In 1984, Barry Marshall and Robin Warren published a landmark study suggesting a central role for Helicobacter pylori in the pathogenesis of gastritis and peptic ulceration, igniting decades of groundbreaking research that has considerably advanced our understanding of infection-associated carcinogenesis. Studies conducted over the past 40 years, including Marshall’s legendary self-experimentation to fulfil Koch’s postulates (leading to the award of the 2005 Nobel Prize in Physiology or Medicine), have provided insight into multifaceted molecular determinants underscoring H. pylori-induced gastric disease. Several years after the initial report, it was firmly established that in addition to peptic ulcer disease, persistent H. pylori infection is associated with a significantly increased risk for the predominant types of gastric cancer. Curiously, while H. pylori chronically colonizes the stomach in half the global population, the vast majority of infected individuals never develop symptomatic disease. When I entered graduate school in 2007, I was fascinated by this concept — what traits enable a prevalent bacterium to stimulate cancer in some individuals but not others?
Gastric cancer is the fourth leading cause of cancer-related deaths worldwide, claiming the lives of nearly 800,000 people annually. Despite many decades of research, we do not fully understand how the interplay between microbial and host factors influences disease risk. Within the protected gastric niche, H. pylori secretes diverse substrates that alter cellular function and trigger phenotypic changes in the mucosa, initiating disease progression from superficial non-atrophic gastritis to gastric adenocarcinoma (termed the ‘Correa cascade’ in recognition of Pelayo Correa who delineated the canonical histological stages that occur during gastric carcinogenesis). A seminal publication in Cancer Research by Blaser et al. was one of the first studies to investigate gastric cancer risk in patients colonized by H. pylori strains harbouring the bacterial oncoprotein CagA. Prior to this work, studies initiated by a postdoctoral fellow in the Blaser group (Timothy Cover, who later served as my graduate advisor and mentor) employed a clever strategy to identify important H. pylori antigens that correlate with gastric injury. Using a combination of H. pylori culture supernatants, Escherichia coli clones expressing various H. pylori antigens and serum IgG from a patient with chronic H. pylori infection (which was later revealed to be Martin Blaser), Cover and colleagues identified a strongly immunoreactive antigen that was subsequently characterized and designated cytotoxin-associated gene A (cagA). Simultaneous discoveries of CagA by groups in Italy and England confirmed the observations reported by the Blaser group and set the stage for exciting studies to elucidate the role of this immunodominant antigen in gastric inflammation and epithelial cell damage.
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