| 1. |
- Belting, Mattias
(författare)
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Glycosaminoglycans in cancer treatment.
- 2014
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Ingår i: Thrombosis Research. - 1879-2472. ; 133, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- Studies aimed at the identification of biomarkers and treatment targets of cancer have focused on mRNAs, miRNAs, and proteins expressed by malignant cells, while glycoproteins mainly produced by stromal cells remain relatively unexplored. Glycans lack a given template for their biosynthesis that involves the concerted action of several, sometimes >15 different enzymes. This fact complicates the analysis at the genomic level of the role of glycoproteins in clinical oncology. The glycosaminoglycans (GAGs) stand out as highly polyanionic components at the surface of malignant and stromal tumor cells as well as their surrounding matrix. Published data thus describe a multifaceted regulatory role of GAGs and GAG-conjugated proteins, proteoglycans, in e.g. tumor associated angiogenesis, coagulation, invasion, and metastasis. Relatively small, randomized clinical trials suggest that heparin, an over-sulfated variant of the GAG heparan sulfate, may have direct, anti-tumor effects. Several ongoing trials aim at establishing whether heparin and its derivatives should be added to standard treatment of cancer patients or not, based on progression free- and overall survival end-point data. Given the potential bleeding complications with this treatment, other strategies to block GAG function should provide interesting alternatives. In the emerging era of personalized medicine, one can foresee the development of predictive biomarkers to select patients that may benefit from GAG-targeted treatments, aiming at individualized prevention of thromboembolic complications as well as inhibition of tumor development and progression. Here, the role of GAGs as targets and vehicles of cancer treatment is discussed with special emphasis on angiogenesis and coagulation associated mechanisms. © 2014 Elsevier Ltd. All rights reserved.
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| 2. |
- Belting, Mattias, et al.
(författare)
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Vasoactive Peptides with Angiogenesis-Regulating Activity Predict Cancer Risk in Males.
- 2012
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 21:3, s. 513-522
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tumor development requires angiogenesis, and antiangiogenesis has been introduced in the treatment of cancer patients; however, how the cardiovascular phenotype correlates with cancer risk remains ill-defined. Here, we hypothesized that vasoactive peptides previously implicated in angiogenesis regulation predict long-term cancer risk.METHODS: We measured midregional proatrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), and C-terminal preprovasopressin (copeptin) in fasting plasma from participants of the Malmö Diet and Cancer Study that were free from cancer prior to the baseline exam in 1991 to 1994 (1,768 males and 2,293 females). We used Cox proportional hazards models to determine the time to first cancer event in relation to baseline levels of vasoactive peptides during a median follow-up of 15 years.RESULTS: First cancer events occurred in 366 males and in 368 females. In males, one SD increase of MR-proANP, copeptin, and MR-proADM was independently related to incident cancer [HR (95% CI)] by 0.85 (0.74-0.96), P = 0.012; 1.17 (1.04-1.32), P = 0.009; and 1.12 (0.99-1.26), P = 0.065, respectively, and a summed biomarker score identified an almost 2-fold difference in cancer risk between the top and bottom quartile (P < 0.001). In younger males, the biomarker score identified a more than 3-fold increase in risk between the top and bottom quartile (P < 0.001). Among females, we found no relationship between biomarkers and cancer incidence.CONCLUSIONS: Our data suggest that vasoactive peptide biomarkers predict cancer risk in males, particularly in younger males.Impact: Our findings may have implications for cancer risk prediction and present novel, potentially drug modifiable, mechanisms underlying cancer development. Cancer Epidemiol Biomarkers Prev; 1-10. ©2012 AACR.
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| 3. |
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| 4. |
- Cheng, Fang, et al.
(författare)
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APP/APLP2 expression is required to initiate endosome-nucleus-autophagosome trafficking of glypican-1-derived heparan sulfate.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:30, s. 20871-20878
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Tidskriftsartikel (refereegranskat)abstract
- Anhydromannose (anMan)-containing heparan sulfate (HS) derived from the proteoglycan glypican-1 (Gpc-1) is generated in endosomes by an endogenously or ascorbate induced SNO-catalyzed reaction. Processing of the amyloid precursor protein (APP) and APP-like protein 2 (APLP2) by β- and γ-secretases into amyloid beta (Aβ) and Aβ-like peptides also takes place in these compartments. Moreover, anMan-containing HS suppresses the formation of toxic Aβ assemblies in vitro. We show by using deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody as well as 35S-labeling experiment that expression of APP/APLP2 is required for ascorbate-induced transport of HS from endosomes to the nucleus. Nuclear translocation was observed in wild-type mouse embryonic fibroblasts (Wt-MEF), Tg2576 MEF and N2a neuroblastoma cells but not in APP-/- and APLP2-/- MEF. Transfection of APP-/- cells with a vector encoding APP restored nuclear import of anMan-containing HS. In Wt-MEF and N2a neuroblastoma cells exposed to β- or γ-secretase inhibitors, nuclear translocation was greatly impeded, suggesting involvement of APP/APLP2 degradation products. In Tg2576 MEF, the β-inhibitor blocked transport but the γ- inhibitor did not. During chase in ascorbate-free medium, anMan-containing HS disappeared from the nuclei of Wt-MEF. Confocal immunofluorescence microscopy showed that they appeared in acidic, LC3-positive vesicles in keeping with an autophagosomal location. There was increased accumulation of anMan-containing HS in nuclei and cytosolic vesicles upon treatment with chloroquine indicating that HS was degraded in lysosomes. Manipulations of APP expression and processing may have deleterious effects upon HS function in the nucleus.
