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      Dietary modifications for enhanced cancer therapy

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      Springer Science and Business Media LLC

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          Vascular endothelial cells synthesize nitric oxide from L-arginine.

          Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue and for the inhibition of platelet aggregation and platelet adhesion attributed to endothelium-derived relaxing factor. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay, chemiluminescence or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
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            VEGF as a Key Mediator of Angiogenesis in Cancer

            Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1–2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the ‘angiogenic switch’, where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.
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              Lactate Metabolism in Human Lung Tumors

              Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                0028-0836
                1476-4687
                March 2020
                March 25 2020
                March 2020
                : 579
                : 7800
                : 507-517
                Article
                10.1038/s41586-020-2124-0
                © 2020

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