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

Christianson, Helena C LU ; Menard, Julien A LU ; Chandran, Vineesh Indira LU ; Bourseau-Guilmain, Erika LU ; Shevela, Dmitry ; Lidfeldt, Jon LU orcid ; Månsson, Ann-Sofie LU ; Pastorekova, Silvia ; Messinger, Johannes and Belting, Mattias LU (2017) In Oncotarget 8(40). p.66960-66974
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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncotarget
volume
8
issue
40
pages
66960 - 66974
publisher
Impact Journals
external identifiers
  • pmid:28978009
  • scopus:85048904817
ISSN
1949-2553
DOI
10.18632/oncotarget.16921
language
English
LU publication?
yes
id
cd230644-686b-418c-a811-66e9d48df0b2
date added to LUP
2021-10-29 06:24:37
date last changed
2025-07-13 12:48:40
@article{cd230644-686b-418c-a811-66e9d48df0b2,
  abstract     = {{<p>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.</p>}},
  author       = {{Christianson, Helena C and Menard, Julien A and Chandran, Vineesh Indira and Bourseau-Guilmain, Erika and Shevela, Dmitry and Lidfeldt, Jon and Månsson, Ann-Sofie and Pastorekova, Silvia and Messinger, Johannes and Belting, Mattias}},
  issn         = {{1949-2553}},
  language     = {{eng}},
  number       = {{40}},
  pages        = {{66960--66974}},
  publisher    = {{Impact Journals}},
  series       = {{Oncotarget}},
  title        = {{Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity}},
  url          = {{http://dx.doi.org/10.18632/oncotarget.16921}},
  doi          = {{10.18632/oncotarget.16921}},
  volume       = {{8}},
  year         = {{2017}},
}