胃肠道组织的细菌感染可能引发了遗传易感人群的前癌细胞的发育。Laurence Rahme及其同事用一种绿脓杆菌(Pseudomonas aeruginosa)的有毒菌株感染了经过遗传改造的果蝇,这种细菌也能感染人类。结果他们发现了细菌感染与肠道细胞发育不良之间的联系。这个经过改造的果蝇模型含有了Ras基因,科学家已经把这种基因与许多类型的癌症联系了起来。
这组科学家发现,这种病原体的感染对于这些具有遗传易感性的果蝇起到了协同增效的作用;它极大地增加了果蝇肠道内的新的肠道干细胞的数量,而且这些细胞中的许多表现出了不正常的细胞极性,这是癌症的标记。在绿脓杆菌从果蝇肠道中清除出去之后,这些异常细胞仍然存在,这提示感染对于引发肿瘤具有持久相应。肠组织能迅速再生,但是病原体感染和肠自我更新的组合可能导致慢性胃肠病。这组作者说,这项研究可能有助于抗击癌症,而且可能有助于开发更好的诊断工具。(生物谷Bioon.com)
生物谷推荐原始出处:
PNAS November 23, 2009, doi: 10.1073/pnas.0911797106
Synergy between bacterial infection and genetic predisposition in intestinal dysplasia
Yiorgos Apidianakisa,b,1, Chrysoula Pitsoulic,1, Norbert Perrimonc,2 and Laurence Rahmea,b,d,2
aDepartment of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115;
bShriners Burns Institute, Boston, MA 02114;
cDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; and
dDepartment of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115
Accumulating evidence suggests that hyperproliferating intestinal stem cells (SCs) and progenitors drive cancer initiation, maintenance, and metastasis. In addition, chronic inflammation and infection have been increasingly recognized for their roles in cancer. Nevertheless, the mechanisms by which bacterial infections can initiate SC-mediated tumorigenesis remain elusive. Using a Drosophila model of gut pathogenesis, we show that intestinal infection with Pseudomonas aeruginosa, a human opportunistic bacterial pathogen, activates the c-Jun N-terminal kinase (JNK) pathway, a hallmark of the host stress response. This, in turn, causes apoptosis of enterocytes, the largest class of differentiated intestinal cells, and promotes a dramatic proliferation of SCs and progenitors that serves as a homeostatic compensatory mechanism to replenish the apoptotic enterocytes. However, we find that this homeostatic mechanism can lead to massive over-proliferation of intestinal cells when infection occurs in animals with a latent oncogenic form of the Ras1 oncogene. The affected intestines develop excess layers of cells with altered apicobasal polarity reminiscent of dysplasia, suggesting that infection can directly synergize with the genetic background in predisposed individuals to initiate SC-mediated tumorigenesis. Our results provide a framework for the study of intestinal bacterial infections and their effects on undifferentiated and mature enteric epithelial cells in the initial stages of intestinal cancer. Assessment of progenitor cell responses to pathogenic intestinal bacteria could provide a measure of predisposition for apoptotic enterocyte-assisted intestinal dysplasias in humans.