In patients with pT3/4 tumors about 50% are at risk of developing metastases despite of extended surgery. Therefore, it is of great importance to elucidate the pathophysiology of BC and to develop more precise diagnostic markers for progression of this subset of muscle-invasive carcinomas that confer high risk of cancer specific mortality. Hyaluronan is a polymer of alternating Nacetylglucosamine and glucuronic acid residues and is one of the main carbohydrate components of the extracellular matrix. HA is synthesized by three HA-synthase isoenzymes and is either retained near the cell surface where it forms a pericellular HA-rich microenvironment or is released from the cell surface and deposited in the extracellular matrix. HA itself is not transforming but has been shown to support many important facets of the malignant cell phenotype, such as proliferation, migration and resistance to apoptosis. Even inflammation can be promoted by HA forming supramolecular structures, HA-cables, which bind monocytes and lymphocytes and are therefore thought to enhance inflammation. 4-(Benzyloxy)phenol different cancers are associated with increased tumor cell or stroma cell associated HA and with differential expression of HAS-isoenzymes. So far it is not clear whether the specific association of HAS isoenzymes with specific cancer entities reflects different biological roles of the HAS isoenzymes or is the result of the presence of different autocrine and paracrine factors and/or the specific cell types involved in each cancer entity. It is, however, likely that HAS isoenzymes differ with regard to the size of the secreted HA-polymer which could consecutively evoke different biological functions. The most efficient mechanism to modify the length of HA polymers are the hyaluronidases that have been shown to strongly support tumor progression by, Tulathromycin B generating HA fragments that are activators of HA signaling through either CD44 or tolllike receptors. Furthermore, sHA is implicated in tumor angiogenesis which contributes to the tumor supporting effect of HA. In general, HA induces cellular signaling through HA receptors such as CD44 and the receptor of hyaluronanmediated motility. Both HA receptors have been implicated in the progression of cancer likely by promoting malignant cancer cell phenotypes. Especially, activation of the ERK1/2 signaling pathway and the PI3K pathway could contribute to the tumor promoting effects of both receptors. RHAMM was identified as receptor involved in cell motility during physiological and malignant processes. RHAMM can be associated with the cell surface or function intracellular. RHAMM is involved in ECM induced cell signaling through regulating the stability of focal adhesion complexes and activates Ras-, src-, Erk-kinase and protein-kinase-C. In addition, the intracellular form of RHAMM binds to mitotic spindles and regulates mitosis. In this regard both, overexpression and loss of RHAMM, cause perturbation of the mitotic spindle and subsequently genetic instability. Whereas HA is the principle ligand of RHAMM, CD44 binds also various other ligands such as osteopontin, fibronectin or collagen. Interestingly, in some cases RHAMM and CD44 appear even to cooperate with respect to signaling. In addition, HA has been attributed a role in mediating chemoresistance either by controlling the diffusion of anticancer drugs and/or by affecting multi-drug resistance transporters that mediate efflux of xenobiotics. BC has been studied earlier with respect to HA and HAassociated genes. Previous studies revealed that especially the HAS1 isoenzyme is associated with BC progression. Furthermore, urinary excretion of HA was established as an indicator of poor prognosis in BC. Recently, again HAS1 mRNA expression was associated with BC metastasis.
Transitional cell carcinomas of the bladder represent a heterogenous group of tumors with regard to clinical outcome
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