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The CD44 protein is a single-chain transmembrane glycoprotein able to bind several ligands. Hyaluronic acid is its main ligand and this interaction is the most extensively studied. Hyaluronic acid, as a component of the extracellular matrix, through CD44 is able to modulate several mechanisms that control stem cell behavior, such as migration and anchorage, efflux of toxic compounds, growth in hypoxic conditions and quiescence, besides their self-renewal and differentiation potential. In this chapter we describe the hyaluronic acid–CD44 interaction as part of the communication between the extracellular matrix and different cells that belong to the stem niche, focusing on the hematopoietic and adipose niche. Finally, we discuss the role of these interactions in the transformation of the normal stem niche to a tumorigenic niche that allows the development of cancer stem cells.

The extracellular matrix is part of the microenvironment and its functions are associated with the physical and chemical properties of the tissue. Among the extracellular components, the glycosaminoglycan hyaluronan is a key component, defining both the physical and biochemical characteristics of the healthy matrices. The hyaluronan metabolism is strictly regulated in physiological conditions, but in the tumoral tissues, its expression, size and binding proteins interaction are dysregulated. Hyaluronan from the tumor microenvironment promotes tumor cell proliferation, invasion, immune evasion, stemness alterations as well as drug resistance. This chapter describes data regarding novel concepts of hyaluronan functions in the tumor. Additionally, we discuss potential clinical applications of targeting HA metabolism in cancer therapy.