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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。肾细胞癌很少出现症状，患者通常已处于晚期疾病，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相一致，这种失调伴随着 von Hippel-Lindau (VHL) 肿瘤抑制因子的失活。抗血管生成疗法似乎有望作为控制肿瘤生长的策略，因此是需要进一步开发的主要治疗方案。大多数抗血管生成研究都集中在靶向血管生成脉管系统中的内皮细胞，但人们越来越认识到，同时靶向内皮细胞和支持血管周细胞可能是一种更有效的策略。在专注于研究肾素-血管紧张素系统在肾器官发生中的作用的研究过程中，我们已经着手分离并获得发育中的肾血管系统的肾素表达细胞的表达谱。我们注意到表达肾素的细胞具有似乎对应于“活化的血管周细胞”的表达特征，并且观察到的许多细胞特异性表达是最近鉴定的ccRCC标记。我们假设这些表达被识别为标记物是高度活跃的血管生成过程启动的结果，作为致瘤“受伤过程”的一部分，与成人肾脏通常静止的脉管系统形成对比。我们建议严格调查肾周细胞的扩展表达特征，目的是识别其他标记物和靶标。为此，将实现 3 个具体目标。在目标 1 下，将辨别发育中肾血管系统的肾素表达细胞的扩展细胞特异性表达谱，并将其与先前报告的人类 ccRCC 表达谱进行映射，以识别特定的候选基因。在目标 2 下，将在发育和成熟小鼠肾脏中分析特定候选基因，以验证候选基因表达与发育中而非静止成熟血管的特定关联。最后，在目标 3 下，将通过对人 ccRCC 和正常肾脏中的表达特征进行比较分析来验证已确定的小鼠“活化周细胞”候选者的人直系同源物。经验证的标志物和靶标可用于诊断和确定预后，或为透明细胞肾细胞癌的治疗干预策略提供基础。