Proteoglycans and glycosaminoglycans as regulators of cancer stem cell function and therapeutic resistance

Daiana Vitale, Sampath Kumar Katakam, Burkhard Greve, Bohee Jang, Eok Soo Oh, Laura Alaniz, Martin Götte

Research output: Contribution to journalReview articlepeer-review

52 Scopus citations

Abstract

In contrast to the bulk of the tumor, a subset of cancer cells called cancer stem cells (CSC; or tumor-initiating cells) is characterized by self-renewal, unlimited proliferative potential, expression of multidrug resistance proteins, active DNA repair capacity, apoptosis resistance, and a considerable developmental plasticity. Due to these properties, CSCs display increased resistance to chemo- and radiotherapy. Recent findings indicate that aberrant functions of proteoglycans (PGs) and glycosaminoglycans (GAGs) contribute substantially to the CSC phenotype and therapeutic resistance. In this review, we summarize how the diverse functions of the glycoproteins and carbohydrates facilitate acquisition and maintenance of the CSC phenotype, and how this knowledge can be exploited to develop novel anticancer therapies. For example, the large transmembrane chondroitin sulfate PG NG2/CSPG4 marks stem cell (SC) populations in brain tumors. Cell surface heparan sulfate PGs of the syndecan and glypican families modulate the stemness-associated Wnt, hedgehog, and notch signaling pathways, whereas the interplay of hyaluronan in the SC niche with CSC CD44 determines the maintenance of stemness and promotes therapeutic resistance. A better understanding of the molecular mechanisms by which PGs and GAGs regulate CSC function will aid the development of targeted therapeutic approaches which could avoid relapse after an otherwise successful conventional therapy. Chimeric antigen receptor T cells, PG-primed dendritic cells, PG-targeted antibody–drug conjugates, and inhibitory peptides and glycans have already shown highly promising results in preclinical models.

Original languageEnglish
Pages (from-to)2870-2882
Number of pages13
JournalFEBS Journal
Volume286
Issue number15
DOIs
StatePublished - 2019

Keywords

  • CD44
  • CSPG4
  • cancer stem cell
  • chemotherapy
  • heparan sulfate
  • hyaluronan
  • proteoglycan
  • radiation
  • stem cell niche
  • syndecan

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