MECHANISIMS OF BLADDER CANCER PROGRESSION

描述：(改编自调查人员的摘要)两个关键的 影响膀胱癌患者预后的因素为高级别 侵袭性肿瘤和肿瘤复发率高。透明质酸酶是一种 一种将透明质酸(HA)--一种糖胺聚糖--降解为小分子的酶 新生血管碎片。两种透明质酸酶已被确定为潜在的 高级别膀胱癌(BT)的分子标志物。长期的 本提案的目的是阐明这些功能 透明质酸酶在Bt中的进展及开发一种简单、无创和 准确检测膀胱癌早期诊断和治疗后监测 癌症。 为了验证Bt来源的透明质酸酶在结构上是 与其他已知的透明质酸酶不同，在肿瘤中表达， 组织或细胞特有的方式，Bt衍生的透明质酸酶将被分离， 纯化、克隆、测序(AIM 1)。这些酶将是 具有底物特异性和对抑制剂的敏感性的特点 它们的表达将在正常人群的蛋白质和mRNA水平进行检测 组织、肿瘤组织和肿瘤细胞(目标2)。测试是否提升了 Bt来源的透明质酸酶水平可使转移性表型不 懒惰的Bt细胞，低级别的Bt细胞将被导入 这些酶与裸鼠原位种植转移瘤的关系 将会被检查。此外，血管生成HA片段在血管生成中的作用 Bt细胞和Bt来源的内皮细胞对Bt的调节作用 将检查进展情况(目标3)。Bt患者尿液HA水平升高 慢性阻塞性肺疾病患者尿液透明质酸酶水平升高 高档BT。为了测试HA-透明质酸酶试验是否能检测到膀胱 肿瘤复发并提示其恶性潜能，尿路 将如期检测150例BT患者的HA-透明质酸酶水平 监测访问和结果将与膀胱镜或尿液检查进行比较。 细胞学检查结果(目标4)。 拟议的研究可能导致确定和在功能上 一种新的可提高诊断水平的Bt高级别标志物的鉴定 以及膀胱癌的治疗。

DESCRIPTION: (adapted from the investigator's abstract) Two critical factors that affect the prognosis of bladder cancer patients are high-grade invasive tumors and the high rate of tumor recurrence. Hyaluronidase is an enzyme that degrades hyaluronic acid (HA), a glycosaminoglycan, into small angiogenic fragments. Two hyaluronidases have been identified as potential "molecular markers" of high-grade bladder tumors (BT). The long-term objectives of this proposal are to elucidate functions of these hyaluronidases in BT progression and to develop a simple, non-invasive and accurate test for early detection and post-therapy surveillance of bladder cancer. To test the hypothesis that BT-derived hyaluronidases are structurally distinct from other known hyaluronidases and are expressed in a tumor, tissue, or cell specific manner, BT-derived hyaluronidases will be isolated, purified, cDNA cloned and sequenced (Aim 1). These enzymes will be characterized for substrate specificity and sensitivity to inhibitors and their expression will be examined at protein and mRNA levels in normal tissues, tumor tissues, and tumor cells (Aim 2). To test whether elevated BT-derived hyaluronidase levels confer metastatic phenotype to otherwise indolent BT cells, low-grade BT cells will be transfected with cDNAs of these enzymes and following orthotopic implantation in nude mice metastasis will be examined. In addition, the role of angiogenic HA fragments on functions of BT cells and BT-derived endothelial cells which regulate BT progression will be examined (Aim 3). Urinary HA levels are elevated in BT patients and urinary hyaluronidase levels are elevated in patients with high-grade BT. To test whether a HA-hyaluronidase test can detect bladder tumor recurrence and indicate its malignant potential, urinary HA-hyaluronidase levels in 150 BT patients will be measured at scheduled surveillance visits and results will be compared with cystoscopic or urine cytology findings (Aim 4). The proposed study could result in identifying and functionally characterizing a new marker of high-grade BT which could improve diagnosis and treatment of bladder cancer.