Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility

Thomas Mandel Clausen, Marina Ayres Pereira, Nader Al Nakouzi, Htoo Zarni Oo, Mette Agerbæk, Sherry Lee, Maj Sofie Ørum-Madsen, Anders Riis Kristensen, Amal El-Naggar, Paul M. Grandgenett, Jean L Grem, Michael A Hollingsworth, Peter J. Holst, Thor Theander, Poul H. Sorensen, Mads Daugaard, Ali Salanti

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21 Scopus citations

Abstract

Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.

Original languageEnglish (US)
Pages (from-to)1288-1299
Number of pages12
JournalMolecular Cancer Research
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2016

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Clausen, T. M., Pereira, M. A., Nakouzi, N. A., Oo, H. Z., Agerbæk, M., Lee, S., Ørum-Madsen, M. S., Kristensen, A. R., El-Naggar, A., Grandgenett, P. M., Grem, J. L., Hollingsworth, M. A., Holst, P. J., Theander, T., Sorensen, P. H., Daugaard, M., & Salanti, A. (2016). Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility. Molecular Cancer Research, 14(12), 1288-1299. https://doi.org/10.1158/1541-7786.MCR-16-0103