How does hyaluronan matrix synthesis and remodeling promote progression?
Hyaluronan (HA) is a glycosaminoglycan not normally found in the prostate, but very abundant in advanced stage prostate tumors. HA can be secreted by tumor cells into the extracellular space, where it alters the architecture of the prostate gland. Tumor cells that synthesize and process HA have a growth and metastatic advantage because they use HA as a proliferation signal, a cellular transformation stimulus, and a motility scaffold, which allows them to remodel their local environment in the prostate and in metastatic sites. Our lab has developed a series of cell culture models that allow us to investigate the tumor and metastasis promoting potential of individual components of HA metabolism and signaling.
Model for HA involvement in prostate tumor cell biology. Production of hairlike HA polymers occurs at the cell surface from membrane embedded HA synthases. Reuptake and/or degradation of HA may require secreted hyaluronidases to generate low MW oligomers of HA. HA is retained by ligation to specific cell surface receptors such as CD44, and may act in autocrine or paracrine fashion on tumor cells and associated stromal cells. Internalization of HA fragments by endothelial cells via HARE or other HA receptors may regulate angiogenesis, lymphangiogenesis or other tissue architectural remodeling. HA internalized by prostate epithelial cells may contribute to cellular transformation, proliferation, motility, and ultimately may be required for sustained tumor growth and metastasis.