**5. HA regulates mammary cell functions that promote BCA progression**

#### **5.1 Cell migration**

Considerable evidence indicates that HA fragmentation is required for immune cell trafficking, fibroblast migration, stem cell migration from niches to the wound site and endothelial cell migration during angiogenesis. For example, acellular hydrogel matrix composed of fibronectin and HA, which simulates a wound microenvironment, supports proliferation, migration and spreading of human dermal fibroblasts *in vitro*. HA seems to regulate motility via a variety of mechanisms that include indirect and direct effects on the migrating cell population. An example of an indirect effect was provided by a study of the role of HA on fibroblast migration using a porcine skin wound model. The wound matrix, which contained HA, promoted cell migration and recruitment of fibroblasts. This was shown to be in part due to wounding produced HA, which promotes collagen fibril formation, thus indirectly affecting cell motility (Docherty *et al*., 1989). Direct effects of HA on cell motility can result from its structural properties and from its ability to activate motogenic signalling cascades such as ERK1,2 and PI3 kinase. Both of these effects have been related to an association of HA with cell surface receptors such as CD44 and RHAMM. For example, extracellular HA accumulation induces penetration of stromal cells by increasing turgidity and hydration or disrupting cell-to-cell junctions. These effects may be a result of interactions with CD44 and RHAMM (Itano *et al*., 2008). HA fragments bind to CD44 and/or RHAMM to induce activation of MAPK (ERK1,2) that results in enhanced BCA cell migration and invasion (Hamilton *et al*., 2007). Moreover, upon HA-mediated activation of PI3 kinase, increased HAS2 production induces faster migration in scratch wound assays (Itano *et al*., 2002).
