Thrombospondin-1 expression in bladder cancer: Association with p53 alterations, tumor angiogenesis, and tumor progression
Thrombospondin-1 expression in bladder cancer: Association with p53 alterations, tumor angiogenesis, and tumor progression
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DOI：
10.1093/jnci/89.3.219
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发表时间：
1997-02-05
期刊：
影响因子：
--
通讯作者：
Cote, RJ
中科院分区：
文献类型：
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作者：
Grossfeld, GD;Ginsberg, DA;Cote, RJ
背景：血小板反应蛋白-1 (TSP) 是一种 430 kd 的糖蛋白，是细胞外基质的重要组成部分，并且已知在体外和体内都是血管生成（即新血管的形成）的有效抑制剂。一些报告表明 TSP 具有肿瘤抑制功能，可能是通过其抑制肿瘤新生血管形成的能力来实现的。最近的研究表明，p53 基因（也称为 TP53）的产物可增强 TSP 表达。目的：我们研究了 TSP 表达在浸润性膀胱癌患者肿瘤复发和总生存中的作用。我们还检查了 p53 蛋白表达、TSP 表达和肿瘤血管生成之间的关系。方法：对 163 例因膀胱浸润性移行细胞癌接受根治性膀胱切除术的患者（中位随访时间为 7.7 年）进行肿瘤检查（其中 63 例患者病变局限于器官且无淋巴结受累，48 例患者疾病扩散至膀胱外且无淋巴结受累，52 例患者转移至区域淋巴结） 使用单克隆抗体 MA-II 通过免疫组织化学法检测 TSP 表达，该抗体可识别 TSP 氨基末端区域的表位。对于每个肿瘤，还确定了微血管密度计数和 p53 蛋白表达状态（通过免疫组织化学）。在不了解临床结果、p53 状态和微血管密度计数的情况下，TSP 表达被分为低、中或高；具有中度和高 TSP 水平的肿瘤被视为一组。通过总体生存的 Kaplan-Meier 乘积极限估计、无复发生存的累积发生率曲线的补集以及分层对数秩检验来比较各组患者。报告的 P 值是双向的。结果：TSP 表达与疾病复发 (P = .009) 和总生存率 (P = .023) 显着相关。 TSP 表达低的患者表现出复发率增加和总生存率降低。在对肿瘤分期、淋巴结状态和组织学分级进行分层后，TSP 表达是疾病复发 (P = .002) 和总生存率 (P = .01) 的独立预测因子，但它并不独立于 p53 状态。 TSP 表达与 p53 表达状态 (P = .001) 和微血管密度计数 (P = .001) 显着相关。具有p53改变的肿瘤显着更有可能表现出低TSP表达，并且具有低TSP表达的肿瘤显着更有可能表现出高微血管密度计数。方差分析的结果与p53通过调节TSP表达水平影响肿瘤血管生成的假设相一致。结论和意义：这些数据支持 TSP 可能具有肿瘤抑制功能的概念。 TSP 可能部分通过调节肿瘤新生血管发挥作用。这些结果还可以深入了解 p53 发挥其肿瘤抑制作用的一种机制，即通过控制肿瘤血管生成。
Background: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (i.e., formation of new blood vessels) both in vitro and in vivo. Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization. It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known at TP53). Purpose: We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer. We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis. Methods: Tumors from 163 patients (with a median follow-up of 7.7 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP. For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined. TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group. Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test. Reported P values are two-sided. Results: TSP expression was significantly associated with disease recurrence (P = .009) and overall survival (P = .023). Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival. TSP expression was an independent predictor of disease recurrence (P = .002) and overall survival (P = .01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status. TSP expression was significantly associated with p53 expression status (P = .001) and microvessel density counts (P = .001). Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts, Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression. Conclusions and Implications: These data support the concept that TSP may possess a tumor-inhibitory function. TSP may act, in part, through the regulation of tumor neovascularity. These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, i.e., through the control of tumor angiogenesis.