HYALURONIDASE AND CD44 VARIANTS IN ORAL CANCER

口腔癌中的透明质酸酶和 CD44 变体

• 批准号: 6355568
• 负责人: ROBERT STERN
• 金额: $ 11.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355568
• 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)是治疗恶性肿瘤的主要糖胺聚糖 肿瘤细胞，通过其受体CD44与细胞表面结合。级别 HA与增强的转移行为相关，某些 CD44的亚型。人乳腺癌细胞瘤在SCID小鼠体内的生长 静脉注射后大小减少。透明质酸酶治疗，下降50% 在四天内发生。培养的乳腺癌细胞的短暂暴露 体外对透明质酸酶的作用不仅能消除细胞相关的透明质酸， 也包括CD44的所有恶性变种，只留下两个 “良性”形态，CD44s和CD44E。现在有人提议开发一种动物 人口腔鳞状细胞癌(OSCC)模型的建立 在裸鼠体内原位生长，并确定 在这个模型中，透明质酸酶也可以导致肿瘤的消退。 同时，使用免疫组织化学、FACS进行协调研究 分析，并进行RT-PCR以记录HA和 CD44为透明质酸酶亚型。据推测这种酶是一种 以前未知的抗癌疗法，HA稳定其 自身受体，透明质酸酶清除透明质酸导致 CD44转移性变异异构体的调控，从而导致肿瘤 消退，并防止进一步的癌症扩散。此外，它是 怀疑唾液在口腔中创造了富含HA的环境， 这也是口腔鳞状细胞癌特别激进的过程的基础。 结合这些研究，HA的水平和本地化， 透明质酸酶、CD44及其异构体将在一系列 培养的口腔鳞状细胞癌细胞侵袭性增加，以及在人类 口腔癌组织活检标本及组织病理学观察 核心。口腔鳞状细胞癌占口腔癌的绝大多数，可发生转移。 广泛地。与其他人类癌症不同，侵袭性的程度 与组织学形态无关。它也是无法预测的 哪些异型增生或白斑患者会继续发展为口腔鳞状细胞癌。 这项建议的论点是，HA的新陈代谢是 在恶性进展过程中的基础，以及在 本建议书中测量的参数将具有以下功能 预测性和预测性指标。这些潜在的标记将是 在识别不仅增加的患者方面具有巨大临床价值 发生恶性肿瘤的风险，但也包括那些有现有病变的人 具有特别积极的潜力的公司。