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Christianson HC, Menard JA, Chandran VI, et al. Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity. Oncotarget. 2017;8(40):66960-66974doi: 10.18632/oncotarget.16921.
Christianson, H. C., Menard, J. A., Chandran, V. I., Bourseau-Guilmain, E., Shevela, D., Lidfeldt, J., Månsson, A. S., Pastorekova, S., Messinger, J., & Belting, M. (2017). Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity. Oncotarget, 8(40), 66960-66974. https://doi.org/10.18632/oncotarget.16921
Christianson, Helena C, et al. "Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity." Oncotarget vol. 8,40 (2017): 66960-66974. doi: https://doi.org/10.18632/oncotarget.16921
Christianson HC, Menard JA, Chandran VI, Bourseau-Guilmain E, Shevela D, Lidfeldt J, Månsson AS, Pastorekova S, Messinger J, Belting M. Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity. Oncotarget. 2017 Apr 07;8(40):66960-66974. doi: 10.18632/oncotarget.16921. eCollection 2017 Sep 15. PMID: 28978009; PMCID: PMC5620149.
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Oncotarget. 2017 Apr 07;8(40):66960-66974. doi: 10.18632/oncotarget.16921. eCollection 2017 Sep 15.

Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity.

Oncotarget

Helena C Christianson, Julien A Menard, Vineesh Indira Chandran, Erika Bourseau-Guilmain, Dmitry Shevela, Jon Lidfeldt, Ann-Sofie Månsson, Silvia Pastorekova, Johannes Messinger, Mattias Belting

Affiliations

  1. Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
  2. CNRS UMR 5237 CRBM, Montpellier University, Montpellier, France.
  3. Department of Chemistry, Chemical Biological Centre, Umeå University, Umeå, Sweden.
  4. Biomedical Research Centre, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
  5. Department of Chemistry - Ångström, Molecular Biomimetics, Uppsala University, Uppsala, Sweden.
  6. Department of Oncology, Skåne University Hospital, Lund, Sweden.

PMID: 28978009 PMCID: PMC5620149 DOI: 10.18632/oncotarget.16921

Abstract

Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis,

Keywords: glycosylation; hypoxia; immunotherapy; proteoglycan; tumor antigen

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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