Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity
Open accessAbstract
Significance: Exosome-mediated intercellular transfer of proteins and nucleic acids has attracted considerable attention as exosomes may promote the development of cancer and other pathological conditions; however, the mechanism of exosome uptake by target cells and how this may be inhibited remain as important questions. We provide evidence that heparan sulfate proteoglycans (HSPGs) function as receptors of cancer cell-derived exosomes. Importantly, our data indicate that the HSPG-dependent uptake route is highly relevant for the biological activity of exosomes, and thus a potential target for inhibition of exosome-mediated tumor development. Given that several viruses have previously been shown to enter cells through HSPGs, our data implicate HSPG as a convergence point during cellular uptake of endogenous vesicles and virus particles.
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Exosomes range between 30-100 nm in diameter, have a bilayered membrane, and express CD63.
“Exosomes range between 30–100 nm in diameter, have a bilayered membrane (Johnstone et al., 1987) and express surface marker such as CD63 (Christianson et al., 2013).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Christianson et al., 2013
Heparin inhibits uptake of exosomes by cells.
“heparin has been recently shown to inhibit uptake of exosomes by cells (Christianson et al., 2013).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Christianson et al., 2013
The utilization of exosomes in cancer cell cultures was based on an exosome concentration of 100-400 μg/ml reported in the literature.
“The utilization of exosomes in cancer cell cultures were based on application of 100–400 μg/ml of exosomes concentration that has been reported in literature (Christianson et al., 2013; Zhu et al., 2012).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Christianson et al., 2013
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Cites
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007) · Nature Cell Biology · doi:10.1038/ncb1596 · Cited by 12,834 · see citing works
Membrane vesicles as conveyors of immune responses
Théry, C., Ostrowski, M., & Segura, É. (2009) · Nature reviews. Immunology · doi:10.1038/nri2567 · Cited by 3,869 · see citing works
B lymphocytes secrete antigen-presenting vesicles.
Raposo, G., Nijman, H. W., Stoorvogel, W., Liejendekker, R., Harding, C. V., Melief, C. J., & Geuze, H. J. (1996) · The Journal of experimental medicine · doi:10.1084/jem.183.3.1161 · Cited by 3,546 · see citing works
Rab27a and Rab27b control different steps of the exosome secretion pathway
Ostrowski, M., Carmo, N., Krumeich, S., Fanget, I., Raposo, G., Savina, A., Moita, C. F., Schauer, K., Hume, A. N., Freitas, R. P., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb2000 · Cited by 2,761 · see citing works
Syndecan–syntenin–ALIX regulates the biogenesis of exosomes
Baietti, M. F., Zhang, Z., Mortier, E., Melchior, A., Degeest, G., Geeraerts, A., Ivarsson, Y., Depoortere, F., Coomans, C., Vermeiren, E., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2502 · Cited by 1,899 · see citing works
Shedding microvesicles: artefacts no more
Cocucci, E., Racchetti, G., & Meldolesi, J. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2008.11.003 · Cited by 1,742 · see citing works
Heparan sulphate proteoglycans fine-tune mammalian physiology
Bishop, J. R., Schuksz, M., & Esko, J. D. (2007) · Nature · doi:10.1038/nature05817 · Cited by 1,631 · see citing works
Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A., & Ratajczak, M. Z. (2006) · Leukemia · doi:10.1038/sj.leu.2404296 · Cited by 1,340 · see citing works
A Novel Role for 3-O-Sulfated Heparan Sulfate in Herpes Simplex Virus 1 Entry
Shukla, D., Liu, J., Blaiklock, P., Shworak, N. W., Bai, X., Esko, J. D., Cohen, G. H., Eisenberg, R. J., ROSENBERG, R. D., & Spear, P. G. (1999) · Cell · doi:10.1016/s0092-8674(00)80058-6 · Cited by 1,053 · see citing works
Kucharzewska, P., Christianson, H. C., Welch, J. E., Svensson, K. J., Fredlund, E., Ringnér, M., Mörgelin, M., Bourseau-Guilmain, E., Bengzon, J., & Belting, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220998110 · Cited by 939 · see citing works
Self-citationAs we wait: coping with an imperfect nomenclature for extracellular vesicles
Gould, S. J., & Raposo, G. (2013) · Journal of Extracellular Vesicles · doi:10.3402/jev.v2i0.20389 · Cited by 864 · see citing works
Internalization of HIV-1 Tat Requires Cell Surface Heparan Sulfate Proteoglycans
Tyagi, M., Rusnati, M., Presta, M., & Giacca, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006701200 · Cited by 718 · see citing works
Bobrie, A., Krumeich, S., Reyal, F., Recchi, C., Moita, L. F., Seabra, M. C., Ostrowski, M., & Théry, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0925 · Cited by 647 · see citing works
Gould, S. J., Booth, A. M., & Hildreth, J. E. K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1831413100 · Cited by 638 · see citing works
Filmus, J., Capurro, M., & Rast, J. P. (2008) · Genome biology · doi:10.1186/gb-2008-9-5-224 · Cited by 555 · see citing works
Human tumor virus utilizes exosomes for intercellular communication
Meckes, D. G., Shair, K. H. Y., Marquitz, A. R., Kung, C.-P., Edwards, R. H., & Raab‐Traub, N. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014194107 · Cited by 542 · see citing works
Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry
Shukla, D., & Spear, P. G. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13799 · Cited by 497 · see citing works
Developmental changes in heparan sulfate expression: in situ detection with mAbs.
