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

Department of Radiation Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston 02114.
Cancer Research (Impact Factor: 9.33). 01/1990; 49(23):6449-65.
Source: PubMed


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.

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    • "It is a common characteristic of most advanced tumors but is also naturally occurring during normal embryogenesis [1] [2]. It has been known for many years that hypoxia has a negative impact on the effectiveness of radiation and chemotherapy [1] [3]. More recently, hypoxia has been recognized as a major factor impacting malignant progression, that is, an increased probability of metastasis and recurrence [4]. "
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    ABSTRACT: Hypoxia is an important and common characteristic of many human tumors. It is a challenge clinically due to the correlation with poor prognosis and resistance to radiation and chemotherapy. Understanding the biochemical response to hypoxia would facilitate the development of novel therapeutics for cancer treatment. Here, we investigate alterations in gene expression in response to hypoxia by quantitative proteome analysis using stable isotope labeling with amino acids in cell culture (SILAC) in conjunction with LCMS/MS. Human HeLa cells were kept either in a hypoxic environment or under normoxic conditions. 125 proteins were found to be regulated, with maximum alteration of 18-fold. In particular, three clusters of differentially regulated proteins were identified, showing significant upregulation of glycolysis and downregulation of mitochondrial ribosomal proteins and translocases. This interaction is likely orchestrated by HIF-1. We also investigated the effect of hypoxia on the cell cycle, which shows accumulation in G1 and a prolonged S phase under these conditions. Implications . This work not only improves our understanding of the response to hypoxia, but also reveals proteins important for malignant progression, which may be targeted in future therapies.
    09/2015; 2015(23):1-9. DOI:10.1155/2015/678527
    • "Recent advances in cancer imaging have focused primarily on identifying tumorspecific targets, such as cell surface receptors, that may be used to visualize malignant tissue, and to distinguish it from healthy tissue. Gradients of oxygen, pH and nutrient concentrations form within solid tumors, resulting in a correlation between intratumoral hypoxia, acidity and nutrient deprivation [2]. Oxygen levels vary considerably within tumors, based on distance from local blood vessels, whereby poorly vascularized areas receiving very low levels of oxygen are characterized as hypoxic. "
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    ABSTRACT: Functional and molecular imaging has become increasingly used to evaluate interpatient and intrapatient tumor heterogeneity. Imaging allows for assessment of microenvironment parameters including tumor hypoxia, perfusion and proliferation, as well as tumor metabolism and the intratumoral distribution of specific molecular markers. Imaging information may be used to stratify patients for targeted therapies, and to define patient populations that may benefit from alternative therapeutic approaches. It also provides a method for non-invasive monitoring of treatment response at earlier time-points than traditional cues, such as tumor shrinkage. Further, companion diagnostic imaging techniques are becoming progressively more important for development and clinical implementation of targeted therapies. Imaging-based companion diagnostics are likely to be essential for the validation and FDA approval of targeted nanotherapies and macromolecular medicines. This review describes recent clinical advances in the use of functional and molecular imaging to evaluate the tumor microenvironment. Additionally, this article focuses on image-based assessment of distribution and anti-tumor effect of nano- and macromolecular systems.
    Journal of Controlled Release 09/2015; DOI:10.1016/j.jconrel.2015.09.036 · 7.71 Impact Factor
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    • "In particular, GlcNAc uptake increases intracellular levels of UDP-GlcNAc, which is a critical building block for not only GlcNAc-containing glycans but also mucin O-glycans and sialic acid (Fig. 1, 1e4). Sialic acid itself can be salvaged from exogenous sources and efficiently taken up by cells [8] [9] and the upregulation of sialin upon nutrient deprivation [3] raises the intriguing possibility that this sugar can be scavenged from a cancer cell's microenvironment to overcome glucose deficiency. Once taken into cells, sialic acid can be used for cell surface sialylation either directly (Fig. 1A) or via conversion to ManNAc (Fig. 1B). "
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    ABSTRACT: Cancer is characterized by abnormal energy metabolism shaped by nutrient deprivation that malignant cells experience during various stages of tumor development. This study investigated the response of nutrient-deprived cancer cells and their non-malignant counterparts to sialic acid supplementation and found that cells utilize negligible amounts of this sugar for energy. Instead cells use sialic acid to maintain cell surface glycosylation through complementary mechanisms. First, levels of key metabolites (e.g., UDP-GlcNAc and CMP-Neu5Ac) required for glycan biosynthesis are maintained or enhanced upon Neu5Ac supplementation. In concert, sialyltransferase expression increased at both the mRNA and protein levels, which facilitated increased sialylation in biochemical assays that measure sialyltransferase activity as well as at the whole cell level. In the course of these experiments, several important differences emerged that differentiated the cancer cells from their normal counterparts including resistant to sialic acid-mediated energy depletion, consistently more robust sialic acid-mediated glycan display, and distinctive cell surface vs. internal vesicle display of newly-produced sialoglycans. Finally, the impact of sialic acid supplementation on specific markers implicated in cancer progression was demonstrated by measuring levels of expression and sialylation of EGFR1 and MUC1 as well as the corresponding function of sialic acid-supplemented cells in migration assays. These findings both provide fundamental insight into the biological basis of sialic acid supplementation of nutrient-deprived cancer cells and open the door to the development of diagnostic and prognostic tools. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biomaterials 08/2015; 70:23-36. DOI:10.1016/j.biomaterials.2015.08.020 · 8.56 Impact Factor
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