在幾乎所有胰腺癌中發(fā)現(xiàn)的一個突變蛋白不但在癌癥的形成中而且在癌癥持續(xù)的生長中發(fā)揮著重要的作用,，根據(jù)密歇根大學(xué)綜合癌癥中心研究人員的一項(xiàng)新研究,。這一發(fā)現(xiàn)為開發(fā)新的療法治療這種致命性疾病提供了可能的靶標(biāo),。
研究人員已經(jīng)知道,，Kras基因中的突變導(dǎo)致了胰腺癌的形成,。這些突變在常見的癌前病變中也經(jīng)?？吹?，意味著它在胰腺癌中發(fā)揮了早期作用,。
這項(xiàng)新研究,，發(fā)表于2月份的Journal of Clinical Investigation上。研究發(fā)現(xiàn),，在小鼠中突變的Kras也能保持腫瘤的生長及幫助癌前腫瘤轉(zhuǎn)變成浸潤性腫瘤,。當(dāng)研究人員關(guān)閉Kras后，腫瘤消失了并且沒有復(fù)發(fā)的跡象,。
研究人員能夠在設(shè)計(jì)的小鼠模型中操縱Kras基因,，在癌癥發(fā)展的各個時間點(diǎn)對Kras進(jìn)行研究。在癌前病變中,，關(guān)閉Kras消除了小鼠中的腫瘤,，胰腺組織恢復(fù)正常，沒有復(fù)發(fā)的跡象,。在浸潤性癌中,，失活Kras殺死了癌細(xì)胞，但在胰腺中留下了類似纖維的疤痕,，腫瘤沒有復(fù)發(fā),。
研究人員希望這一發(fā)現(xiàn)能為未來的藥物開發(fā)提供基礎(chǔ)。
"目前還沒有藥物特異性靶向Kras,，但有些藥物是靶向于Kras下游的細(xì)胞過程,。接下來我們需要弄清楚Kras下游的這些因子哪些對胰腺癌來說是重要的，"U-M醫(yī)學(xué)院助理教授,、細(xì)胞發(fā)育生物學(xué)博士Marina Pasca di Magliano說,。
已知Kras在肺癌和結(jié)腸癌中也發(fā)揮著作用。但它可能在胰腺癌中發(fā)揮著最大的作用,，有超過90%的胰腺癌中都有突變的Kras,。胰腺癌是最致命的癌癥類型之一，約4%的患者在診斷后能生存5年,。這種病常常在診斷后沒有可選的手術(shù),，而且它對已知可用的化療藥物都有抗性,。
"在對這種疾病有一個更好的理解基礎(chǔ)上,，迫切需要一個更好的治療胰腺癌的新療法,。目前我的實(shí)驗(yàn)室正在尋找Kras的下游抑制劑，嘗試找到最好的靶標(biāo),，"Pasca di Magliano說,。
更多消息請見：Journal of Clinical Investigation, Vol. 122, No. 2, February 2012。（生物谷bioon.com）
doi:10.1172/JCI59227
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PMID:
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Meredith A. Collins, Filip Bednar, Yaqing Zhang, Jean-Christophe Brisset, Stefanie Galbán, Craig J. Galbán, Sabita Rakshit, Karen S. Flannagan, N. Volkan Adsay, Marina Pasca di Magliano
Abstract：Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.
