在几乎所有胰腺癌中发现的一个突变蛋白不但在癌症的形成中而且在癌症持续的生长中发挥着重要的作用，根据密歇根大学综合癌症中心研究人员的一项新研究。这一发现为开发新的疗法治疗这种致命性疾病提供了可能的靶标。
研究人员已经知道，Kras基因中的突变导致了胰腺癌的形成。这些突变在常见的癌前病变中也经常看到，意味着它在胰腺癌中发挥了早期作用。
这项新研究，发表于2月份的Journal of Clinical Investigation上。研究发现，在小鼠中突变的Kras也能保持肿瘤的生长及帮助癌前肿瘤转变成浸润性肿瘤。当研究人员关闭Kras后，肿瘤消失了并且没有复发的迹象。
研究人员能够在设计的小鼠模型中操纵Kras基因，在癌症发展的各个时间点对Kras进行研究。在癌前病变中，关闭Kras消除了小鼠中的肿瘤，胰腺组织恢复正常，没有复发的迹象。在浸润性癌中，失活Kras杀死了癌细胞，但在胰腺中留下了类似纤维的疤痕，肿瘤没有复发。
研究人员希望这一发现能为未来的药物开发提供基础。
"目前还没有药物特异性靶向Kras，但有些药物是靶向于Kras下游的细胞过程。接下来我们需要弄清楚Kras下游的这些因子哪些对胰腺癌来说是重要的，"U-M医学院助理教授、细胞发育生物学博士Marina Pasca di Magliano说。
已知Kras在肺癌和结肠癌中也发挥着作用。但它可能在胰腺癌中发挥着最大的作用，有超过90%的胰腺癌中都有突变的Kras。胰腺癌是最致命的癌症类型之一，约4%的患者在诊断后能生存5年。这种病常常在诊断后没有可选的手术，而且它对已知可用的化疗药物都有抗性。
"在对这种疾病有一个更好的理解基础上，迫切需要一个更好的治疗胰腺癌的新疗法。目前我的实验室正在寻找Kras的下游抑制剂，尝试找到最好的靶标，"Pasca di Magliano说。
更多消息请见：Journal of Clinical Investigation, Vol. 122, No. 2, February 2012。（生物谷bioon.com）
doi:10.1172/JCI59227
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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.
