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。RCC很少产生症状，患者通常患有晚期疾病，治疗选择有限。肾细胞癌是一种高度血管化的肿瘤，这与经常观察到的主要缺氧途径的失调一致，该途径伴随着von Hippel-Lindau（VHL）肿瘤抑制因子的失活。抗血管生成治疗似乎提供了作为控制肿瘤生长的策略的希望，因此是需要进一步开发的主要治疗方案。大多数抗血管生成的研究都集中在靶向血管生成血管系统中的内皮细胞，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更有效的策略。在研究过程中集中研究的作用，肾素-血管紧张素系统在肾器官发生，我们已经着手分离和获得的表达细胞的肾血管系统的发展。我们已经注意到，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的标志物。我们假设，这些表达作为标志物的鉴定是高度活跃的血管生成过程的启动的结果，作为致瘤性“创伤过程”的一部分，与正常静止的成人肾脏血管形成对比。我们建议严格调查肾周细胞的扩展表达签名，目的是确定其他标志物和靶标。为此，将实现三个具体目标。在目标1下，将识别发育中的肾血管系统的肾素表达细胞的扩展细胞特异性表达谱，并将其与先前报道的人ccRCC的表达谱作图，以鉴定特异性候选基因。根据目标2，将在发育和成熟小鼠肾脏中分析特定候选物，以验证基因表达候选物与发育而非静止成熟血管的特异性相关性。最后，在目标3下，将通过比较分析人ccRCC和正常肾脏中的表达特征来验证鉴定的小鼠“活化周细胞”候选物的人直系同源物。经验证的标志物和靶点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.