Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer

- Synthesis, deposition, and interactions of HA with CD44 are crucial events that regulate tumors onset and progression.
- HA molecules may perform dual functions depending on their size and concentration.
- Post-translational modifications of HASes are critical for the regulation of HA-mediated tumor cell functions.
- The relevance of CD44 proteins for the acquisition and maintenance of a CSC phenotype is presented.
- The understanding of CD44-HA specific role in tumors is essential for the selectivity of targeted therapies.

Synthesis, deposition, and interactions of hyaluronan (HA) with its cellular receptor CD44 are crucial events that regulate the onset and progression of tumors. The intracellular signaling pathways initiated by HA interactions with CD44 leading to tumorigenic responses are complex. Moreover, HA molecules may perform dual functions depending on their concentration and size. Overexpression of variant isoforms of CD44 (CD44v) is most commonly linked to cancer progression, whereas their loss is associated with inhibition of tumor growth. In this review, we highlight that the regulation of HA synthases (HASes) by post-translational modifications, such as O-GlcNAcylation and ubiquitination, environmental factors and the action of microRNAs is important for HA synthesis and secretion in the tumor microenvironment. Moreover, we focus on the roles and interactions of CD44 with various proteins that reside extra- and intracellularly, as well as on cellular membranes with particular reference to the CD44-HA axis in cancer stem cell functions, and the importance of CD44/CD44v6 targeting to inhibit tumorigenesis.