Involvement of tumor acidification in brain cancer pathophysiology

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.

The combination of artificial neural networks and synchrotron radiation-based infrared micro-spectroscopy for a study on the protein composition of human glial tumors

“…In turn, vibration modes corresponding to random coils, beta turn and beta sheets, all of which contribute especially to the low-frequency part of Amide I in the 1650-1620 cm -1 spectral range, are markedly elevated in malignant tumors [46] . Much work proposed a contribution of effects of hypoxia-related neurotoxicity in destruction of proteins due to free radicals generation, pH acidification, and necrosis to this effect [7,51] . Particularly, detailed studies of Sorio et al using cell cultures related this phenomenon to cellular death via apoptosis [31] .…”

“…On top of that, due to intracytoplasmic pH acidification, gliomas cause direct destruction of a surrounding tissue. This may induce neuronal death via glutamate excitotoxicity or destruction of an extracellular matrix [7] . These and many other harmful factors make gliomas' neurobiology rather complex [8] .…”

Autocrine regulation of glioma cell proliferation via pHe-sensitive K+ channels

“…Finally, it is very possible that a residual conductance usually masked by the large quinine-sensitive basal current is unmasked in the quinine-bathed conditions. Glioma cells express many channels, and several of them, including ClC-3 channels, TRP channels, and P2X receptors, have demonstrated pH sensitivity (18).…”

“…The cause of this acidification is multifaceted and includes heterogeneous expression of acid extruders, poor access to nutrients, and a mix of cell populations (18). We wondered if tumor acidification could organically evolve from a clonal population of cells and in the presence of ample nutrients.…”

Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism

“…These ion channels translate these changes by modulating membrane voltage (V m ) and glioma cell proliferation and tumorigenesis. 136 Current Knowledge About the Relationship Between Hypoxia and Na + and K + Channels…”