David, G., Bai, X. M., der Schueren, B. V., Cassiman, J. J., & BERGHE, H. V. D. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.119.4.961 · Cited by 479 · see citing works
Interactions between heparan sulfate and proteins: the concept of specificity
Kreuger, J., Spillmann, D., Li, J., & Lindahl, U. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200604035 · Cited by 465 · see citing works
Self-citationHerpesviruses and heparan sulfate: an intimate relationship in aid of viral entry
Shukla, D., & Spear, P. G. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113799 · Cited by 454 · see citing works
Syndecans: proteoglycan regulators of cell-surface microdomains?
Couchman, J. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1257 · Cited by 430 · see citing works
Microvesicles: Messengers and mediators of tumor progression
Al-Nedawi, K. N. I., Meehan, B., & Rak, J. W. (2009) · Cell Cycle · doi:10.4161/cc.8.13.8988 · Cited by 401 · see citing works
Heparan sulfate proteoglycan as a plasma membrane carrier
Belting, M. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00031-8 · Cited by 312 · see citing works
Self-citationU87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line
Clark, M. J., Homer, N., O’Connor, B. D., Chen, Z., Eskin, A., Lee, H., Merriman, B., & Nelson, S. F. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000832 · Cited by 306 · see citing works
Svensson, K. J., Kucharzewska, P., Christianson, H. C., Sköld, S., Löfstedt, T., Johansson, M. C., Mörgelin, M., Bengzon, J., Ruf, W., & Belting, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104261108 · Cited by 288 · see citing works
Self-citationIzquierdo-Useros, N., Naranjo-Gómez, M., Archer, J., Hatch, S., Erkizia, I., Blanco, J., Borràs, F., Puertas, M., Connor, J., Férnandez-Figueras, M., et al. (2009) · Blood · doi:10.1182/blood-2008-05-158642 · Cited by 233 · see citing works
Kadiu, I., Narayanasamy, P., Dash, P. K., Zhang, W., & Gendelman, H. E. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102244 · Cited by 230 · see citing works
Heparan sulfate: Anchor for viral intruders?
Spillmann, D. (2001) · Biochimie · doi:10.1016/s0300-9084(01)01290-1 · Cited by 185 · see citing works
Nuclear Targeting of Macromolecular Polyanions by an HIV-Tat Derived Peptide
Sandgren, S., Cheng, F., & Belting, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205395200 · Cited by 174 · see citing works
Self-citationBelting, M., & Wittrup, A. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200810038 · Cited by 163 · see citing works
Self-citationAn Animal Cell Mutant Defective in Heparan Sulfate Hexuronic Acid 2- -Sulfation
Bai, X., & Esko, J. D. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.17711 · Cited by 132 · see citing works
Virus-modified exosomes for targeted RNA delivery; A new approach in nanomedicine
Koppers‐Lalic, D., Hogenboom, M. M., Middeldorp, J. M., & Pegtel, D. M. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.07.006 · Cited by 131 · see citing works
Extracellular Vesicles and Their Convergence with Viral Pathways
Wurdinger, T. D., Gatson, N. T., Balaj, L., Kaur, B., Breakefield, X. O., & Pegtel, D. M. (2012) · Advances in Virology · doi:10.1155/2012/767694 · Cited by 130 · see citing works
Tumor attenuation by combined heparan sulfate and polyamine depletion
Belting, M., Borsig, L., Fuster, M. M., Brown, J. R., Persson, L., Fransson, L., & Esko, J. D. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012346499 · Cited by 120 · see citing works
Self-citationProteoglycan involvement in polyamine uptake
Belting, M., PERSSON, S., & Fransson, L. (1999) · Biochemical Journal · doi:10.1042/bj3380317 · Cited by 102 · see citing works
Self-citationCharacterization of Anti-heparan Sulfate Phage Display Antibodies AO4B08 and HS4E4
Kurup, S., Wijnhoven, T. J. M., Jenniskens, G. J., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702073200 · Cited by 81 · see citing works
