Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration
Abstract Background Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cell...
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BMC
2019-06-01
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Series: | Journal of Experimental & Clinical Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13046-019-1228-6 |
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doaj-139878c7c70b43af97497255555f7499 |
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record_format |
Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Svenja Offer Julien A. Menard Julio Enríquez Pérez Kelin G. de Oliveira Vineesh Indira Chandran Maria C. Johansson Anna Bång-Rudenstam Peter Siesjö Anna Ebbesson Ingrid Hedenfalk Pia C. Sundgren Anna Darabi Mattias Belting |
spellingShingle |
Svenja Offer Julien A. Menard Julio Enríquez Pérez Kelin G. de Oliveira Vineesh Indira Chandran Maria C. Johansson Anna Bång-Rudenstam Peter Siesjö Anna Ebbesson Ingrid Hedenfalk Pia C. Sundgren Anna Darabi Mattias Belting Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration Journal of Experimental & Clinical Cancer Research Glioma Lipid metabolism Hypoxia Angiogenesis Macrophages |
author_facet |
Svenja Offer Julien A. Menard Julio Enríquez Pérez Kelin G. de Oliveira Vineesh Indira Chandran Maria C. Johansson Anna Bång-Rudenstam Peter Siesjö Anna Ebbesson Ingrid Hedenfalk Pia C. Sundgren Anna Darabi Mattias Belting |
author_sort |
Svenja Offer |
title |
Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
title_short |
Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
title_full |
Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
title_fullStr |
Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
title_full_unstemmed |
Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
title_sort |
extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-06-01 |
description |
Abstract Background Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor “stressness” represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment. Methods Regions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE−/− mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student’s T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival. Results We show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE−/− mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival. Conclusions Together, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment. |
topic |
Glioma Lipid metabolism Hypoxia Angiogenesis Macrophages |
url |
http://link.springer.com/article/10.1186/s13046-019-1228-6 |
work_keys_str_mv |
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doaj-139878c7c70b43af97497255555f74992020-11-25T03:53:59ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-06-0138111410.1186/s13046-019-1228-6Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltrationSvenja Offer0Julien A. Menard1Julio Enríquez Pérez2Kelin G. de Oliveira3Vineesh Indira Chandran4Maria C. Johansson5Anna Bång-Rudenstam6Peter Siesjö7Anna Ebbesson8Ingrid Hedenfalk9Pia C. Sundgren10Anna Darabi11Mattias Belting12Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Neurosurgery, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Neurosurgery, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityDepartment of Clinical Sciences, Lund, Section of Diagnostic Radiology, Lund UniversityDepartment of Clinical Sciences Lund, Section of Neurosurgery, Lund UniversityDepartment of Clinical Sciences Lund, Section of Oncology and Pathology, Lund UniversityAbstract Background Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor “stressness” represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment. Methods Regions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE−/− mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student’s T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival. Results We show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE−/− mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival. Conclusions Together, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.http://link.springer.com/article/10.1186/s13046-019-1228-6GliomaLipid metabolismHypoxiaAngiogenesisMacrophages |