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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

Ion channels and transporters and cell volume changes associated in normal and cancer cells. Cell sizes refer to expected cell volume changes and lengths of arrows on cells indicates up- or down-regulation or ion transporters/channels. Resistance to apoptosis is associated with down-regulation of several channels and inhibition of some channels (asterisks) induces resistance to apoptosis. In proliferation, several transporters and channels are up-regulated and over-expressed in cancer (see text). The right part of the figure shows ion transporters and channels that would lead to cell volume increase and those in the lower part indicate those that would lead to cell volume decrease. Large arrows next to named ion channels/transporters indicate their up- or down-regulation in cancer. Chronic activation of ion transport may lead to cell death. Dynamic activation or suppression of ion transport/cell volume with specific signals, in time or in given cells may lead to cancer development and progression.
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Figure 2: Ion channels and transporters and cell volume changes associated in normal and cancer cells. Cell sizes refer to expected cell volume changes and lengths of arrows on cells indicates up- or down-regulation or ion transporters/channels. Resistance to apoptosis is associated with down-regulation of several channels and inhibition of some channels (asterisks) induces resistance to apoptosis. In proliferation, several transporters and channels are up-regulated and over-expressed in cancer (see text). The right part of the figure shows ion transporters and channels that would lead to cell volume increase and those in the lower part indicate those that would lead to cell volume decrease. Large arrows next to named ion channels/transporters indicate their up- or down-regulation in cancer. Chronic activation of ion transport may lead to cell death. Dynamic activation or suppression of ion transport/cell volume with specific signals, in time or in given cells may lead to cancer development and progression.

Mentions: While this has still been relatively little studied, it is clear that dys-regulation of ion transport in cancer is involved in important functional interactions with the TME. Firstly, the metabolic switch induced (in part) by hypoxia increases acid production in the cancer cells. This, in conjunction with hypoxia-induced elevation of hypoxia-inducible factor-1α (HIF1α) levels increases the expression and/or activity of acid-extruding ion transport proteins and carbonic anhydrases (CAs). In breast cancer, these include the Na+/H+ exchanger NHE1, the Na+-HCO−3 cotransporter NBCn1, monocarboxylate transporters MCT1 and MCT4, and CAIX (Bartosova et al., 2002; Lauritzen et al., 2010, 2012; Pinheiro et al., 2010; Boedtkjer et al., 2013; see Cardone et al., 2005) (Figure 2). In PDAC, evidence is much sparser, although neurotensin-induced NHE1 activation in PDAC cell lines is reported (Olszewski et al., 2010). Cytokines and growth factors secreted by the cancer cells and stromal cells likely also contribute to the up-regulation of ion transport. For instance, ErbB2 signaling increases NBCn1 expression and post-translationally activates NHE1 by phosphorylation in its C-terminal cytoplasmic domain (Lauritzen et al., 2010, 2012). In turn, ion transporters play major roles in creating the TME. Increased acid extrusion from the cancer cells can cause extracellular pH (pHe) to become as low as 6.0 in some tumor regions (Vaupel, 2004). This favors further cancer development, e.g., through facilitating ECM degradation and cell motility, resistance to chemotherapy, and compromised anti-tumor function of cytotoxic T-cells and natural killer cells (Ward et al., 2013), while their role in maintaining pHi at or above the normal pH 7.0–7.4 favors metabolic, migratory, and proliferative activity and counteracts apoptotic death (Parks et al., 2011; Webb et al., 2011; Boedtkjer et al., 2012). Finally, it has been suggested that NHE1 may directly regulate ECM deposition by fibroblasts (Karydis et al., 2009).


Cell volume regulation in epithelial physiology and cancer.

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

Ion channels and transporters and cell volume changes associated in normal and cancer cells. Cell sizes refer to expected cell volume changes and lengths of arrows on cells indicates up- or down-regulation or ion transporters/channels. Resistance to apoptosis is associated with down-regulation of several channels and inhibition of some channels (asterisks) induces resistance to apoptosis. In proliferation, several transporters and channels are up-regulated and over-expressed in cancer (see text). The right part of the figure shows ion transporters and channels that would lead to cell volume increase and those in the lower part indicate those that would lead to cell volume decrease. Large arrows next to named ion channels/transporters indicate their up- or down-regulation in cancer. Chronic activation of ion transport may lead to cell death. Dynamic activation or suppression of ion transport/cell volume with specific signals, in time or in given cells may lead to cancer development and progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Ion channels and transporters and cell volume changes associated in normal and cancer cells. Cell sizes refer to expected cell volume changes and lengths of arrows on cells indicates up- or down-regulation or ion transporters/channels. Resistance to apoptosis is associated with down-regulation of several channels and inhibition of some channels (asterisks) induces resistance to apoptosis. In proliferation, several transporters and channels are up-regulated and over-expressed in cancer (see text). The right part of the figure shows ion transporters and channels that would lead to cell volume increase and those in the lower part indicate those that would lead to cell volume decrease. Large arrows next to named ion channels/transporters indicate their up- or down-regulation in cancer. Chronic activation of ion transport may lead to cell death. Dynamic activation or suppression of ion transport/cell volume with specific signals, in time or in given cells may lead to cancer development and progression.
Mentions: While this has still been relatively little studied, it is clear that dys-regulation of ion transport in cancer is involved in important functional interactions with the TME. Firstly, the metabolic switch induced (in part) by hypoxia increases acid production in the cancer cells. This, in conjunction with hypoxia-induced elevation of hypoxia-inducible factor-1α (HIF1α) levels increases the expression and/or activity of acid-extruding ion transport proteins and carbonic anhydrases (CAs). In breast cancer, these include the Na+/H+ exchanger NHE1, the Na+-HCO−3 cotransporter NBCn1, monocarboxylate transporters MCT1 and MCT4, and CAIX (Bartosova et al., 2002; Lauritzen et al., 2010, 2012; Pinheiro et al., 2010; Boedtkjer et al., 2013; see Cardone et al., 2005) (Figure 2). In PDAC, evidence is much sparser, although neurotensin-induced NHE1 activation in PDAC cell lines is reported (Olszewski et al., 2010). Cytokines and growth factors secreted by the cancer cells and stromal cells likely also contribute to the up-regulation of ion transport. For instance, ErbB2 signaling increases NBCn1 expression and post-translationally activates NHE1 by phosphorylation in its C-terminal cytoplasmic domain (Lauritzen et al., 2010, 2012). In turn, ion transporters play major roles in creating the TME. Increased acid extrusion from the cancer cells can cause extracellular pH (pHe) to become as low as 6.0 in some tumor regions (Vaupel, 2004). This favors further cancer development, e.g., through facilitating ECM degradation and cell motility, resistance to chemotherapy, and compromised anti-tumor function of cytotoxic T-cells and natural killer cells (Ward et al., 2013), while their role in maintaining pHi at or above the normal pH 7.0–7.4 favors metabolic, migratory, and proliferative activity and counteracts apoptotic death (Parks et al., 2011; Webb et al., 2011; Boedtkjer et al., 2012). Finally, it has been suggested that NHE1 may directly regulate ECM deposition by fibroblasts (Karydis et al., 2009).

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