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. ? ? ?
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