Van Andel研究所的科學家近期的研究為更完整地了解腎癌不同亞型奠定了基礎,，這可能為更好地治療方法鋪平了道路,。
由Kyle Furge博士和Aikseng Ooi博士發(fā)表于Cancer Cell上的一項研究中,，研究者對2型乳頭狀腎細胞癌（PRCC2）提供了一個更為完整的理解,，這為開發(fā)有效的治療策略奠定了基礎（注：PRCC2是一種惡性腎癌,，目前沒有有效的療法）,。
盡管具有明顯的形態(tài)學,、遺傳學和臨床上的差異,，遺傳型PRCC2被認為與另一種腎癌--腎透明細胞癌（CCRCC）有相似的基于基因突變所致的信號通路失調,。CCRCC是腎癌的一個亞型，約占腎癌的75%,，與PRCC2不同,，它對靶向血管內皮生長因子（VEGF，細胞中的一種信號蛋白,，能夠刺激血管的形成）的藥物積極響應,。
該研究是同其他國際學者共同協作完成，包括新加坡國立癌癥中心,、EPFE-INSERM U753遺傳腫瘤所,、巴黎Sud醫(yī)學院、Gustave Roussy癌癥研究所,、密歇根州立大學,、西北紀念醫(yī)院、克利夫蘭診所,、新加坡中央醫(yī)院,、Wistar研究所，鑒定出KEAP1-NRF2信號通路的放松管制是區(qū)別PRCC2和CCRCC的一個因素,，但與遺傳型及散發(fā)型PRCC2相關,。
在另一項發(fā)表于癌癥研究中的研究（由Yan Ding博士和Bin Tean Teh博士與新加坡國立癌癥研究中心合作進行的）中，研究人員綜合了基因表達譜和RNAi篩選數據來鑒定與CCRCC發(fā)生和發(fā)展相關的基因,。
近年來,，一些分子靶向療法如舒尼替尼、索拉非尼,、帕唑帕尼這些靶向血管內皮生長因子的酪氨酸激酶受體已被批準用于治療CCRCC,。盡管這些療法能顯著的延長患者的總生存期，但最終幾乎所有的CCRCC患者仍無法逃過病魔,。
基因組富集分析表明,，細胞周期相關的基因，尤其是PLK1,，與疾病的侵略性相關,。此外，PLK1與疾病的侵染和體外生長促使研究人員檢測小分子抑制劑對CCRCC細胞系的抑制作用,。他們的研究結果強調PLK1是治療CCRCC的非常有潛力的靶標,。（生物谷bioon.com）
doi: DOI 10.1016/j.ccr.2011.08.024
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An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma
Aikseng Ooi, Jing-Chii Wong, David Petillo, Douglas Roossien, Victoria Perrier-Trudova, Douglas Whitten, Bernice Wong Hui Min, Min-Han Tan, Zhongfa Zhang, Ximing J. Yang, Ming Zhou, Betty Gardie, Vincent Molinie, Stephane Richard, Puay Hoon Tan, Bin Tean Teh, Kyle A. Furge
Summary ：Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 (AKR1B10) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.
Highlights ：Increased expression of AKR1B10 is a prominent feature of FH null cells ? Fumarate mediates the stabilization of NRF transcription factors ? The KEAP1-NRF axis is deregulated in type 2 papillary renal cell carcinomas ? Complete gene expression profiles of FH null kidney cancers are presented.
Significance ：Type 2 papillary renal cell carcinoma (PRCC2) is an aggressive disease with no effective treatment. Despite the obvious orphological, genetic, and clinical differences, hereditary PRCC2 is thought to share similar pathway deregulation with ts clear-cell counterpart (CCRCC) that arises as a result of SDH or VHL mutation. Furthermore, the robust response seen ith anti-VEGF agents in CCRCC is not reproducible in PRCC2. This represents a distinct knowledge gap in the understanding of PRCC2 biology. We identi?ed deregulation of the KEAP1-NRF2 axis as a feature that distinguishes PRCC2 rom CCRCC, but links both hereditary and sporadic PRCC2. Therefore, our finding provides a more complete understanding of PRCC2 biology and lays the foundation for the development of effective treatment strategies.
