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      Lipid metabolism and cancer

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          Abstract

          Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. This review discusses current knowledge about the advances in understanding lipid metabolism regulation in cancer cells and introduces therapies that disrupt lipid metabolism for cancer treatment.

          Abstract

          Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Cancer cells harness lipid metabolism to obtain energy, components for biological membranes, and signaling molecules needed for proliferation, survival, invasion, metastasis, and response to the tumor microenvironment impact and cancer therapy. Here, we summarize and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in cancer cells and introduce different approaches that have been clinically used to disrupt lipid metabolism in cancer therapy.

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          Mechanisms and regulation of cholesterol homeostasis

          Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.
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            Reprogramming of fatty acid metabolism in cancer

            A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
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              Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.

              Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Validation
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                J Exp Med
                J Exp Med
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                04 January 2021
                18 December 2020
                : 218
                : 1
                : e20201606
                Affiliations
                [1 ]Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China
                [2 ]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
                [3 ]Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
                [4 ]School of Life Sciences, Tsinghua University, Beijing, China
                [5 ]Zhejiang University Cancer Center, Hangzhou, China
                Author notes
                Correspondence to Zhimin Lu: zhiminlu@ 123456zju.edu.cn

                Disclosures: The authors declare no competing interests exist.

                [*]

                X. Bian, R. Liu, and Y. Meng contributed equally to this paper.

                Author information
                https://orcid.org/0000-0001-9940-8396
                https://orcid.org/0000-0001-8757-3159
                https://orcid.org/0000-0002-1165-9009
                https://orcid.org/0000-0002-2359-0440
                https://orcid.org/0000-0003-0478-2997
                https://orcid.org/0000-0002-2859-2736
                Article
                jem.20201606
                10.1084/jem.20201606
                7754673
                33601415
                a859da44-1970-48ae-9517-7c7e89ed46c5
                © 2020 Bian et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 24 July 2020
                : 15 October 2020
                : 26 October 2020
                Page count
                Pages: 17
                Funding
                Funded by: Zhejiang University, DOI http://dx.doi.org/10.13039/501100004835;
                Award ID: 188020*194221901/029
                Funded by: Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang;
                Award ID: 2019R01001
                Funded by: National Natural Science Foundation of China, DOI http://dx.doi.org/10.13039/501100001809;
                Award ID: 81902880
                Funded by: Qingdao Postdoctoral Application Research Project;
                Funded by: China Postdoctoral Science Foundation, DOI http://dx.doi.org/10.13039/501100002858;
                Award ID: 2019M660160
                Funded by: Ministry of Science and Technology of the People's Republic of China, DOI http://dx.doi.org/10.13039/501100002855;
                Award ID: 2020YFA0803300
                Categories
                Review
                Metabolism
                Cancer Focus
                Cancer Focus

                Medicine
                Medicine

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