If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Why do cancers have high aerobic glycolysis

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

Horseradish peroxidase was administered to mice by intravenous injection, and its distribution in cerebral cortex studied with a recently available technique for localizing peroxidase with the electron microscope. Brains were fixed by either immersion or vascular perfusion 10–60 min after administration of various doses of peroxidase. Exogenous peroxidase was localized in the lumina of blood vessels and in some micropinocytotic vesicles within endothelial cells; none was found beyond the vascular endothelium. Micropinocytotic vesicles were few in number and did not appear to transport peroxidase while tight junctions between endothelial cells were probably responsible for preventing its intercellular passage. Our findings therefore localize, at a fine structural level, a "barrier" to the passage of peroxidase at the endothelium of vessels in the cerebral cortex. The significance of these findings is discussed, particularly with reference to a recent study in which similar techniques were applied to capillaries in heart and skeletal muscle.

/pdf/fine-structural-localization-of-a-blood-brain-barrier-to-107z3ee30y.pdf

Fine structural localization of a blood-brain barrier to exogenous peroxidase

The fish gill is a multipurpose organ that, in addition to providing for aquatic gas exchange, plays dominant roles in osmotic and ionic regulation, acid-base regulation, and excretion of nitrogenous wastes Thus, despite the fact that all fish groups have functional kidneys, the gill epithelium is the site of many processes that are mediated by renal epithelia in terrestrial vertebrates Indeed, many of the pathways that mediate these processes in mammalian renal epithelial are expressed in the gill, and many of the extrinsic and intrinsic modulators of these processes are also found in fish endocrine tissues and the gill itself The basic patterns of gill physiology were outlined over a half century ago, but modern immunological and molecular techniques are bringing new insights into this complicated system Nevertheless, substantial questions about the evolution of these mechanisms and control remain

https://people.clas.ufl.edu/devans/files/PRVGill.pdf

The Multifunctional Fish Gill: Dominant Site of Gas Exchange, Osmoregulation, Acid-Base Regulation, and Excretion of Nitrogenous Waste

The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.

Regulation of angiogenesis by hypoxia: role of the HIF system.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1919.sp001839

The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue.

IN the present paper we propose to describe the changes in ventilation, blood flow, pulse rate, respiratory exchange and alveolar CO2 tension taking place in man during the first few minutes of light or heavy work and we shall attempt further an inquiry into the mechanism of these changes. The experinments have been made by means of the bicycle ergometer and respiration apparatus described in another paper' in which also the main parts of the technique employed have been set forth in detail. We have made experiments on six different suibjects. Three of these, J. L., F. N. and J. J., are trained, mnore or less, to sudden and violent exertions, while the other three, though able to do a fair amount of work over a long period, are not trained to sudden exertions. When told to start with a heavy load the three first named subjects will begin at a very rapid rate, which soon declines, while the other threeeven when told to start as rapidly as possible, and meaning to do sowill begin comparatively slowly and work up during a certain time. (Compare for example Exps. X and IX, p. 135.) On the subjects J. J., J. K. and H. P. we have made determinations of pulmonary volumes, ventilations and rates of work only, under varying conditions. On A. K. and F. N. we have made a few \" complete \" experiments involving determinations of the respiratory exchange and the composition of the alveolar air at several moments, especially during the first minute of work. The most detailed study has been made on J. L. The respiration of this subject is deep, slow and extremely regular, which greatly facilitates the correct sampling of the alveolar air. We wish to state explicitly-though it may seem superfluous-that the breathing in all cases (except when a subject was told to breathe

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1913.sp001616

The regulation of respiration and circulation during the initial stages of muscular work

The Anatomy and Physiology of Capillaries

August Krogh, 242 pp., $1.75, Dover, New York, 1966. Material in this book is presented in a systematic fashion with separate chapters devoted to osmotic regulation in each of the major phyla of invertebrates and vertebrates, and one chapter is devoted to osmotic problems encountered by eggs and embryos of aquatic animals. The scientific name of each animal discussed is given and at least some mention is made of osmoregulation in several hundred genera with some discussed at length. A section perhaps as useful to the teacher of zoology or comparative physiology as any part of the book is the final short chapter dealing with methods. Among others, simple techniques for determination of osmotic concentration and of volume changes are included. The methods presented are ones feasible for use in student laboratories and do not require elaborate equipment. An extensive list of references concludes the volume but, by the author's own admission, it is not a comprehensive list. Since the book was first published in 1939 and has not been altered, no recent references are included. Information is presented in a fashion perhaps too sophisticated to make the book of great use to the beginning science student since the author presupposes some knowledge of biology and chemistry on the part of his reader. However, such an accumulation of material concerning osmoregulation as is presented by Professor Krogh would be difficult, if not impossible to find in any other single volume. For this reason, this book could well occupy a place in the library of any biologist. Barbara Shirley Department of Life Sciences University of Tulsa Tulsa, Oklahoma

Osmotic Regulation in Aquatic Animals

THE rate at which gases and especially oxygen will diffuse through tissues has, so far as I am aware, never been systematically investigated and practicallv never been investigated at all, though a knowledge of the gas diffusion is obviously essential for the solution of one of the problems of the physiology of to-day: the supply of oxygen to the cells. The brilliant work of B a rcroft and his collaborators has made it comparatively easy to obtain a quantitative idea of the average oxygen tension in the capillaries and has furnished many of the necessary data concerning the call for oxygen of the tissues, but in order to make out how this call can be met it is necessary (1) to measure and calculate the average distances which the oxygen molecules have to travel from the capillaries until they enter into chemical combination, and (2) to know the rates at which they travel, that is the diffusion coefficients for oxygen in the different tissues. The present paper is intended to supply the second of these desiderata for certain tissues. The diffusion of gases through animal tissues must take place in essentiallv the same way as their diffusion through fluids or colloidal membranes. The gases are dissolved in the tissue fluids and diffuse in a liquid state. The laws governing the diffusion of gases through water and watery solutions have been worked out by Exner(i), who found that the rates of diffusion for different gases in the same fluid are proportional to the absorption coefficients of the gases in the fluid and inversely proportional to the square roots of their molecular weights. Exner could onlv measure relative diffusion rates for different gases. Stefan(2) measured directly the rate of diffusion of carbon dioxide. Hufn er (3) devised a method for measuring directly the diffusion rates

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1919.sp001838

August Krogh

Papers

The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue.

The regulation of respiration and circulation during the initial stages of muscular work

The Anatomy and Physiology of Capillaries

Osmotic Regulation in Aquatic Animals

The rate of diffusion of gases through animal tissues, with some remarks on the coefficient of invasion