How protons pave the way to aggressive cancers

Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid–base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease

Opening of Small and Intermediate Calcium-Activated Potassium Channels Induces Relaxation Mainly Mediated by Nitric-Oxide Release in Large Arteries and Endothelium- Derived Hyperpolarizing Factor in Small Arteries from Rat

ABSTRACT This study was designed to investigate whether calcium-activated potassium channels of small (SK Ca or K Ca 2) and intermediate (IK Ca or K Ca 3.1) conductance activated by 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) are involved in both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in large and small rat mesenteric arteries. Segments of rat superior and small mesenteric arteries were mounted in myographs for functional studies. NO was recorded using NO microsensors. SK Ca and IK Ca channel currents and mRNA expression were investigated in human umbilical vein endothelial cells (HUVECs), and calcium concentrations were investigated in both HUVECs and mesenteric arterial endothelial cells. In both superior (ϳ1093 m) and small mesenteric (ϳ300 m) arteries, NS309 evoked endothelium-and concentration-dependent relaxations. In superior mesenteric arteries, NS309 relaxations and NO release were inhibited by both N G ,N G -asymmetric dimethyl-L-arginine (ADMA) (300 M), an inhibitor of NO synthase, and apamin (0.5 M) plus 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) (1 M), blockers of SK Ca and IK Ca channels, respectively. In small mesenteric arteries, NS309 relaxations were reduced slightly by ADMA, whereas apamin plus an IK Ca channel blocker almost abolished relaxation. Iberiotoxin did not change NS309 relaxation. HUVECs expressed mRNA for SK Ca and IK Ca channels, and NS309 induced increases in calcium, outward current, and NO release that were blocked by apamin and TRAM-34 or charybdotoxin. These findings suggest that opening of SK Ca and IK Ca channels leads to endothelium-dependent relaxation that is mediated mainly by NO in large mesenteric arteries and by EDHF-type relaxation in small mesenteric arteries. NS309-induced calcium influx appears to contribute to the formation of NO

Acidosis inhibits rhythmic contractions of human thoracic ducts

Abstract Lymph vessels counteract edema by transporting interstitial fluid from peripheral tissues to the large veins and serve as conduits for immune cells, cancer cells, and pathogens. Because edema during inflammation and malignancies is frequently associated with acidosis, we tested the hypothesis that acid‐base disturbances affect human thoracic duct contractions. We studied, by isometric and isobaric myography, the contractile function of human thoracic duct segments harvested with written informed consent from patients undergoing esophageal cancer surgery. Human thoracic ducts produce complex contractile patterns consisting of tonic rises in tension (isometric myography) or decreases in diameter (isobaric myography) with superimposed phasic contractions. Active tone development decreases substantially (~90% at 30 vs. 7 mmHg) at elevated transmural pressure. Acidosis inhibits spontaneous as well as noradrenaline‐ and serotonin‐induced phasic contractions of human thoracic ducts by 70–90% at extracellular pH 6.8 compared to 7.4 with less pronounced effects observed at pH 7.1. Mean tension responses to noradrenaline and serotonin – averaged over the entire period of agonist exposure – decrease by ~50% at extracellular pH 6.8. Elevating extracellular [K+] from the normal resting level around 4 mmol/L increases overall tension development but reduces phasic activity to a level that is no different between human thoracic duct segments investigated at normal and low extracellular pH. In conclusion, we show that extracellular acidosis inhibits human thoracic duct contractions with more pronounced effects on phasic than tonic contractions. We propose that reduced phasic activity of lymph vessels at low pH attenuates lymph propulsion and increases the risk of edema formation