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      Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging

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      Scientific Reports
      Nature Publishing Group

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          Abstract

          Six different types of cancer ( i.e., breast, lung, colorectal, esophageal, gastric, and thyroid cancer) have high rates of incidence or mortality worldwide. It has been shown that activation of de novo lipogenesis is an early and common event in the cancer microenvironment. In this study, we performed lipid imaging and profiling for 134 tissue samples from six different types of cancer using matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry, with 2,5-dihydroxybenzoic acid and 1,8-bis(dimethyl-amino)naphthalene as matrices in the positive and negative ion modes, respectively. Multivariate statistical analysis coupled with lipid distribution images revealed that significantly increased levels of monounsaturated fatty acids and monounsaturated phosphatidylcholines relative to polyunsaturated fatty acids and polyunsaturated phosphatidylcholines were observed in the cancer microenvironment compared with the adjacent normal tissue. The immunohistochemical assay indicated that fatty acid synthase, stearoyl-CoA desaturase-1, and choline kinase α were up-regulated in the cancer microenvironment compared with the adjacent normal tissue. Our findings suggest that de novo lipogenesis was activated in six types of cancer to promote a biosynthesis of lipids with monounsaturated acyl chains and to suppress a biosynthesis of polyunsaturated lipids in the cancer microenvironment.

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          De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

          Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. ©2010 AACR.
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            Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression.

            Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.
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              Mass spectrometric imaging for biomedical tissue analysis.

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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                05 August 2014
                2014
                : 4
                : 5959
                Affiliations
                [1 ]Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100005, P.R. China
                [2 ]Department of Clinical Laboratory, Heze Municipal Hospital , Shandong 274031, P.R. China
                Author notes
                Article
                srep05959
                10.1038/srep05959
                4121604
                25091112
                78548efa-e041-4e5e-a3ba-c321c65397a3
                Copyright © 2014, Macmillan Publishers Limited. All rights reserved

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 30 May 2014
                : 16 July 2014
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