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| 5. |
- Christianson, Helena, et al.
(författare)
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Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:43, s. 17380-17385
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo.
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| 6. |
- Christianson, Helena, et al.
(författare)
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Exosome and microvesicle mediated phene transfer in mammalian cells.
- 2014
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 28:Apr 23, s. 31-38
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Forskningsöversikt (refereegranskat)abstract
- Extracellular vesicles (EVs), e.g. exosomes and microvesicles, emerge as new signaling organelles in the exchange of information between cells at the paracrine and systemic level. It is clear that these virus like particles carry complex biological information that can elicit a pleiotropic response in recipient cells with potential relevance in physiology as well as in cancer and other pathological conditions. Numerous studies convincingly show that the molecular composition of EVs closely reflects their cell or tissue of origin. Thus, the signaling status of donor cells, more specifically their endosomal compartments, may largely determine the biological output in recipient cells, a process that we then may conceptualize as vesicle mediated phene transfer. Whereas more conventional modes of cell-cell communication mostly depend on extracellular ligand concentration and cell-surface receptor availability, the magnitude of the EV signaling response relies on the capture and uptake by target cells, allowing release of the EV content. Numerous reports point at the intriguing possibility that, among thousands of mRNAs, miRNAs, and proteins, single EV constituents effectuate the biological response, e.g. stimulation of angiogenesis and cancer cell metastasis, in recipient cells; however, we find it conceivable that strategies targeted at general mechanisms of EV function should provide more rational avenues for therapeutic intervention directed at the EV system. Such strategies include manipulation of EV formation in the endolysosomal system, EV stability in the extracellular milieu, and EV entry into target cells. Here, we provide important insights into potential mechanisms of EV transport in mammalian cells and how these may be targeted.
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| 7. |
- Christianson, Helena, et al.
(författare)
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Heparan sulfate proteoglycan as a cell-surface endocytosis receptor.
- 2014
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Ingår i: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 35:Oct 18, s. 51-55
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Tidskriftsartikel (refereegranskat)abstract
- How various macromolecules are exchanged between cells and how they gain entry into recipient cells are fundamental questions in cell biology with important implications e.g. non-viral drug delivery, infectious disease, metabolic disorders, and cancer. The role of heparan sulfate proteoglycan (HSPG) as a cell-surface receptor of diverse macromolecular cargo has recently been manifested. Exosomes, cell penetrating peptides, polycation-nucleic acid complexes, viruses, lipoproteins, growth factors and morphogens among other ligands enter cells through HSPG-mediated endocytosis. Key questions that partially have been unraveled over recent years include the respective roles of HSPG core protein and HS chain structure specificity for macromolecular cargo endocytosis, the down-stream intracellular signaling events involved in HSPG-dependent membrane invagination and vesicle formation, and the biological significance of the HSPG transport pathway. Here, we discuss the intriguing role of HSPGs as a major entry pathway of macromolecules in mammalian cells with emphasis on recent in vitro and in vivo data that provide compelling evidence of HSPG as an autonomous endocytosis receptor.
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| 8. |
- Christianson, Helena, et al.
(författare)
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ScFv Anti-Heparan Sulfate Antibodies Unexpectedly Activate Endothelial and Cancer Cells through p38 MAPK: Implications for Antibody-Based Targeting of Heparan Sulfate Proteoglycans in Cancer.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer. In this context, heparan sulfate proteoglycans (HSPGs) emerge as interesting targets, owing to their function as co-receptors of major, pro-angiogenic factors. Accordingly, previous studies have suggested anti-tumor effects of heparin, i.e. over-sulfated HS, and various heparin mimetics; however, a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties. Here, we have explored the use of human ScFv anti-HS antibodies (αHS) as a more rational approach to target HSPG function in endothelial cells (ECs). αHS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors, i.e. highly angiogenic brain tumors. Unexpectedly, we found that these αHS exhibited potent pro-angiogenic effects in primary human ECs. αHS were shown to stimulate EC differentiation, which was associated with increased EC tube formation and proliferation. Moreover, αHS supported EC survival under hypoxia and starvation, i.e. conditions typical of the tumor microenvironment. Importantly, αHS-mediated proliferation was efficiently counter-acted by heparin and was absent in HSPG-deficient mutant cells, confirming HS-specific effects. On a mechanistic level, binding of αHS to HSPGs of ECs as well as glioblastoma cells was found to trigger p38 MAPK-dependent signaling resulting in increased proliferation. We conclude that several αHS that recognize HS epitopes abundant in the tumor vasculature may elicit a pro-angiogenic response, which has implications for the development of antibody-based targeting of HSPGs in cancer.
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| 9. |
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| 10. |
- Kucharzewska, Paulina, et al.
(författare)
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Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress.
- 2013
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 2
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Forskningsöversikt (refereegranskat)abstract
- Cells are constantly subjected to various types of endogenous and exogenous stressful stimuli, which can cause serious and even permanent damage. The ability of a cell to sense and adapt to environmental alterations is thus vital to maintain tissue homeostasis during development and adult life. Here, we review some of the major phenotypic characteristics of the hostile tumour microenvironment and the emerging roles of extracellular vesicles in these events.
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