Moreover, high expression of Hyal1 has recently been suggested to predict progressive muscle-invasive and recurrent BC and to associate with metastasis and decreased disease specific survival. All together, the available data on HA in BC point to increased synthesis of HA mainly by HAS1 and degradation to tumor promoting sHA by Hyal 1. In turn, the effects of HA and sHA are likely transduced through activation of HA-receptors. In BC certain splice variants of CD44, such as CD44V8-10, were Butenafine hydrochloride upregulated and associated with poor prognosis. In addition, it has been shown that CD44 might be involved in the angiogenic response to HA in BC. However, a recent analysis revealed that CD44v was upregulated and CD44s was downregulated without diagnostic or prognostic value. RHAMM has been described to be upregulated but also without clear correlation with clinical parameters. Because it appears plausible that the amount of HA-receptors plays an important role in the transduction of HA signaling and thereby in the progression of human BC, the aim of the present study was to study the expression of HA-receptors and HAS isoenzymes and to achieve mechanistic information in a patient collective characterized by >50% muscle-invasive BC. Patients suffering from urothelial transitional cell cancer of the bclinical outcometheir prognosis. Patients with non-muscleinvasive BC are treated by TUR of the tumor. In most cases this procedure combines diagnostic and curative treatment leading to excellent tumor control. Within TUR representative tissue samples can be taken for histopathological diagnosis and determine the necessity of more aggressive treatment. For many patients this local procedure can become a long-term bladder preserving strategy. However, 3-5% of the patients suffering from nonmuscle-invasive BC experience progression to muscle-invasive disease and need radical treatment. Only about 50% of the patients with muscle-invasive BC benefit from the radical operation with long-term disease-free survival. To 
develop more individualized therapeutic strategies, it is crucial to identify tumor-related parameters allowing risk stratification within the group of muscle-infiltrating transitional cell carcinomas and in the long run represent potential therapeutic targets. In this regard HA and HA-associated genes, such as HAS isoenzymes, HA receptors and HA catabolic enzymes, appear to be interesting because these genes are of pathophysiological significance and of diagnostic value in various cancer entities. Interestingly, the association of HA with cancer parenchyma or with tumor stroma is specific for certain cancer types and can also be stage-dependent. These observations suggest that HA affects both tumor cells and stromal cells. Furthermore, it is likely that tumor-associated fibroblasts can LOUREIRIN-B secrete HA that is subsequently utilized by tumor cells. The expression of HA-related genes has been studied also in BC. As a result, especially HAS1, Hyal1 and urinary HA excretion were found to be associated with BC progression and/or prognosis. The present investigation revealed a stage-dependent increase of RHAMM expression in human BC specimens as evidenced by real-time RT PCR and by immunohistochemistry. Of note, high RHAMM expression levels were associated with increased disease-specific and increased overall mortality. Importantly, in this study we present for the first time that RHAMM mRNA expression is even an independent risk factor in muscle-invasive BC. Subsequently knock-down of RHAMM caused significant inhibition of xenograft tumor growth in nu/nu athymic mice. This reduction of tumor progression was likely caused by inhibited proliferation of BC tumor cells as evidenced by Ki67 staining. Further in vitro experiments verified the antiproliferative effect of RHAMM knock-down.