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

Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.20166

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

The literature describing 31P, 1H, 13C, 23Na and 19F MRS in vivo in human cancers is reviewed. Cancers have typical metabolic characteristics in 31P and 1H MRS including high levels of phospholipid metabolites and a cellular pH more alkaline than normal. These alone are not specific for cancer but are diagnostic in appropriate clinical settings. Some metabolic characteristics appear to be prognostic indices and correlation with treatment response is emerging as an important potentially cost-effective use of MRS in oncology. 19F MRS examines pharmacokinetics of 5-fluorouracil and by demonstrating its retention predicts response of a cancer to treatment. Current needs include improvement of diagnostic specificity by use of techniques like multivoxel MRS, proton decoupling of 31P, short echo time and fat-suppressed 1H MRS, 13C MRS direct or via 1H-observe, and statistical analysis of multiple spectral features. Trials in large populations in well defined clinical settings are needed to determine if MRS can provide independent prognostic indices useful in cancer management.

Studies of human tumors by MRS: a review.

Local rates of cortical glucose metabolism were estimated by positron emission tomography in 13 right-handed patients with Alzheimer's disease. Individuals with disproportionate failure of language function had markedly diminished metabolism in the left frontal, temporal, and parietal regions. Patients with predominant visuo-constructive dysfunction evidenced a hypometabolic focus in the right parietal cortex. Patients with memory failure as the most apparent feature had no significant metabolic asymmetry in cortical regions. In all subjects, verbal competency generally correlated with metabolic activity in the left frontal and temporal areas, while visuo-constructive test performance was linked to glucose utilization in the right parietal lobe.

Alzheimer's disease: Focal cortical changes shown by positron emission tomography

“Functional” tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0–4): 0: no response or progression; 1: 1–33%; 2: >33%–66%; 3: >66%–99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called δTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, δTLG (LGI) = {[(SUVave)1 * (Vol)1 – (SUVave)2 * (Vol)2]/[(SUVave)1 * (Vol)1]} * 100. Where “1” and “2” denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of δTLG with % change in SUVave and % change in SUVmax, as widely used parameters of response, were 0.73 and 0.78 (P

Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis.

Positron emission tomography was used to measure local cerebral glucose utilization by the 2-[ 18 F]fluoro-2-deoxy-D-glucose technique in 23 patients with cerebral gliomas. All 10 high-grade (III and IV) astrocytomas demonstrated a region of high activity with a glucose consumption of 7.4 ± 3.5 (SD) mg/100 gm per minute. The 13 low-grade (I and II) gliomas had a glucose metabolic rate of 4.0 ± 1.8 mg/100 gm per minute, with no distinctly visible hot spot. Thus, we found a correlation between rate of glycolysis and malignancy in primary cerebral tumors. Cerebral cortical glucose utilization was often depressed in areas adjacent to or neurally connected to the tumor site, and there was focal irregular delta wave EEG activity in these areas.

Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography

The spectrum of malignancy in cerebral gliomas is quite vast, from slow-growing, relatively benign lesions (e. g., astrocytoma grade I and certain oligodendrogliomas) to highly malignant tumors characterized by a fast growth rate (e. g., astrocytoma grade IV and glioblastoma multiforme) (Kernohan and Sayre 1952). In a number of cases the preoperative recognition of the various types of cerebral gliomas represents a diagnostic challenge. Among the neuro-radiological techniques, cerebral angiography and particularly transmission X-ray computed tomography (CT) provide substantial information in this area (Tchang et al. 1977; Joyce et al. 1978). Difficulties are encountered, however, even with CT, which may be inconclusive in the detection of the early tumor and in the discrimination of neoplastic tissue from edema (Kendall et al. 1979; Lilja et al. 1981). Discrepancy between histology and the preoperative CT diagnosis is frequent (Lilja et al. 1981). Finally, the assessment of tumor recurrence following surgery, radiotherapy, and chemotherapy may be a formidable task. Quite often we are not able to ascertain if the tumor is recurring and/or if the histological type of the lesion has changed.

L. Sokoloff

Papers

Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography

Glycolytic Rate and Histologic Grade of Human Cerebral Gliomas: A Study with [18F]Fluorodeoxyglucose and Positron Emission Tomography