An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy ...generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.
A circular time-switched array (TSA) is analysed and configured to radiate radio waves which correspond to the modes associated with orbital angular momentum (OAM) theory. Results are presented to ...show that the harmonic frequencies radiated by the circular TSA directly correspond to OAM modes of progressive order, including negative modes. PUBLICATION ABSTRACT
A circular phased array antenna that can generate orbital angular momentum (OAM) radio beams in the 10 GHz band is described. The antenna consists of eight inset-fed patch elements and a microstrip ...corporate feeding network. A full-wave electromagnetic simulator is used to aid the antenna design and theoretical simulations are confirmed by measurements.
Classical hydrodynamics is a remarkably versatile description of the coarse-grained behaviour of many-particle systems once local equilibrium has been established1. The form of the hydrodynamical ...equations is determined primarily by the conserved quantities present in a system. Some quantum spin chains are known to possess, even in the simplest cases, a greatly expanded set of conservation laws, and recent work suggests that these laws strongly modify collective spin dynamics, even at high temperature2,3. Here, by probing the dynamical exponent of the one-dimensional Heisenberg antiferromagnet KCuF3 with neutron scattering, we find evidence that the spin dynamics are well described by the dynamical exponent z = 3/2, which is consistent with the recent theoretical conjecture that the dynamics of this quantum system are described by the Kardar–Parisi–Zhang universality class4,5. This observation shows that low-energy inelastic neutron scattering at moderate temperatures can reveal the details of emergent quantum fluid properties like those arising in non-Fermi liquids in higher dimensions.Quantum systems possessing conserved quantities are expected to show quantum fluid properties governed by hydrodynamic equations. This behaviour is now evidenced in a neutron scattering study on the one-dimensional Heisenberg antiferromagnet KCuF3.
Summary Hypoxia inducible transcription factors (HIFs) activate diverse pathways that regulate cellular metabolism, angiogenesis, proliferation, and migration, enabling a cell to respond to a low ...oxygen or hypoxic environment. HIFs are regulated by oxygen-dependent and independent signals including: mitochondrial dysfunction, reactive oxygen species, endoplasmic reticular stress, and viral infection. HIFs have been reported to play a role in the pathogenesis of liver disease of diverse aetiologies. This review explores the impact of HIFs on hepatocellular biology and inflammatory responses, highlighting the therapeutic potential of targeting HIFs for an array of liver pathologies.
Hypoxia is a critical driver of cancer pathogenesis, directly inducing malignant phenotypes such as epithelial-mesenchymal transition, stem cell-like characteristics and metabolic transformation. ...However, hypoxia-associated phenotypes are often observed in cancer in the absence of hypoxia, a phenotype known as pseudohypoxia, which is very well documented in specific tumour types, including in paraganglioma/pheochromocytoma (PPGL). Approximately 40% of the PPGL tumours carry a germ line mutation in one of a number of susceptibility genes of which those that are found in succinate dehydrogenase (
SDH
) or in von Hippel-Lindau (
VHL
) genes manifest a strong pseudohypoxic phenotype. Mutations in SDH are oncogenic, forming tumours in a select subset of tissues, but the cause for this remains elusive. Although elevated succinate levels lead to increase in hypoxia-like signalling, there are other phenotypes that are being increasingly recognised in
SDH
-mutated PPGL, such as DNA hypermethylation. Further, recently unveiled changes in metabolic re-wiring of SDH-deficient cells might help to decipher cancer related roles of SDH in the future. In this review, we will discuss the various implications that the malfunctioning SDH can have and its impact on cancer development.
Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many ...reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Low oxygen tension (hypoxia) is a pervasive physiological and pathophysiological stimulus that metazoan organisms have contended with since they evolved from their single-celled ancestors. The effect ...of hypoxia on a tissue can be either positive or negative, depending on the severity, duration and context. Over the long-term, hypoxia is not usually consistent with normal function and so multicellular organisms have had to evolve both systemic and cellular responses to hypoxia. Our reliance on oxygen for efficient adenosine triphosphate (ATP) generation has meant that the cellular metabolic network is particularly sensitive to alterations in oxygen tension. Metabolic changes in response to hypoxia are elicited through both direct mechanisms, such as the reduction in ATP generation by oxidative phosphorylation or inhibition of fatty-acid desaturation, and indirect mechanisms including changes in isozyme expression through hypoxia-responsive transcription factor activity. Significant regions of cancers often grow in hypoxic conditions owing to the lack of a functional vasculature. As hypoxic tumour areas contain some of the most malignant cells, it is important that we understand the role metabolism has in keeping these cells alive. This review will outline our current understanding of many of the hypoxia-induced changes in cancer cell metabolism, how they are affected by other genetic defects often present in cancers, and how these metabolic alterations support the malignant hypoxic phenotype.
In the early 1920s Otto Warburg observed that cancer cells have altered metabolism and from this, posited that mitochondrial dysfunction underpinned the aetiology of cancers. The more recent ...identification of mutations of mitochondrial metabolic enzymes in a wide range of human cancers has now provided a direct link between metabolic alterations and cancer. In this review we discuss the consequences of dysfunction of three metabolic enzymes involved in or associated with the tricarboxylic acid (TCA) cycle: succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) focusing on the similarity between the phenotypes of cancers harbouring these mutations.
Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these ...transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.
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► Glycogen metabolism is upregulated by hypoxia in cancer cells in vitro and in vivo ► Synthesis versus degradation enzymes have a marked difference in temporal induction ► Metabolism of glucose via glycogen sustains the pentose phosphate pathway ► Depletion of PYGL induces senescence and inhibits tumor growth
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