Evaluation of Pericyte Molecular Markers in Clear Cell Kidney Cancer

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。肾细胞癌很少产生症状，患者通常表现为疾病晚期，治疗方案有限。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的失调相一致，这种缺氧途径伴随着von Hippel-Lindau （VHL）肿瘤抑制因子的失活。抗血管生成疗法作为一种控制肿瘤生长的策略似乎提供了希望，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血管生成血管中的内皮细胞，但越来越多的人认识到内皮细胞和支持血管周细胞的双重靶向可能是一种更有效的策略。在研究肾素-血管紧张素系统在肾脏器官发生中的作用的过程中，我们分离并获得了肾素表达细胞的表达谱。我们已经注意到，肾素表达细胞的表达特征似乎与“激活的血管周细胞”相对应，并且观察到的许多细胞特异性表达是最近发现的ccRCC标记物。我们假设，这些表达作为标志物的识别是一个高度活跃的血管生成过程的开始的结果，作为致瘤性“损伤过程”的一部分，与成人肾脏正常静止的血管系统形成对比。我们建议严格调查肾周细胞的扩展表达特征，以确定额外的标记和靶标。为此，将追求3个具体目标。在Aim 1下，将识别肾素表达细胞的扩展细胞特异性表达谱，并将其与先前报道的人类ccRCC表达谱进行比对，以确定特定的候选基因。在Aim 2中，将在发育和成熟的小鼠肾脏中分析特定的候选血管，以验证候选基因表达与发育中的血管（而不是静止的成熟血管）之间的特定关联。最后，在Aim 3下，鉴定的小鼠“活化周细胞”候选物的人类同源物将通过比较分析人类ccRCC和正常肾脏的表达特征来验证。经过验证的标记物和靶标可用于诊断和确定预后，或为透明细胞RCC的治疗干预策略提供基础。

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.