In prostate cancer progression, prostate epithelial cells undergo phenotypic and genotypic changes that facilitate inappropriate proliferation, invasion of surrounding stromal matrices, entry into the lymphatic system and/or the bloodstream, and colonization of other tissues.  Hyaluronan (HA), a secreted glycosaminoglycan component of extracellular matrices, is critical for cellular proliferation and motility during development.  However, elevated circulating and cell associated levels correlate with various types of cancer, including prostate.  In histopathologic analyses of human prostate cancer, excessive stromal HA accumulation is detectable in early stages and intensifies throughout progression.  Eventually, advanced cancers exhibit tumor cell associated HA, which correlates to poor patient prognosis.

Aggressive prostate tumor cell lines were shown to synthesize excessive HA relative to less aggressive cells, and to express correspondingly higher levels of HA biosynthetic enzymes HAS2 and HAS3.  Inhibition of these enzymes by antisense HAS2 or HAS3 expression diminished HA synthesis and surface retention, and effected slower growth rate of cells in culture.  Subcutaneous injection of SCID mice with HAS antisense transfected cells produced tumors 3-4 fold smaller than control transfectants.  Tumors from HAS antisense transfectants were histologically HA deficient relative to controls.  Quantification of blood vessel density within tumor sections revealed 70-80% diminished vascularity of HAS antisense tumors.  Collectively, the results suggest HA synthase overexpression by prostate tumor cells may facilitate their growth and proliferation in a complex environment by enhancing intrinsic cell growth rates and promoting angiogenesis.

Current research in my lab is focused on understanding the causes and impacts of HA overproduction by prostate tumor cells. Specifically, we are interested in identifying external regulatory mechanisms leading to HAS overexpression, as well as defining the processes by which tumor cells accumulate and retain surface HA. We are also characterizing changes in intracellular signaling that result from altered HA synthesis and the effect of these changes on prostate tumor cell behavior in mouse orthotopic injections.