Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration
(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.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/052d3f90-3e42-4495-8fb2-dccc9d8ba0a5
- author
- organization
-
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Tumor microenvironment (research group)
- Tumor microenvironment
- Glioma immunotherapy group (research group)
- Neurosurgery
- The Liquid Biopsy and Tumor Progression in Breast Cancer (research group)
- Breast and Ovarian Cancer Genomics (research group)
- Breastcancer-genetics
- Diagnostic Radiology, (Lund)
- publishing date
- 2019-06-07
- 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}}, }