77 research outputs found
Brush border inositol transport by intestines of carnivourus and herbivourus teleosts. Am. J. Physiol. 256: G501-G508.
No full textHydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis
No full textTumour angiogenesis and cellular pH regulation, mainly represented by Na+/H+ antiporter exchange, have been heretofore considered unrelated subfields of cancer research. In this short review, the available experimental evidence relating these areas of modern cancer research is introduced. This perspective also helps to design a new approach that facilitates the opening and development of novel research lines oriented towards a rational incorporation of anticancer drugs into more selective and less toxic therapeutic protocols. The final aim of these efforts is to control cancer progression and dissemination through the control of tumour angiogenesis. Finally, different antiangiogenic drugs that can already be clinically used to this effect are briefly presented
pH regulators in invadosomal functioning: Proton delivery for matrix tasting.
No full textInvadosomes are actin-rich finger-like cellular structures sensing and interacting with the surrounding extracellular matrix (ECM) and involved in its proteolytic remodeling. Invadosomes are structures distinct from other adhesion complexes, and have been identified in normal cells that have to cross tissue barriers to fulfill their function such as leukocytes, osteoclasts and endothelial cells. They also represent features of highly aggressive cancer cells, allowing them to escape from the primary tumor, to invade surrounding tissues and to reach systemic circulation. They are localized to the ventral membrane of cells grown under 2-dimensional conditions and are supposed to be present all around cells grown in 3-dimensional matrices. Indeed invadosomes are key structures in physiological processes such as inflammation and the immune response, bone remodeling, tissue repair, but also in pathological conditions such as osteopetrosis and the development of metastases. Invadosomes are subdivided into podosomes, found in normal cells, and into invadopodia specific for cancer cells. While these two structures exhibit differences in organization, size, number and half-life, they share similarities in molecular composition, participation in cell-matrix adhesion and promoting matrix degradation. A key determinant in invadosomal function is the recruitment and release of proteases, such as matrix metalloproteinases (MMPs), serine proteases and cysteine cathepsins, together with their activation in a tightly controlled and highly acidic microenvironment. Therefore numerous pH regulators such as V-ATPases and Na(+)/H(+) exchangers, are found in invadosomes and are directly involved in their constitution as well as their functioning. This review focuses on the participation of pH regulators in invadosome function in physiological and pathological conditions, with a particular emphasis on ECM remodeling by osteoclasts during bone resorption and by cancer cells
Resistance to antiangiogenic treatments: A review
No full textAngiogenesis (blood vessel formation) is essential for tissue growth in both normal development and physiology and in some diseases such as inflammation and cancer. Angiogenesis is a hallmark of cancer, however, it took many years to establish its importance. Ever since Judah Folkman’s seminal publications in 1971, that clearly showed cancer angiogenesis-dependence, researchers have been investigating the mechanisms of angiogenesis and how to block them. This search blossomed with the finding of inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathways. These new molecules and monoclonal antibodies showed therapeutic efficacy in both the laboratory and human clinical settings and hopes rose. Unfortunately, the benefits did not reach all the patients and they were short-lived: sooner or later tumors resumed their growth and proliferation and became refractory to further antiangiogenic treatments. Worse, antiangiogenic treatments seemed to increase metastatic risk. The development of treatment resistance is still one of the main causes of failure in cancer therapy. Antiangiogenic treatments are no exception and a deeper knowledge of the mechanisms of resistance is necessary if we intend to delay or eliminate them.Two different mechanisms have been identified: primary or evasive resistance and secondary or adaptive resistance.The existence of these two mechanisms led to the non-mainstream conclusion, now shared by many authors, that there are at least two different angiogenic pathways: one is the canonical VEGF- VEGF receptor (VEGFR) axis and others, which are independent of this axis and not fully known. Primary resistance works exclusively through these independent pathways, while secondary resistance, which initially is VEGF-VEGFR-dependent, switches to the other pathways becoming non-responsive to classical antiangiogenic treatments. For the time being, the clear identification of these other pathways belongs to the realm of hypothesis. However, there is enough experimental evidence supporting their existence. We will discuss this evidence as a central issue in antiangiogenic treatment resistance. Some non-conventional pharmacologic strategies against resistance will also be considered
Role of Stromal Cells in Determining Tumor and Cancer Stem Cell Behaviors and Therapeutic Response
No full textWhile research previously focused extensively on the tumor cells, over the last two decades, the tumor microenvironment (TME) has received increasing attention with a particular emphasis in its role in tumor development, metabolism, progression, and treatment response [...
