Role of hyaluronan synthesis for tumor-host interactions and progression of esophageal squamous neoplasms

点击翻译按钮获取中文摘要

Esophageal cancer is the sixth leading cause of cancer deaths worldwide. Hyaluronan (HA), a polysaccharide of the extracellular matrix (ECM), accumulates in the parenchyma and stroma of human esophageal carcinoma and is induced in the stroma by invading esophageal cancer cells. HA is produced by three isoforms of the hyaluronan synthase family (HAS1-3) at the plasma membrane and interacts with HA-receptors RHAMM (receptor of HA mediated motility) and CD44. Previously, we found that the inhibition of HA function in tumor cells strongly inhibits esophageal cancer cells in vitro and tumor growth in vivo. The induction of HA in the stroma and the utilisation by both tumor and stroma cells likely contributes to the cellular phenotypes and subsequently to the pathophysiological characteristics of the tumor. To date, we have no mechanistic information about the roles of HAS isoenzymes, HA receptors, and HA turnover in the interactions between esophageal squamous carcinoma cells and stroma. In the proposed project, we aim to elucidate 1) the interrelationships and functional significance of the HA system of esophageal cancer cells and stromal cells, 2) the roles of the HA receptors RHAMM and CD44 in the interactions between tumor and host in vitro and in a xenograft tumor model, and 3) the effect of a small molecule HA-synthase inhibitor, 4-methylumbelliferone, on tumor growth and responsiveness to receptor tyrosine kinase inhibitors.