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.

Full-text preview

Available from:
    • "Despite the avidity with which they take up glucose and amino acids, cancer cells in vivo often encounter conditions of nutrient scarcity as a result of the increased rates of nutrient consumption and the inadequacies of the tumor vascular supply (Vaupel et al., 1989). To deal with depleted supplies of the normal anabolic precursors, certain cancers acquire mutations that activate the cellular ability to utilize alternative ways of obtaining necessary nutrients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.
    No preview · Article · Jan 2016 · Cell metabolism
  • Source
    • "Capillaries in tumors form a complex network with different features compared to that of normal tissues. The main differences reside in structural and functional abnormalities such as dilatations, incomplete or absent basement membranes, high permeability, irregular architecture, blind ends, absence of vascular smooth muscle, and pharmacological/physiological receptors [46, 47]. Since all these altered characteristics in the vasculature determine irregular blood flow and tumor cells spread rapidly beyond the diffusion distance of oxygen (about 100 í µí¼‡m) in the tissue, O 2 as well as nutrients is supplied with increasing difficulty and hypoxic or anoxic areas develop throughout the tumor mass [47]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Among all solid tumors, the high-grade glioma appears to be the most vascularized one. In fact, “microvascular hyperplasia” is a hallmark of GBM. An altered vascular network determines irregular blood flow, so that tumor cells spread rapidly beyond the diffusion distance of oxygen in the tissue, with the consequent formation of hypoxic or anoxic areas, where the bulk of glioblastoma stem cells (GSCs) reside. The response to this event is the induction of angiogenesis, a process mediated by hypoxia inducible factors. However, this new capillary network is not efficient in maintaining a proper oxygen supply to the tumor mass, thereby causing an oxygen gradient within the neoplastic zone. This microenvironment helps GSCs to remain in a “quiescent” state preserving their potential to proliferate and differentiate, thus protecting them by the effects of chemo- and radiotherapy. Recent evidences suggest that responses of glioblastoma to standard therapies are determined by the microenvironment of the niche, where the GSCs reside, allowing a variety of mechanisms that contribute to the chemo- and radioresistance, by preserving GSCs. It is, therefore, crucial to investigate the components/factors of the niche in order to formulate new adjuvant therapies rendering more efficiently the gold standard therapies for this neoplasm.
    Full-text · Article · Jan 2016 · Stem cell International
  • Source
    • "Gastric cancer cells are usually present in an environment with acidic pH (Stubbs et al., 1999; Stubbs et al., 1994). Higher rate of proliferation in gastric cancer cells accompanied by faster rates of glycolysis results production of molecules acidic in nature (Holm et al., 1995; Vaupel et al., 1989). Since the increased concentration of acid molecules inside the cells is harmful for their growth and proliferation, these cells eliminate the protons into outer environment (Tannock and Rotin, 1989; Helmlinger et al., 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study investigates the effect of rubriflordilactone A on the viability and its underlying mechanism in gastric cancer cell lines (SNU-1 and SNU-5) and normal gastric epithelial cell line (GES‑1). Incubation of the gastric cancer and non cancer cell lines in acidic media led to reduction in the viability of the non cancer cells without any effect on cancer cells. Apoptosis in SNU-1 and SNU-5 cells was induced on exposure to rubriflordilactone A after 48 hours compared to the control cells (p<0.01). The percentage of apoptosis in SNU-1 and SNU-5 cells on exposure to rubriflordilactone A was 79.3 ± 4.7 and 74.0 ± 5.1, respectively after 48 hours. Exposure of SNU-1 and SNU-5 cancer cell lines to rubriflordilactone A at a concentration of 10 μM in media with acidic pH decreased phosphorylation of ERK ½. The similar reduction was caused by ERK 1/2 phosphorylation inhibition, PD98059. Thus rubriflordilactone A reduces viability of gastric cancer cell lines by inducing apoptosis through the reduction of ERK 1/2 phosphorylation.
    Preview · Article · Dec 2015 · Bangladesh Journal of Pharmacology
Show more