“…In fact, anionic exchangers (e.g., carbonic anhydrase 9 or CA IX) can convert carbon dioxide (CO 2 ) and water (H 2 O) generated by oxidative processes to bicarbonate (HCO 3 – ) and proton ( H + ). The acid-extruding mechanisms are enhanced in cancer cells [ 3 , 11 ]. …”
mentioning
confidence: 99%
“…Extracellular acidification within the tumor habitat is vital for invasive properties [2] , [3] , [4] , [5] and overwhelming the immune response [9] , whereas salinity is important for uncontrolled mitosis [6] and immune cell activity [7] . While extracellular pH imaging has become an invaluable biomarker for early diagnosis and tracking treatments by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) [10] , imaging compartmental sodium levels is still a desirable goal [11] . Fig.…”
mentioning
confidence: 99%
“… Fig. 2 Metabolic pathways of energy production and biosynthesis in tumors are closely associated with dysregulated transmembrane proton/sodium gradients [ [1] , [2] , [3] , 11 ]. Glucose is transported across the cell membrane by glucose transporters (e.g., GLUT1), which are upregulated in cancer.…”
mentioning
confidence: 99%
“…These are transported out of the cell by MCTs, specifically MCT4, and ion exchangers (e.g., NHE and vacuolar H + -ATPase). The MCTs, specifically MCT1, also allow transport of other substrates (i.e., β-hydroxybutyrate (BHB) and acetate) [ 3 , 11 ]. Both carbon dioxide (CO 2 ) and water (H 2 O) generated by oxidative processes also produce extracellular acidification using CA IX, generating bicarbonate (HCO 3 – ) and proton ( H + ).…”
mentioning
confidence: 99%
“…1 and 2 ) . Given the range of 1 H-MRI [14] and 1 H-MRSI [11] methods that can measure pH dysregulation in cancer, combining 23 Na-MRSI innovations [ 13 , 15 ] can allow pioneering explorations of how transmembrane sodium/proton gradients synchronously change within the tumor habitat, with and without therapy [1] , [2] , [3] , [4] , [5] .…”
Highlights
The hallmarks of cancer all directly linked to proton and sodium imbalances, where reduced extracellular pH and salinity are both the resultant of oncogenic metabolic changes in the tumor microenvironment and are supported by upregulated cellular mechanisms like carbonic anhydrase 9 (CA IX) and sodium proton exchanger (NHE). The dysregulated proton and sodium gradients highlight cancer invasion and proliferation and can be imaged by merging of
23
Na and
1
H magnetic resonance techniques.
“…In fact, anionic exchangers (e.g., carbonic anhydrase 9 or CA IX) can convert carbon dioxide (CO 2 ) and water (H 2 O) generated by oxidative processes to bicarbonate (HCO 3 – ) and proton ( H + ). The acid-extruding mechanisms are enhanced in cancer cells [ 3 , 11 ]. …”
mentioning
confidence: 99%
“…Extracellular acidification within the tumor habitat is vital for invasive properties [2] , [3] , [4] , [5] and overwhelming the immune response [9] , whereas salinity is important for uncontrolled mitosis [6] and immune cell activity [7] . While extracellular pH imaging has become an invaluable biomarker for early diagnosis and tracking treatments by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) [10] , imaging compartmental sodium levels is still a desirable goal [11] . Fig.…”
mentioning
confidence: 99%
“… Fig. 2 Metabolic pathways of energy production and biosynthesis in tumors are closely associated with dysregulated transmembrane proton/sodium gradients [ [1] , [2] , [3] , 11 ]. Glucose is transported across the cell membrane by glucose transporters (e.g., GLUT1), which are upregulated in cancer.…”
mentioning
confidence: 99%
“…These are transported out of the cell by MCTs, specifically MCT4, and ion exchangers (e.g., NHE and vacuolar H + -ATPase). The MCTs, specifically MCT1, also allow transport of other substrates (i.e., β-hydroxybutyrate (BHB) and acetate) [ 3 , 11 ]. Both carbon dioxide (CO 2 ) and water (H 2 O) generated by oxidative processes also produce extracellular acidification using CA IX, generating bicarbonate (HCO 3 – ) and proton ( H + ).…”
mentioning
confidence: 99%
“…1 and 2 ) . Given the range of 1 H-MRI [14] and 1 H-MRSI [11] methods that can measure pH dysregulation in cancer, combining 23 Na-MRSI innovations [ 13 , 15 ] can allow pioneering explorations of how transmembrane sodium/proton gradients synchronously change within the tumor habitat, with and without therapy [1] , [2] , [3] , [4] , [5] .…”
Highlights
The hallmarks of cancer all directly linked to proton and sodium imbalances, where reduced extracellular pH and salinity are both the resultant of oncogenic metabolic changes in the tumor microenvironment and are supported by upregulated cellular mechanisms like carbonic anhydrase 9 (CA IX) and sodium proton exchanger (NHE). The dysregulated proton and sodium gradients highlight cancer invasion and proliferation and can be imaged by merging of
23
Na and
1
H magnetic resonance techniques.
The term “in vivo (“in the living”) chemistry” refers to chemical reactions that take place in a complex living system such as cells, tissue, body liquids, or even in an entire organism. In contrast, reactions that occur generally outside living organisms in an artificial environment (e.g., in a test tube) are referred to as in vitro. Over the past decades, significant contributions have been made in this rapidly growing field of in vivo chemistry, but it is still not fully understood, which transformations proceed efficiently without the formation of by‐products or how product formation in such complex environments can be characterized. Potential applications can be imagined that synthesize drug molecules directly within the cell or confer new cellular functions through controlled chemical transformations that will improve the understanding of living systems and develop new therapeutic strategies. The guiding principles of this contribution are twofold: 1) Which chemical reactions can be translated from the laboratory to the living system? 2) Which characterization methods are suitable for studying reactions and structure formation in complex living environments?
A unique feature of the tumor microenvironment is extracellular acidosis in relation to intracellular milieu. Metabolic reprogramming in tumors results in overproduction of H+ ions (and lactate), which are extruded from the cells to support tumor survival and progression. As a result, the transmembrane pH gradient (ΔpH), representing the difference between intracellular pH (pHi) and extracellular pH (pHe), is posited to be larger in tumors compared with normal tissue. Controlling the transmembrane pH difference has promise as a potential therapeutic target in cancer as it plays an important role in regulating drug delivery into cells. The current study shows successful development of an MRI/MRSI‐based technique that provides ΔpH imaging at submillimeter resolution. We applied this technique to image ΔpH in rat brains with RG2 and U87 gliomas, as well as in mouse brains with GL261 gliomas. pHi was measured with Amine and Amide Concentration‐Independent Detection (AACID), while pHe was measured with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). The results indicate that pHi was slightly higher in tumors (7.40–7.43 in rats, 7.39–7.47 in mice) compared with normal brain (7.30–7.38 in rats, 7.32–7.36 in mice), while pHe was significantly lower in tumors (6.62–6.76 in rats, 6.74–6.84 in mice) compared with normal tissue (7.17–7.22 in rats, 7.20–7.21 in mice). As a result, ΔpH was higher in tumors (0.64–0.81 in rats, 0.62–0.65 in mice) compared with normal brain (0.13–0.16 in rats, 0.13–0.16 in mice). This work establishes an MRI/MRSI‐based platform for ΔpH imaging at submillimeter resolution in gliomas.
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