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

食管癌是全球第六大癌症死亡原因。透明质酸（HA）是细胞外基质（ECM）中的一种多糖，在人食管癌的实质和间质中积累，并被侵入的食管癌细胞诱导进入间质。HA由透明质酸合酶家族（HAS 1 -3）的三种同种型在质膜上产生，并与HA受体RHAMM（HA介导的运动性的受体）和CD 44相互作用。以前，我们发现抑制肿瘤细胞中的HA功能强烈抑制体外食管癌细胞和体内肿瘤生长。HA在基质中的诱导以及肿瘤和基质细胞的利用可能有助于细胞表型，并随后有助于肿瘤的病理生理学特征。到目前为止，我们还没有关于HAS同工酶、HA受体和HA周转在食管鳞癌细胞和间质相互作用中的作用的机制信息。在这个项目中，我们的目标是阐明1）食管癌细胞和基质细胞的HA系统的相互关系和功能意义，2）HA受体RHAMM和CD 44在体外肿瘤和异种移植肿瘤模型中肿瘤与宿主之间相互作用中的作用，以及3）小分子HA合成酶抑制剂4-甲基伞形酮，对肿瘤生长和对受体酪氨酸激酶抑制剂的反应性的影响。

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.