title: Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis.
abstract: Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential. Cancer Res; 76(16); 4828-40. ©2016 AACR.
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Julien A
authors.initials: JA
authors.lastname: Menard
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Christianson
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Paulina
authors.initials: P
authors.lastname: Kucharzewska
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Bourseau-Guilmain
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Katrin J
authors.initials: KJ
authors.lastname: Svensson
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Lindqvist
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Vineesh
authors.initials: V
authors.lastname: Indira Chandran
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden. Center of Excellence in Biological and Medical Mass Spectrometry "CEBMMS", Biomedical Centre D13, Lund University, Lund, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Welinder
authors.affiliation: Lund Stem Cell Center, Lund University, Lund, Sweden. Department of Clinical Sciences, Section of Neurosurgery, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Bengzon
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Johansson
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden. Skåne University Hospital, Lund, Sweden. Mattias.Belting@med.lu.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000222:Adaptation, Physiological / Q000502:physiology; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004705:Endocytosis / Q000502:physiology*; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D061346:Laser Capture Microdissection; D008074:Lipoproteins / Q000378:metabolism*; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D008074:Lipoproteins; D011509:Proteoglycans; C036090:heparin proteoglycan; D006493:Heparin