Review article: the role of inflammation in the pathogenesis of gastric cancer
Review article: the role of inflammation in the pathogenesis of gastric cancer
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DOI：
10.1046/j.1365-2036.1999.00003.x
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发表时间：
1999-03-01
影响因子：
7.6
通讯作者：
Ernst, P
中科院分区：
文献类型：
--
作者：
Ernst, P
幽门螺杆菌诱导多形核细胞和巨噬细胞以及 T 和 B 淋巴细胞浸润胃粘膜。矛盾的是，这种免疫/炎症反应不能清除感染，从而使宿主容易出现慢性炎症引起的并发症。这种炎症反应的一个不良后果可能是胃癌，因为炎症与肠化生的发展和胃腺癌发展之前的癌基因突变有关。感染宿主的幽门螺杆菌菌株对胃炎症反应有一定影响。因此，与某些菌株相关的更严重的临床表现可能归因于它们诱导的更高程度的炎症。感染过程中诱导的幽门螺杆菌、幽门螺杆菌和细胞因子都会刺激包括中性粒细胞和巨噬细胞在内的炎症细胞的募集和激活。激活时，这些细胞会产生包括活性氧 (ROS) 在内的炎症介质，这些介质会对附近的细胞（在本例中为胃上皮细胞）产生氧化应激。通常情况下，氧化应激可被维生素 C 等天然抗氧化剂中和，但是，胃液中这种抗氧化剂的水平在感染过程中会降低。氧化剂水平的增加和抗氧化剂的减少会产生压力，从而改变胃上皮细胞中的许多过程，例如，细胞内ROS调节许多基因的表达并可诱导DNA损伤。 DNA 中的点突变破坏了抑制细胞生长的基因（即 p53）的表达和功能，被认为与胃癌的发病机制有关。多项研究表明，上皮细胞更新受到幽门螺杆菌炎症反应的影响。这一观点得到了研究的支持，这些研究描述了感染后上皮细胞增殖以及细胞凋亡导致的细胞死亡的增加。细胞凋亡是一种受调节的细胞死亡过程，由幽门螺杆菌以及各种炎症介质（包括肿瘤坏死因子和干扰素-γ）触发。激活的 T 细胞也直接杀死胃上皮细胞。此外，宿主反应增加幽门螺杆菌受体的表达，从而增加细菌结合和诱导细菌凋亡。还有几种其他免疫/炎症反应有助于上皮细胞损伤粘膜和胃癌的发病机制。例如，胃 B 细胞产生与胃上皮细胞结合的自身反应性抗体。由于这种抗原-抗体复合物形成，补体被激活，这表明一些炎症和上皮细胞损伤可归因于免疫复合物的形成。上皮细胞死亡可以刺激上皮细胞前体的增殖反应。 总之，所提出的模型可以解释胃炎症反应如何促进癌症的发病机制。该模型提出了一种可能性，即最好确定罹患胃癌风险最高的患者，然后采取干预措施消除感染和炎症反应。或者，临床干预措施至少应减轻直接归因于炎症的氧化应激。这些机制必须在儿科人群中进行检查。
Helicobacter pylori induces infiltration of the gastric mu,:osa by polymorphonuclear cells and macrophages, as well as T and B lymphocytes. Paradoxically, this rob Ist immune/inflammatory response cannot clear the infection, and thus leaves the host prone to complications resulting from chronic inflammation, One adverse consequence of this inflammatory response may be gastric cancer, as inflammation has been implicated in the development of intestinal metaplasia and mutations in oncogenes that precede the development of gastric adenocarcinoma, The gastric inflammatory response is affected somewhat, by the strain of H, pylori that infects the host. Thus, the more severe clinical manifestation associated with some strains may be attributed to the higher grade of inflammation that they induce.Both H, pylori and cytokines induced during infection dan stimulate the recruitment and activation of inflammatory cells including neutrophils and macrophages. When activated, these cells produce inflammatory mediators that include reactive oxygen spe:ies (ROS), These mediators impart an oxidative stress on the cells in the immediate vicinity, in this case, the gastric epithelium, Normally, oxidative stress is neutralized by natural antioxidants such as vitamin C, however, levels of this antioxidant in the gastric juice are decreased during infection, The increased levels of oxidants and decreased antioxidants create a stress that can change many processes in the gastric epithelium, For example, an accumulation of intracellular ROS regulates the expression of many genes and can induce DNA damage. Point mutations in the DNA that disrupt the expression and function of genes that inhibit cell growth (i.e. p53) are believed to contribute to the pathogenesis of gastric cancer,Several studies suggest that epithelial cell turnover is affected by the inflammatory response to H. pylori. This notion is supported by studies describing an increase in both epithelial cell proliferation, as well as cell death by apoptosis, in response to infection, Apoptosis is a regulated process of cell death that is triggered by H, pylori as well as various inflammatory mediators, including tumour necrosis factor and interferon-gamma.Activated T-cells also kill gastric epithelial cells directly. Moreover, the host response increases the expression of receptors for H. pylori and thus increases bacterial binding and the induction of apoptosis by the bacteria, There are several other immune/inflammatory responses that contribute to epithelial cell damage mucosa and the pathogenesis of gastric cancer. For example, gastric B cells produce autoreactive antibodies that bind to gastric epithelial cells. As a consequence of this antigen-antibody complex formation, complement becomes activated suggesting that some of the inflammation and epithelial cell damage is attributable to immune-complex formation. Epithelial cell death can then stimulate the proliferative response of epithelial cell precursors.In summary, the proposed model may explain how the gastric inflammatory response contributes to the pathogenesis of cancer. This model raises the possibility that it could be preferable to identify the patients at highest risk of developing gastric cancer and then apply an intervention that eliminates the infection and inflammatory response. Alternatively, clinical interventions should at least attenuate the oxidative stress that is directly attributed to inflammation. These mechanisms have to be examined in the paediatric population.