https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00621-X.pdf

The Emerging Hallmarks of Cancer Metabolism

The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.

https://cancerres.aacrjournals.org/content/canres/49/23/6449.full.pdf

Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review

Thermo- and pH-responsive polymers in drug delivery.

Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

/pdf/tumor-hypoxia-definitions-and-current-clinical-biologic-and-5gkgj1718s.pdf

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their tailored mesoporous structure and high surface area, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we overview the recent progress in the synthesis of MSNs for drug delivery applications. First, we provide an overview of synthesis strategies for fabricating ordered MSNs and hollow/rattle-type MSNs. Then, the in vitro and in vivo biocompatibility and biotranslocation of MSNs are discussed in relation to their chemophysical properties including particle size, surface properties, shape, and structure. The review also highlights the significant achievements in drug delivery using mesoporous silica nanoparticles and their multifunctional counterparts as drug carriers. In particular, the biological barriers for nano-based targeted cancer therapy and MSN-based targeting strategies are discussed. We conclude with our personal perspectives on the directions in which future work in this field might be focused.

Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery

A computerized pO2 measurement system with a novel electrode motion pattern (Sigma-pO2-histography) was evaluated in vitro and in vivo. The system was found to be reliable in 0.9% saline and 10% hydroxyethylene starch solution and in fresh donor blood. Marked deviations were found in lipid and hemoglobin solutions and in fluorocarbon emulsions. Histograms obtained in rat liver, mouse muscle, and subcutis were similar to previously reported distributions. Direct comparison between Sigma-Eppendorf and self-constructed Whalen-type electrodes in hypoxic tumors gave similar results. A large series of measurements indicated that hypoxic and anoxic tissue areas were frequently found both in isografted rodent and in xenografted human tumors. The extent of oxygen deprivation depended on the cell line studied, tumor size, implantation site, the vascularity, and the actual tissue perfusion. Pentobarbital anesthesia redistributed the tumor oxygenation without affecting the median pO2 value. Tumors growing in a pre-irradiated bed were less oxygenated than those at untreated sites. Hyperthermia at therapeutically relevant temperatures reduced pO2 levels in adequately oxygenated tumors whereas little change was detected in poorly oxygenated tumors. First measurements in tumors in patients revealed marked inter- and intratumor heterogeneity. It is concluded that this novel technique is suitable for routine measurements of tissue oxygenation of solid tumors in situ.

Tumor tissue oxygenation as evaluated by computerized-pO2-histography.

Size-dependent changes in therapeutically relevant and interrelated metabolic parameters of a murine fibrosarcoma (FSaII) were investigated in vivo using conscious (unanesthetized) animals and tumor sizes less than or equal to 2% of body weight Tumor pH and bioenergetics were evaluated by 31P nuclear magnetic resonance spectroscopy (31P-MRS), and tumor tissue oxygen tension (pO2) distribution was examined using O2-sensitive needle electrodes During growth FSaII tumors showed a progressive loss of phosphocreatine (PCr) and nucleoside triphosphate (NTP) with increasing inorganic phosphate (Pi) and phosphomonoester (PME) signals Ratios for PCr/Pi, PME/Pi, NTP/Pi, and phosphodiester/inorganic phosphate (PDE/Pi) as well as pH determined by 31P-NMR (pHNMR) and the mean tissue pO2 progressively declined as the tumors increased in size The only relevant ratio increasing with tumor growth was PME/NTP When the mean tissue pO2 value was plotted against pHNMR, NTP/Pi, PCr/Pi, PME/Pi, and PDE/Pi for tumor groups of similar mean volumes, a highly significant positive correlation was observed There was a negative correlation between mean tumor tissue pO2 values and PME/NTP From these results we concluded that 31P-MRS can detect changes in tumor bioenergetics brought about by changes in tumor oxygenation Furthermore, the close correlation between oxygenation and energy status suggests that the microcirculation in FSaII tumors yields an O2-limited energy metabolism Finally, a correlation between the proportion of pO2 readings between 0 and 25 mmHg and the radiobiologically hypoxic cell fraction in FSaII tumors was observed The latter finding might be of particular importance for radiation therapy

Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma.

Oxygen diffusion distances in human breast cancer xenografts are computed considering cell line-specific in vivo data. By introducing variations into a set of experimental data characterizing a "standard" situation, the impacts of various tumor-specific or systemic mechanisms are studied. Evidence is given that radioresistance may develop at intercapillary distances above 100 μm. If intercapillary distances exceed 140 μm, hypoxia is present at the arterial end of microvessels already. Hypoxia evidenced under "standard" conditions is distinctly aggravated by reduction of microvascular blood flow, increased arterio-venous shunt perfusion, reduced red blood cell flux, elongation of tumor microvessels, anemia or arterial hypoxemia. Hypoxic tissue fractions calculated for these various conditions are found to be in accordance with the proportion of tumor tissue P O 2 -readings at 0–1 mmHg.

Evaluation of oxygen diffusion distances in human breast cancer xenografts using tumor-specific in vivo data: Role of various mechanisms in the development of tumor hypoxia

A method has been developed for metabolic imaging on a microscopic level in tumors, tumor spheroids, and normal tissues. The technique makes it possible to determine the spatial distribution of glucose, lactate, and ATP in absolute terms at similar locations within tissues or cell aggregates. The substrate distributions are registered in serial cryostat sections from tissue cryobiopsies or from frozen spheroids with the use of bioluminescence reactions. The light emission is measured directly by a special imaging photon counting system enabling on-line image analysis. The technique has been applied to human breast cancer xenografts, to spheroids originating from a human colon adenocarcinoma, and to skeletal rat muscle. Preliminary data obtained indicate that heterogeneities in the substrate distributions measured are much more pronounced in tumors than in normal tissue. There was no obvious correlation among the three quantities measured at similar locations within the tissues. The distribution of ATP corresponded well with the histological structure of larger spheroids; values were low in the necrotic center and high in the viable rim of these cell aggregates.

P. Vaupel

Papers

Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review

Tumor tissue oxygenation as evaluated by computerized-pO2-histography.

Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma.

Evaluation of oxygen diffusion distances in human breast cancer xenografts using tumor-specific in vivo data: Role of various mechanisms in the development of tumor hypoxia

Metabolic Imaging in Microregions of Tumors and Normal Tissues With Bioluminescence and Photon Counting