Overcoming Fas-mediated apoptosis accelerates Helicobacter-induced gastric cancer in mice.
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.
Cai
Xun
X
Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Stoicov
Calin
C
Li
Hanchen
H
Carlson
Jane
J
Whary
Mark
M
Fox
James G
JG
Houghton
JeanMarie
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D044922:Helicobacter felis / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology*
D019014:fas Receptor