Evaluation of Pericyte Molecular Markers in Clear Cell Kidney Cancer

透明细胞肾癌周细胞分子标志物的评价

基本信息

批准号：
7230150
负责人：
KENNETH W GROSS
金额：
$ 18.25万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Clear cell renal cell carcinoma(RCC) is the most common kidney cancer subtype. RCC rarely produces symptoms and patients often present with advanced disease for which there are limited treatment options. RCC is a highly vascularized neoplasm consistent with the frequently observed dysregulation of major hypoxia pathways that accompanies inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Anti-angiogenic therapy would appear to offer promise as a strategy to control tumor growth and is thus a prime therapeutic regimen requiring further development. Most anti-angiogenesis research has focused on targeting the endothelial cell in angiogenic vasculature, but there is a growing realization that dual targeting of both endothelial cells and the supporting vascular pericytes might be a more efficient strategy. In the course of studies focused on studying the role of the renin-angiotensin system in renal organogenesis, we have undertaken to isolate and obtain expression profile of the renin-expressing cell of the developing renal vasculature. We have noted that the renin-expressing cell has an expression signature which appears to correspond to an 'activated vascular pericyte' and that a number of the cell specific expressions observed are recently identified markers for ccRCC. We hypothesize that the identification of these expressions as markers is the consequence of the initiation of a highly active angiogenic process, as part of the tumorigenic 'wounding process' that contrasts with the normally quiescent vasculature of adult kidney. We propose to rigorously survey the extended expression signature of the renal pericyte with the aim of identifying additional markers and targets. To do so, 3 specific aims will be pursued. Under Aim 1, the extended cell specific expression profile of the renin-expressing cell of developing renal vasculature will be discerned and mapped against previously reported expression profiles for human ccRCC to identify specific gene candidates. Under Aim 2, specific candidates will be analyzed in developing and mature mouse kidney to verify specific association of the gene expression candidate with developing as opposed to quiescent mature vessels. Finally, under Aim 3, the human orthologs of identified mouse 'activated pericyte' candidates will be validated by comparative analysis of expression characteristics in human ccRCC and normal kidney. Validated markers and targets may be of utility for diagnosis and determining prognosis, or provide the basis for therapeutic intervention strategies in clear cell RCC.

描述（由申请人提供）：透明细胞肾细胞癌（RCC）是最常见的肾癌亚型。 RCC很少产生症状，患者经常出现晚期疾病，治疗选择有限。 RCC是一种高度血管化的肿瘤，与经常观察到的主要缺氧途径失调，伴随着von Hippel-Lindau（VHL）抑制肿瘤抑制剂的失活。抗血管生成疗法似乎提供了有望作为控制肿瘤生长的策略，因此是一种需要进一步发展的主要治疗方案。大多数抗血管生成研究都集中在靶向血管生成脉管中的内皮细胞，但是人们越来越认识到，内皮细胞的双重靶向和支撑的血管周细胞可能是更有效的策略。在研究过程中，重点是研究肾素 - 血管紧张素系统在肾脏器官发生中的作用，我们已承诺分离并获得发育中肾脏脉管肾素表达细胞的表达谱。我们已经注意到，表达肾素的细胞具有表达特征，似乎对应于“活化的血管周细胞”，并且最近观察到的许多细胞特异性表达式被确定为CCRCC的标记。我们假设将这些表达式鉴定为标志物是启动高度活跃的血管生成过程的结果，这是肿瘤性“伤害过程”的一部分，与通常静止的成人肾脏的脉管系统形成鲜明对比。我们建议严格调查肾周细胞的扩展表达特征，以识别其他标记和靶标。为此，将追求3个具体目标。在AIM 1下，将与先前报道的人CCRCC的表达曲线进行识别，并映射出肾脏脉管系统的表达肾素表达细胞的扩展细胞特异性表达谱，以鉴定特定的基因候选物。在AIM 2下，将在发育和成熟的小鼠肾脏中分析特定的候选者，以验证候选基因表达者与发育型而不是静态成熟血管的特定关联。最后，在AIM 3下，通过对人CCRCC和正常肾脏表达特征的比较分析，将验证已鉴定出的小鼠“活化的周细胞”候选者的人类直系同源物。经过验证的标记和目标可能是诊断和确定预后的实用性，或为清晰细胞RCC的治疗干预策略提供基础。