Wittrup, A., Zhang, S., Svensson, K. J., Kucharzewska, P., Johansson, M. C., Mörgelin, M., & Belting, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002622107 · Cited by 71 · see citing works
Self-citationFransson, L., Sjöberg, I., & Havsmark, B. (1980) · PubMed · Cited by 69 · see citing works
Wittrup, A., Zhang, S., ten Dam, G. B., Kuppevelt, T. H. V., Bengtson, P., Johansson, M. C., Welch, J. E., Mörgelin, M., & Belting, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.036129 · Cited by 60 · see citing works
Self-citationStructural Studies on Heparan Sulphates
Fransson, L., Sjöberg, I., & Havsmark, B. (1980) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1980.tb05997.x · Cited by 53 · see citing works
HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells
Mani, K., Sandgren, S., Lilja, J., Cheng, F., Svensson, K. J., Persson, L., & Belting, M. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0370 · Cited by 27 · see citing works
Self-citationBame, K. J., Li, Z., David, G., et al. (1994) · Biochemical Journal · doi:10.1042/bj3030081 · Cited by 23 · see citing works
The role of negative charge in spontaneous aggregation of transformed and untransformed cell lines
Wright, T. C., Smith, B. A., Ware, B. R., et al. (1980) · Journal of Cell Science · doi:10.1242/jcs.45.1.99 · Cited by 22 · see citing works
Selection of Glycosaminoglycan-Deficient Mutants
Bai, X., Crawford, B. E., & Esko, J. D. (2003) · Humana Press eBooks · doi:10.1385/1-59259-209-0:309 · Cited by 10 · see citing works
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Colombo, M., Raposo, G., & Théry, C. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122326 · Cited by 6,186 · see citing works
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O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0251-y · Cited by 1,811 · see citing works
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Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., et al. (2016) · eLife · doi:10.7554/elife.10250 · Cited by 927 · see citing works
Tian, T., Zhu, Y.-L., Zhou, Y.-Y., Liang, G.-F., Wang, Y.-Y., Hu, F.-H., & Xiao, Z.-D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.588046 · Cited by 726 · see citing works
Johnsen, K. B., Gudbergsson, J. M., Skov, M. N., Pilgaard, L., Moos, T., & Duroux, M. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.04.005 · Cited by 704 · see citing works
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Prada, I., Gabrielli, M., Turola, E., Iorio, A., D’Arrigo, G., Parolisi, R., De Luca, M., Pacifici, M., Bastoni, M., Lombardi, M., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-017-1803-x · Cited by 312 · see citing works
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- Authors
- Christianson, H. C., Svensson, K. J., van Kuppevelt, T. H., Li, J.-P., & Belting, M.
- Affiliations
- Lund University (SE)
- Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands;
- Uppsala University (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-10-07
- Volume
- 110
- Issue
- 43
- Pages
- 17380-17385
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3808637
- OpenAlex
- W2008627178
- Cited by
- 903
- References
- 44
- Citations by year
- 2026: 51 · 2025: 46 · 2024: 80 · 2023: 81 · 2022: 76 · 2021: 87 · 2020: 81 · 2019: 95 · 2018: 79 · 2017: 77 · 2016: 57 · 2015: 48 · 2014: 44 · 2013: 1
- FWCI
- 22.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- heparan sulfate proteoglycans, exosome internalization, extracellular vesicles, syndecans, glypicans, chondroitin sulfate, sulfation, xylosides, ERK signaling, tumor cell migration
- MeSH terms
- Animals, Cell Membrane, Cricetulus, Cytoplasm, Dose-Response Relationship, Drug, Endocytosis, Flow Cytometry, Glycosides, Cricetinae, Heparan Sulfate, Heparitin Sulfate, Humans, Microscopy, Electron, Mutation, Protein Binding, Blotting, Western, CHO Cells, Heparan Sulfate Proteoglycans, Mitogen-Activated Protein Kinase 1, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3, Exosomes
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