Abstract
Tumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor.
Highlights
For a systemically administered drug to act preferentially on a tumor, the drug must recognize some specific characteristic of the tumor
We have looked at an isoform of the enzyme carbonic anhydrase, carbonic anhydrase IX (CAIX), which is upregulated in vitro by HIF-1a and, like MCT4, has been found in hypoxic parts of tumors [55,56,57,58,59,60]
On each section, we stained nucleic acids with Hoechst 33342 and immunolabeled two of four proteins involved in proton transport: NHE1, MCT1, MCT4 and CAIX
Summary
For a systemically administered drug to act preferentially on a tumor, the drug must recognize some specific characteristic of the tumor. Inhibition of angiogenesis has given disappointing results in the long term [1]. Another specific characteristic of tumors, which concerns us here, is their unusually acidic extracellular pH (pHe). The transmembrane gradient of H+ activity is reversed: pHi can be greater than 7.3 [2,3,4,5], and pHe is typically in the range 6.4–7.0 [6,7,8,9,10,11,12]. Tumors overexpress extracellular proteinases [15], and these too are being used, in animal models, to target molecules by cleaving linkers and activating cell penetrating peptides [16]. Available data suggest that both the secretion and the catalytic activity of proteinases, including matrix metalloproteinases (MMPs), are increased at acidic pHs [17,18] and that they promote the progression of tumors [19]
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