also applicable to other secreting epithelia. The luminal Cl− channels include CFTR and TMEM16A/ANO1, as well as a SLC26 family Cl−/HCO−3 exchanger. The basolateral membrane contains the Na+/K+/2Cl− transporter NKCC1, SLC7 family Na+-HCO−3 cotransporters (NBCs), and the Na+/H+ exchanger NHE1. The epithelium also expresses H+/K+ pumps, as well as several types of K+ channels such as IK-KCa3.1, BK-KCa1.1, KCNQ1 and voltage-activated K+ channels, some of which may be expressed on both luminal and basolateral membranes. The major Ca2+ and cAMP signalling pathways are not elaborated and for simplicity, Ca2+ -channels/transporters and aquaporins are not included. (B) Carcinogenesis and postulated dysregulation of cells volume and secretion. Increased activity of fibroblastic cells, such as cancer associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) (green). (C) The epithelial-to-mesenchymal (EMT) transition showing cells that loose apico-basal polarity and the appearance of some ion transporters from the lumimal membrane in the rear of the cells and some from the basolateral membrane in the leading edge, contributing to driving cell migration. (D) Progression to cancer, showing tumor with extensive fibrosis (gray), fibrogenic cells (green) and immune cells (blue). (Blood vessels are not shown). In the center of the tumor cells may die, while surrounding cells are proliferating and cell volume and corresponding ion transport is up-regulated (see the text).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757443&req=5

Figure 1: The development of epithelial cancer and roles of ion transport and cell volume. (A) Normal secreting epithelium showing net movements of ions and fluid across the basolateral and luminal membranes. Black arrows show the movement of ions and fluid across cell membranes. The insert shows the detailed model of a cell with basic ion channels and transporters that operate, for example, in pancreatic ducts, but are also applicable to other secreting epithelia. The luminal Cl− channels include CFTR and TMEM16A/ANO1, as well as a SLC26 family Cl−/HCO−3 exchanger. The basolateral membrane contains the Na+/K+/2Cl− transporter NKCC1, SLC7 family Na+-HCO−3 cotransporters (NBCs), and the Na+/H+ exchanger NHE1. The epithelium also expresses H+/K+ pumps, as well as several types of K+ channels such as IK-KCa3.1, BK-KCa1.1, KCNQ1 and voltage-activated K+ channels, some of which may be expressed on both luminal and basolateral membranes. The major Ca2+ and cAMP signalling pathways are not elaborated and for simplicity, Ca2+ -channels/transporters and aquaporins are not included. (B) Carcinogenesis and postulated dysregulation of cells volume and secretion. Increased activity of fibroblastic cells, such as cancer associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) (green). (C) The epithelial-to-mesenchymal (EMT) transition showing cells that loose apico-basal polarity and the appearance of some ion transporters from the lumimal membrane in the rear of the cells and some from the basolateral membrane in the leading edge, contributing to driving cell migration. (D) Progression to cancer, showing tumor with extensive fibrosis (gray), fibrogenic cells (green) and immune cells (blue). (Blood vessels are not shown). In the center of the tumor cells may die, while surrounding cells are proliferating and cell volume and corresponding ion transport is up-regulated (see the text).
Mentions: Here, we will focus on secretory epithelia such as pancreas, salivary glands, colorectum, stomach, mammary glands, and prostate, which, as will be discussed below, might not fully regulate their cell volume during stimulated secretion. Notably, several of these epithelia are among the tissues in the body that are most commonly afflicted by cancer (Siegel et al., 2013). One of the most common mechanisms for initiating fluid secretion by agonists or hormones is opening of luminal Cl− channels and luminal and basolateral K+ channels, and this also leads to a cell volume decrease. A number of transport mechanisms on the basolateral membrane are activated to provide ions for luminal exit and thus secretion, and this will potentially lead to regain of cell volume. Concurrently, the cells need to regulate their intracellular pH (pHi), and for cells exhibiting net secretion of H+ or HCO−3 (stomach, pancreatic ducts), this is a particular challenge. Figure 1A shows the basic model for ion transport across secretory cells such as pancreatic duct cell. As seen, this model includes a toolbox of ion channels and transporters (Novak et al., 2011; Frizzell and Hanrahan, 2012; Wilschanski and Novak, 2013), some of which are dys-regulated in cancer, as will be described below. The ion channels include: the cystic fibrosis transmembrane conductace regulator (CFTR) and Ca2+-activated Cl− channels (ANO1/TMEM16A), intermediate and large conductance K+ channels (IK—KCa3.1; BK—KCa1.1), volume sensitive KCNQ1 channels, and possibly voltage-regulated channels (HERG—Kv11.1; EAG2—Kv10.2) (Hayashi et al., 2012; Wang et al., 2013). The ion transporters include Na+-K+-2Cl− cotransporters (NKCC1), Na+/H+ exchangers (NHEs), Cl−/HCO−3 exchangers (SLC26A3,6 and SCL4A family), Na+-HCO−3 transporters (NBCs) and H+/K+-pumps. Another mechanism of achieving secretion, which is beyond the scope of this review, is that driven at least in part by exocytosis, such as in mammary epithelial cells secreting milk, or, for example, parietal cell secreting hydrochloric acid following exocytotic recruitment of the H+/K+ pump from tubulovesicles to the apical membrane (Forte and Zhu, 2010).

Bottom Line: The physiological function of epithelia is transport of ions, nutrients, and fluid either in secretory or absorptive direction.In healthy epithelia, specific ion channels/transporters localize to the luminal and basolateral membranes, contributing to functional epithelial polarity.Furthermore, epithelial architecture and coordinated ion transport function are lost, cell survival/death balance is altered, and new interactions with the stroma arise, all contributing to drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
The physiological function of epithelia is transport of ions, nutrients, and fluid either in secretory or absorptive direction. All of these processes are closely related to cell volume changes, which are thus an integrated part of epithelial function. Transepithelial transport and cell volume regulation both rely on the spatially and temporally coordinated function of ion channels and transporters. In healthy epithelia, specific ion channels/transporters localize to the luminal and basolateral membranes, contributing to functional epithelial polarity. In pathophysiological processes such as cancer, transepithelial and cell volume regulatory ion transport are dys-regulated. Furthermore, epithelial architecture and coordinated ion transport function are lost, cell survival/death balance is altered, and new interactions with the stroma arise, all contributing to drug resistance. Since altered expression of ion transporters and channels is now recognized as one of the hallmarks of cancer, it is timely to consider this especially for epithelia. Epithelial cells are highly proliferative and epithelial cancers, carcinomas, account for about 90% of all cancers. In this review we will focus on ion transporters and channels with key physiological functions in epithelia and known roles in the development of cancer in these tissues. Their roles in cell survival, cell cycle progression, and development of drug resistance in epithelial cancers will be discussed.

No MeSH data available.


Related in: MedlinePlus