Interactions of
hyaluronan (HA) and
tumor and stromal cells are highly discussed as one of the major contributors in
tumor progression and
metastasis. The balance of HA in the tissue is highly regulated by two key
enzyme classes;
hyaluronan synthases (HAS) and hyaluronidases (HYAL). Current reports hint that the HA amount in the tissue is correlated with poor prognosis in
melanoma, the most life-threatening skin
tumor. In this work, we generated in vivo mouse models with low and high expression of Has2 and used the models for studying
melanoma proliferation of the B78D14
melanoma cell line. We found that a strong reduction of HA amount in the skin was correlated to decreased tissue stiffness and a reduction in
tumor weight. Since
tumor cells have a direct contact to the HA in the
tumor and at the stroma interface, we reconstituted different biomimetic in vitro models using fibroblasts derived from a mouse model to recapitulate
melanoma cell behavior at the
tumor boundary, namely, (i) decellularized fibroblast matrix (FbECM), (ii) fibroblast embedded into 3D
collagen matrices (FbColl), and (iii) well-defined HA-functionalized 3D
collagen matrices (HAColl). We found no considerable effect of high and low amounts of fibroblast-derived HA in the matrices on
melanoma proliferation and invasion. However, HYAL1-treated FbECM and FbColl, as well as HAColl functionalized with low molecular weight HA (34 kDa) promoted proliferation and invasion of
melanoma cells in a concentration dependent manner. Our results emphasize the molecular weight specific effects of HA in regulation of
melanoma behavior and provide an alternative explanation for the in vivo observation of HA dependent
tumor growth.