HYALURONIDASE AND CD44 VARIANTS IN ORAL CANCER

口腔癌中的透明质酸酶和 CD44 变体

• 批准号: 6270369
• 负责人: ROBERT STERN
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270369
• 关键词: CD44 molecule; antineoplastics; athymic mouse; biomarker; disease /disorder model; flow cytometry; hyaluronate; hyaluronidase; immunocytochemistry; neoplasm /cancer invasiveness; neoplastic process; oral pharyngeal neoplasm; polymerase chain reaction; protein isoforms; receptor binding; squamous cell carcinoma; tissue /cell culture

Hyaluronic acid (HA), the predominant glycosaminoglycan on malignant tumor cells, is bound to the cell surface by its receptor CD44. Levels of HA correlate with enhanced metastatic behavior, as do certain of the isoforms of CD44. Human breast cancer cell tumors grown in SCID mice decrease in size following i.v. hyaluronidase treatment, a 50% decrease occurring in four days. Brief exposure of cultured breast cancer cells in vitro to hyaluronidase eliminates not only the cell-associated HA, but also all of the malignant variants of CD44, leaving only two "benign" forms, CD44S and CD44E. It is now proposed to develop an animal model of oral squamous cell carcinoma (OSCC) using human cell lines grown orthotopically in nude mice, and to determine whether hyaluronidase can also cause tumor regression in this model. Simultaneously, coordinated studies using immunohistochemistry, FACS analyses, and RT-PCR will be performed to document modulation of HA and CD44 isoforms with hyaluronidase. It is postulated that the enzyme is a previously unrecognized anticancer therapeutic, that HA stabilizes its own receptor, and that eradication of HA by hyaluronidase causes down regulation of CD44 metastatic variant isoforms, thereby causing tumor regression, and prevention of further cancer spread. Furthermore, it is suspect that saliva creates an HA-rich environment in the oral cavity, and underlies the particularly aggressive course of OSCC's. In conjunction with these studies, levels and localization of HA, hyaluronidase, CD44, and its isoforms will be documented in an array of cultured OSCC cells of increasing aggressiveness, as well as in human biopsy specimens obtained from the oral cancer tissue and histopathology core. OSCC, comprising the vast majority of oral cancers, metastasizes widely. The degree of aggressiveness, unlike other human cancers, does not correlate with the histological appearance. Nor can it be predicted which patients with dysplasia or leukoplakia will go on to develop OSCC. The contention of this proposal is that the metabolism of HA is fundamental to the process of malignant progression, and that among the parameters measured in this proposal will be those that can function as predictive and prognostic indicators. Such potential markers will be of enormous clinical value in identifying not only patients at increased risk for developing malignancy, but also those with existing lesions that have particularly aggressive potential.

透明质酸（HA）是恶性肿瘤中主要的糖胺聚糖， 肿瘤细胞通过其受体CD 44结合到细胞表面。水平 与增强的转移行为相关，某些 CD 44亚型。在SCID小鼠中生长的人乳腺癌细胞肿瘤 静脉注射透明质酸酶治疗后尺寸减小，减小50% 发生在四天内。培养的乳腺癌细胞的短暂暴露 体外透明质酸酶不仅消除了细胞相关的HA， 也包括所有的恶性CD 44变异体，只剩下两个 “良性”形式，CD 44 S和CD 44 E。现在有人提议开发一种动物 使用人细胞系的口腔鳞状细胞癌（OSCC）模型 在裸鼠中原位生长，并确定是否 透明质酸酶在该模型中也可引起肿瘤消退。 同时，使用免疫组织化学、流式细胞仪 将进行RT-PCR分析，以记录HA的调节， CD 44亚型与透明质酸酶。据推测，这种酶是一种 以前未被认识到的抗癌治疗，HA稳定其 自身受体，并且透明质酸酶清除HA会导致降低 调节CD 44转移性变体同种型，从而引起肿瘤 消退和防止癌症进一步扩散。再者是 怀疑唾液在口腔中创造了富含HA的环境， 并且是口腔鳞状细胞癌特别具有侵袭性的基础。 结合这些研究，HA的水平和定位， 透明质酸酶、CD 44及其亚型将记录在一系列 培养的OSCC细胞的攻击性增加，以及在人类 从口腔癌组织和组织病理学中获得的活检标本 核心口腔鳞状细胞癌占口腔癌的绝大多数， 广泛地。与其他人类癌症不同， 与组织学表现无关。也无法预测 哪些发育不良或白斑患者会继续发展为口腔鳞状细胞癌。 该提案的论点是，HA的代谢是 这是恶性进展过程的基础， 本建议中测量的参数将是那些可以作为 预测和预后指标。这些潜在的标志物将是 巨大的临床价值，不仅确定患者在增加 发生恶性肿瘤的风险，但也有那些现有的病变 具有特别的攻击性。