Chm 635-10

Chm 635-10 - Cancer and Glycolysis Gatenby & Gillies...

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1 Cancer and Glycolysis Gatenby & Gillies Nature 2004, 891.
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2 • A near universal property of primary and metastatic cancers is upregulation of glycolysis. The mediastinal nodes (purple arrow) and supraclavicular nodes (green arrows) show high uptake of 18fluorodeoxyglucose (FdG), showing that tumours in these nodes have high levels of FdG uptake. The bladder (yellow arrow) also has high activity, because of excretion of the radionuclide. Upregulation of glycolysis leads to microenvironmental acidosis requiring evolution of phenotypes requiring evolution to phenotypes resistant to acid induced cell toxicity. Gatenby & Gillies Nature 2004, 891.
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3 A common property of invasive cancer is altered glucose metabolism. In most mammalian cells, glycolysis is inhibited in the presence of oxygen (Pasteur Effect) . Conversion of glucose to lactic acid in the presence of oxygen is called Warburg Effect or Aerobic Glycolysis . Increased aerobic glycolysis is uniquely observed in cancers. Increased glucose uptake is largely dependent on the rate of glycolysis. Upregulation of glucose transporters GLUT1 and GLUT3 and Hexokinases 1 and 2. FdG PET imaging consistently correlates with poor prognosis and increased tumor aggressiveness. Hypoxic tumors are often more invasive and metastatic.
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4 In both cell lines, glucose consumption is reduced in the presence of oxygen — the Pasteur effect (P). However, the more aggressive cell line, MDA-MB-231, has much higher glucose consumption in the presence of oxygen than the MCF-7 cells with a non- invasive phenotype — the Warburg effect (W). This is consistent with positron-emission tomography scans with 18fluorodeoxyglucose, which show that higher glucose uptake correlates with more aggressive phenotypes and poorer clinical outcomes. Pasteur and Warburg effects in non-invasive and metastatic breast cancer cell lines. Model for cell–environment interactions in carcinogenesis. Normal epithelial cells (grey) become hyperproliferative (pink) following induction. As they reach the oxygen diffusion limit, they become hypoxic (blue), which can either lead to cell death (apoptotic cells shown with blebbing) or adaptation of a glycolytic phenotype (green), which allows cells to survive. As a consequence of glycolysis, lesions become acidotic, which selects for motile cells (yellow) that eventually breach the basement membrane. As cancer progression proceeds, the mutations in cells increase (nuclei shown as light orange for one mutation and darker oranges for more mutations). Following breakdown of the basement membrane, cells gain access to existing and newly formed blood and lymphatic vascular routes for metastasis.
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5 Regulation of Glycolysis The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth Christofk et al. (2008) Nature 452: 230-34.
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Chm 635-10 - Cancer and Glycolysis Gatenby & Gillies...

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