Overcoming Fas-Mediated Apoptosis Accelerates Helicobacter-Induced Gastric Cancer in Mice

Abstract

The initiating molecular events in Helicobacter -induced gastric carcinogenesis are not known. Early in infection, Fas antigen-mediated apoptosis depletes parietal and chief cell populations, leading to architectural distortion. As infection progresses, metaplastic and dysplastic glands appear, which are resistant to Fas-mediated apoptosis. These abnormal lineages precede, and are thought to be the precursor lesions of, gastric cancer. Acquisition of an antiapoptotic phenotype before transformation of cells suggests that loss of Fas sensitivity may be an early required trait for gastric cancer. We reasoned that forced Fas-apoptosis resistance would result in earlier and more aggressive gastric cancer in our mouse model. Fas antigen-deficient (lpr) mice or C57BL/6 wild-type mice were irradiated and reconstituted with C57BL/6 marrow forming partial lpr/wt chimera or wt/wt control mice, extending the life span of the lpr and ensuring a competent immune response to Helicobacter felis infection. Infected lpr/ wt mice developed gastric cancer as early as 7 months after infection (compared with 15 months in wt/wt mice). At 10 months (90%) and 15 months (100%), mice developed aggressive invasive lesions. This earlier onset and more aggressive histology strongly argues that Fas-apoptosis resistance is an early and important feature of gastric cancer formation. (Cancer Res 2005; 65(23): 10912-20)

Cell death in the host response to infection

“…32 Overcoming Fas-mediated apoptosis in this case accelerates H. pylori-induced gastric cancer, highlighting the key role of apoptosis not only in the host defense to infection but also in protection from gastric cancer. 33 Indeed, apoptosis has multifaceted roles in hostpathogen interactions. In addition to containing pathogen dissemination, apoptosis is required for termination of the inflammatory response, as it eliminates inflammatory cells following the control of infection.…”

Helicobacter pylori and gastric cancer

“…H. pylori has recently been shown to upregulate expression of TRAIL, TRAIL-R1 and Fas in gastric epithelial cells [35]. The functional consequences of abnormalities in this pathway have been demonstrated in an animal model, as increased gastric carcinogenesis was observed following H. felis infection of irradiated C57BL/6 mice that received bone marrow transplants from Fas antigen deficient (lpr)/wild type chimaeric mice [36].…”

Role of Helicobacter pylori on cancer of human adipose-derived mesenchymal stem cells and metastasis of tumor cells—an in vitro study

“…When MSCs are attracted toward the H. pylori chronic infection tissue, H. pylori induces the cellular apoptosis by enhancing the expression of p53 gene. Actually, apoptosis reaction is the first biological expected action of cells when meeting mutagen agents, and here, enhancing of p53 may be interpreted as the first reaction of hA-MSCs in front of H. pylori as a mutagenic infection risk factor [30,31]. However, in the response to expression of p53 gene, overexpression of bcl2 gene occurs directly or indirectly due to H. pylori infection.…”