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

食道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)的一种多糖，聚集在人食管癌的实质和间质中，并由侵袭的食管癌细胞在间质中诱导。透明质酸由透明质酸合成酶家族(HAS1-3)的三种异构体在质膜上产生，并与HA受体RHAMM(HA介导的运动受体)和CD44相互作用。此前，我们发现肿瘤细胞中HA功能的抑制在体外对食道癌细胞有很强的抑制作用，在体内对肿瘤的生长有很强的抑制作用。间质中HA的诱导以及肿瘤和间质细胞对HA的利用可能有助于肿瘤的细胞表型和随后的病理生理学特征。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。在拟议的项目中，我们旨在阐明1)食道癌细胞和基质细胞HA系统的相互关系和功能意义，2)HA受体RHAMM和CD44在体外和异种移植瘤模型中肿瘤与宿主相互作用中的作用，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.