Evaluation of Pericyte Molecular Markers in Clear Cell Kidney Cancer

描述(申请人提供)：肾透明细胞癌(RCC)是最常见的肾癌亚型。肾癌很少出现症状，患者通常患有晚期疾病，治疗选择有限。肾癌是一种高度血管化的肿瘤，与常见的伴随von Hippel-Lindau(VHL)肿瘤抑制因子失活的主要缺氧途径的失调一致。抗血管生成疗法似乎有望成为控制肿瘤生长的一种策略，因此是一种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血管新生血管中的内皮细胞，但越来越多的人意识到，双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，我们致力于分离和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，表达肾素的细胞有一个似乎对应于“激活的血管周细胞”的表达特征，并且观察到的一些细胞特异性表达是最近发现的ccRCC的标记。我们假设，将这些表达确定为标志物是启动了一个高度活跃的血管生成过程的结果，这是与成人肾脏通常静止的血管形成过程形成对比的致癌‘创伤过程’的一部分。我们建议严格研究肾周细胞的延伸表达特征，以确定更多的标志物和靶点。要做到这一点，将追求3个具体目标。在目标1下，将识别发育中的肾血管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肾小管细胞癌的表达谱进行比较，以确定特定的候选基因。在目标2下，将对发育和成熟的小鼠肾脏中的特定候选基因进行分析，以验证候选基因表达与发育中的成熟血管(而不是静止的成熟血管)的特定关联。最后，在目标3下，将通过对比分析人类ccRCC和正常肾脏的表达特征来验证已识别的鼠‘激活周细胞’候选者的人类同源基因。经过验证的标志物和靶点可能有助于诊断和判断预后，或为透明细胞肾癌的治疗干预策略提供依据。

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.