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Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration

Offer, Svenja LU ; Menard, Julien LU ; Enriquez Perez, Julio LU orcid ; Goncalves De Oliveira, Kelin LU ; Indira Chandran, Vineesh LU ; Johansson, Maria C LU ; Bång-Rudenstam, Anna LU orcid ; Siesjö, Peter LU orcid ; Ebbesson, Anna LU and Hedenfalk, Ingrid LU orcid , et al. (2019) In Journal of Experimental & Clinical Cancer Research 38.
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... (More)
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.
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Experimental & Clinical Cancer Research
volume
38
article number
241
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85066973652
  • pmid:31174567
ISSN
1756-9966
DOI
10.1186/s13046-019-1228-6
language
English
LU publication?
yes
id
052d3f90-3e42-4495-8fb2-dccc9d8ba0a5
date added to LUP
2019-06-27 10:54:36
date last changed
2024-05-14 16:40:31
@article{052d3f90-3e42-4495-8fb2-dccc9d8ba0a5,
  abstract     = {{Background<br/><br/>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.<br/>Methods<br/><br/>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.<br/>Results<br/><br/>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.<br/>Conclusions<br/><br/>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.<br/>}},
  author       = {{Offer, Svenja and Menard, Julien and Enriquez Perez, Julio and Goncalves De Oliveira, Kelin and Indira Chandran, Vineesh and Johansson, Maria C and Bång-Rudenstam, Anna and Siesjö, Peter and Ebbesson, Anna and Hedenfalk, Ingrid and Maly Sundgren, Pia and Darabi, Anna and Belting, Mattias}},
  issn         = {{1756-9966}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Experimental & Clinical Cancer Research}},
  title        = {{Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration}},
  url          = {{http://dx.doi.org/10.1186/s13046-019-1228-6}},
  doi          = {{10.1186/s13046-019-1228-6}},
  volume       = {{38}},
  year         = {{2019}},
}