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Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity
Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden..
Montpellier Univ, CNRS, UMR 5237, CRBM, Montpellier, France..
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 40, p. 66960-66974Article in journal (Refereed) Published
Abstract [en]

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, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2017. Vol. 8, no 40, p. 66960-66974
Keyword [en]
tumor antigen, glycosylation, hypoxia, immunotherapy, proteoglycan
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-336048DOI: 10.18632/oncotarget.16921ISI: 000410790500017PubMedID: 28978009OAI: oai:DiVA.org:uu-336048DiVA, id: diva2:1165304
Funder
Swedish Cancer Society, 2014/378Swedish Research Council, 2014-3421Swedish Childhood Cancer Foundation, 2015-0078Gunnar Nilsson Cancer FoundationThe Kamprad Family FoundationKnut and Alice Wallenberg Foundation
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2017-12-13Bibliographically approved

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