Synergy between low dose metronomic chemotherapy and the pH-centered approach against cancer
No full textLow dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer. However, one of the main limitations of this therapy is its short-term effectiveness: 6 to 12 months, after which resistance develops. pH-centered cancer treatment (pHT) has been proposed as a complementary therapy in cancer, but it has not been adopted or tested as a mainstream protocol, in spite of existing evidence of its advantages and benefits. Many of the factors directly or indirectly involved in MC and anti-angiogenic treatment resistance are appropriately antagonized by pHT. This led to the testing of an association between these two treatments. Preliminary evidence indicates that the association of MC and pHT has the ability to reduce anti-angiogenic treatment limitations and develop synergistic anti-cancer effects. This review will describe each of these treatments and will analyze the fundamentals of their synergy
Intestinal glucose transport and salinity adaptation in a euryhaline teleost
No full textGlucose transport by upper and lower intestinal brush-border membrane vesicles of the African tilapia (Oreochromis mossambicus) was characterized in fish acclimated to either freshwater or full-strength seawater. D-[3H]-glucose uptake by vesicles was stimulated by a transmembrane Na gradient, was electrogenic, and was enhanced by counter-transport of either D-glucose or D-galactose. Glucose transport was greater in the upper intestine than in the lower intestine and in seawater animals rather than in fish acclimated to freshwater. Glucose influx (10-s uptake) involved both saturable and nonsaturable transport components. Seawater adaptation increased apparent glucose influx K(t), J(max), apparent diffusional permeability (P), and the apparent Na affinity of the cotransport system in both intestinal segments, but the stoichiometry of Na-glucose transfer (1:1) was unaffected by differential saline conditions or gut region. It is suggested that increased sugar transport in seawater animals is due to the combination of enhanced Na-binding properties and an increase in number of transfer rate of the transport proteins. Freshwater animals compensate for reduced Na affinity of the coupled process by markedly increasing the protein affinity for glucose
Brush-border inositol transport by intestines of carnivorous and herbivorous teleosts
No full textTransport characteristics of myoinositol by isolated brush-border membrane vesicles of two fish, the herbivorous tilapia (Oreochromis mossambicus) and the carnivorous eel (Anguilla anguilla), were measured. [3H]myoinositol uptake by vesicles of both fish was stimulated by a transmembrane Na gradient, was electrogenic, and was inhibited by phloridzin. Kinetic analysis of myoinositol influx disclosed species differences (tilapia, K = 0.15 mM, J(max) = 0.2 nmol·mg protein-1·min-1; eel, K = 2.6 mM, J(max) = 0.8 nmol·mg protein-1·min-1). D-Glucose inhibition of myoinositol influx was shown to be noncompetitive. Additional inhibition studies with a range of sugars demonstrated that aldohexoses in the C-1 chair conformation were preferred substrates. Myoinositol had no effect on D-glucose transport. Preloading vesicles with myoinositol transstimulated [3H]myoinositol uptake, while the use of internal D-glucose was without effect. These results suggest that the intestinal brush border may have a pathway for myoinositol transport entirely separate from that for D-glucose but inhibited by D-glucose via binding to a regulator site on the myoinositol transporter. Markedly dissimilar influx kinetic constants suggest possible differences in myoinositol needs by carnivorous and herbivorous fish
Intestinal glycyl-L-phenylalanine and L-phenylalanine transport in a euryhaline teleost
No full textThe transport mechanisms for the dipeptide glycyl-L-phenylalanine (Gly-Phe) and L-phenylalanine (Phe) were characterized in fish intestinal brush-border membrane vesicles (BBMV). Gly-Phe was rapidly hydrolyzed only intravesicularly with almost total hydrolysis occurring even at 10 s. Dipeptide uptake was not stimulated by an inward gradient of Na, K, or H. Phe uptake was stimulated by an inward gradient of either Na or K but displayed an overshoot phenomenon only in the presence of an Na gradient. Kinetic analysis of the effect of substrate concentration on transport rate revealed that transport of both Gly-Phe and Phe occurred by a saturable process conforming to Michaelis-Menten kinetics. The K(m) for Gly-Phe was 9.8 ± 3.5 mM, whereas that for Phe in the presence of Na or K, respectively, was 0.74 ± 0.13 and 1.1 ± 0.37 mM. Maximum uptake for Gly-Phe and for Phe in the presence of Na and K was 5.1, 0.9, and 0.4 nmol·mg and protein-1·5 s-1, respectively. Gly-Phe and Phe transport displayed different patterns of inhibition by dipeptides and amino acids. These results suggest that Gly-Phe and Phe are transported via different mechanisms, with Gly-Phe being hydrolyzed during a carrier-mediated, cation-independent process and Phe being transferred via a Na+ cotransport process similar to that described in mammals. During conditions of high luminal dipeptide concentrations, the Gly-Phe pathway may make a significant contribution to total Phe uptake
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