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Involvement of tumor acidification in brain cancer pathophysiology.

Honasoge A, Sontheimer H - Front Physiol (2013)

Bottom Line: Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth.As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions.In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth. While they share many qualities with other solid tumors, gliomas have developed special mechanisms to convert the cramped brain space and other limitations afforded by the privileged central nervous system into pathophysiological advantages. In this review we discuss gliomas and other primary brain cancers in the context of acid-base regulation and interstitial acidification; namely, how the altered proton (H(+)) content surrounding these brain tumors influences tumor development in both autocrine and paracrine manners. As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions. In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system. We will highlight what is known about pH-sensitive processes in brain tumors in addition to gleaning insight from other solid tumors.

No MeSH data available.


Related in: MedlinePlus

Examples of pH-dependent physiology in solid tumors. (1) Radiation efficacy. (2) Salt water flux via K+, Cl−, and H2O channels. (3) Downstream expression patterns of tumorigenic genes. (4) Mislocalization of cyclin D1 and disruption of the cell cycle. (5) Ca2+ permeation through ion channels (ASIC, P2X, TRP) and subsequent downstream effects. (6) Metabolic enzyme activity. (7) H+-coupled lactate efflux. (8) Vesicular fusion and protease enzymatic activity. (9) Interaction with the extracellular matrix. (10) Distribution of weak acids/bases.
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Figure 2: Examples of pH-dependent physiology in solid tumors. (1) Radiation efficacy. (2) Salt water flux via K+, Cl−, and H2O channels. (3) Downstream expression patterns of tumorigenic genes. (4) Mislocalization of cyclin D1 and disruption of the cell cycle. (5) Ca2+ permeation through ion channels (ASIC, P2X, TRP) and subsequent downstream effects. (6) Metabolic enzyme activity. (7) H+-coupled lactate efflux. (8) Vesicular fusion and protease enzymatic activity. (9) Interaction with the extracellular matrix. (10) Distribution of weak acids/bases.

Mentions: The most direct (and obvious) consequence of pHi regulation is pHe alteration. The aforementioned mechanisms of pHi regulation mostly act as intracellular alkalinizing agents, leading to a large proton efflux into the extracellular space (ECS). The magnitude of pHi and pHe changes depends on buffering capacity, total compartment volume, and molecular diffusivity (Chesler, 2003). These protons do not dissipate readily in the poorly perfused spaces within solid tumors, resulting in pHe heterogeneity and pockets of increased acidity. Therefore, protons may serve as messenger molecules that alter both intratumoral and extratumoral physiology (Figure 2). This section will both review known mechanisms of pH-directed pathophysiology in brain tumors as well as draw lessons from other solid tumor types.


Involvement of tumor acidification in brain cancer pathophysiology.

Honasoge A, Sontheimer H - Front Physiol (2013)

Examples of pH-dependent physiology in solid tumors. (1) Radiation efficacy. (2) Salt water flux via K+, Cl−, and H2O channels. (3) Downstream expression patterns of tumorigenic genes. (4) Mislocalization of cyclin D1 and disruption of the cell cycle. (5) Ca2+ permeation through ion channels (ASIC, P2X, TRP) and subsequent downstream effects. (6) Metabolic enzyme activity. (7) H+-coupled lactate efflux. (8) Vesicular fusion and protease enzymatic activity. (9) Interaction with the extracellular matrix. (10) Distribution of weak acids/bases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814515&req=5

Figure 2: Examples of pH-dependent physiology in solid tumors. (1) Radiation efficacy. (2) Salt water flux via K+, Cl−, and H2O channels. (3) Downstream expression patterns of tumorigenic genes. (4) Mislocalization of cyclin D1 and disruption of the cell cycle. (5) Ca2+ permeation through ion channels (ASIC, P2X, TRP) and subsequent downstream effects. (6) Metabolic enzyme activity. (7) H+-coupled lactate efflux. (8) Vesicular fusion and protease enzymatic activity. (9) Interaction with the extracellular matrix. (10) Distribution of weak acids/bases.
Mentions: The most direct (and obvious) consequence of pHi regulation is pHe alteration. The aforementioned mechanisms of pHi regulation mostly act as intracellular alkalinizing agents, leading to a large proton efflux into the extracellular space (ECS). The magnitude of pHi and pHe changes depends on buffering capacity, total compartment volume, and molecular diffusivity (Chesler, 2003). These protons do not dissipate readily in the poorly perfused spaces within solid tumors, resulting in pHe heterogeneity and pockets of increased acidity. Therefore, protons may serve as messenger molecules that alter both intratumoral and extratumoral physiology (Figure 2). This section will both review known mechanisms of pH-directed pathophysiology in brain tumors as well as draw lessons from other solid tumor types.

Bottom Line: Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth.As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions.In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth. While they share many qualities with other solid tumors, gliomas have developed special mechanisms to convert the cramped brain space and other limitations afforded by the privileged central nervous system into pathophysiological advantages. In this review we discuss gliomas and other primary brain cancers in the context of acid-base regulation and interstitial acidification; namely, how the altered proton (H(+)) content surrounding these brain tumors influences tumor development in both autocrine and paracrine manners. As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions. In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system. We will highlight what is known about pH-sensitive processes in brain tumors in addition to gleaning insight from other solid tumors.

No MeSH data available.


Related in: MedlinePlus