PNAS：炎性疾病如何引发癌症

肝癌、结肠癌或胃癌的最大危险因素之一是病毒或细菌感染引起这些器官的慢性炎症。

近日，一项新的麻省理工学院的研究为炎症如何发生演变成癌症提供了全面的解释。

这项研究论文发表在PNAS杂志上，这一发现可能有助于研究人员开发的方法来预测慢性炎症的最终后果，并设计药物来制止这种炎症。

麻省理工学院生物工程教授Peter Dedon说：如果你了解其中机制，那么你就可以设计出干预措施。

在过去的30年中， Tannenbaum带领一群麻省理工学院的研究人员致力于研究慢性炎症和癌症之间的联系。炎症是十分常见而又重要的基本病理过程，体表的外伤感染和各器官的大部分常见病和多发病都属于炎症性疾病。 具有血管系统的活体组织对损伤因子的防御性反应称为炎症。

当人体的免疫系统检测病原体或细胞损伤时，激活的巨噬细胞和中性粒细胞的大量涌入感染组织入。这些细胞能吞噬细菌、死细胞和碎片。

研究人员用H.肝螺杆感染小鼠，在20周后，小鼠肝脏和结肠发生慢性感染，一些小鼠罹患结肠癌。在整个20周期间内，研究人员测量了大概有十几个不同类型的DNA、RNA和蛋白质。他们还检查了组织的损伤情况，测量哪些基因被开启和关闭了。

在未来的研究中，MIT研究小组计划更深入更详细的研究癌症发展的机制，包括某些癌症细胞为什么会发生某些类型的DNA损伤，但某些癌症细胞不发生DNA损伤。

doi:10.1073/pnas.1207829109
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Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer

Aswin Mangericha,b, Charles G. Knutsona, Nicola M. Parryc, Sureshkumar Muthupalanic, Wenjie Yea, Erin Prestwicha, Liang Cuia,1, Jose L. McFalinea, et al.

Helicobacter hepaticus-infected Rag2^-/- mice emulate many aspects of human inflammatory bowel disease, including the development of colitis and colon cancer. To elucidate mechanisms of inflammation-induced carcinogenesis, we undertook a comprehensive analysis of histopathology, molecular damage, and gene expression changes during disease progression in these mice. Infected mice developed severe colitis and hepatitis by 10 wk post-infection, progressing into colon carcinoma by 20 wk post-infection, with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages. Transcriptional profiling revealed decreased expression of DNA repair and oxidative stress response genes in colon, but not in liver. Mass spectrometric analysis revealed higher levels of DNA and RNA damage products in liver compared to colon and infection-induced increases in 5-chlorocytosine in DNA and RNA and hypoxanthine in DNA. Paradoxically, infection was associated with decreased levels of DNA etheno adducts. Levels of nucleic acid damage from the same chemical class were strongly correlated in both liver and colon. The results support a model of inflammation-mediated carcinogenesis involving infiltration of phagocytes and generation of reactive species that cause local molecular damage leading to cell dysfunction, mutation, and cell death. There are strong correlations among histopathology, phagocyte infiltration, and damage chemistry that suggest a major role for neutrophils in inflammation-associated cancer progression. Further, paradoxical changes in nucleic acid damage were observed in tissue- and chemistry-specific patterns. The results also reveal features of cell stress response that point to microbial pathophysiology and mechanisms of cell senescence as important mechanistic links to cancer.