Clinical evidence suggests that infection with Helicobacter pylori cagA+ strains dramatically increases the risk of developing gastric cancer. Newly reported research by scientists across research organizations in Japan offers up new insights into a mechanism by which oncogenic CagA action may promote gastric cancer development, by disrupting the Wnt/PCP pathway. The preclinical in vitro and vivo study, in multiple models, offers up a potential target for preventing gastric cancer development by H. pylori CagA.

Reporting in Science Signaling on their study, titled The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells,” lead author Atsushi Takahashi-Kanemitsu, an assistant professor, department of biochemistry and systems biomedicine, Juntendo University, and colleagues, stated, “… CagA may contribute to the development of gastric cancer by subverting a Wnt/PCP-dependent mechanism that restrains pyloric gland stem cell proliferation and promotes enteroendocrine differentiation.”

Helicobacter pylori infections are commonly associated with abdominal pain, bloating, and acidity. Infection with H. pylori cagA+ is also the strongest risk factor for gastric cancer, the authors pointed out. The oncoprotein CagA delivered by H. pylori into the host has been shown to interact with multiple host proteins and promote gastric carcinogenesis. “CagA delivered into gastric epithelial cells acts as a pathogenic scaffold that promiscuously interacts with and thereby functionally perturbs multiple host proteins to promote gastric carcinogenesis,” the authors wrote. “Systemic expression of cagA in transgenic mice causes spontaneous gastrointestinal and hematological malignancies, confirming the oncogenic potential of the bacterial CagA protein in mammals.” However, despite these observations the mechanisms underlying the biochemical activity of CagA have not yet been fully determined.

“CagA interacts with multiple host proteins within the gastric epithelial cells, thereby inducing pathways associated with oncogenesis and promoting gastric carcinogenesis,” added Takahashi-Kanemitsu. “We were curious to find out which pathways were involved in this process.”

For their reported study the team set out to investigate the effects on host cells and pathways, of expressing oncoprotein CagA in three different models; embryos of Xenopus laevis (the African clawed frog), the stomachs of adult mice, and cultured human gastric epithelial cells. They results showed that expression of the CagA oncoprotein in X. laevis embryos led to impairment of convergent extension movements—cell movements observed during embryonic development that are involved in shaping or elongating organismal tissues and organs. This impairment further interfered with subsequent key embryonic development processes, including body axis formation. “Ectopic expression of CagA in Xenopus laevis embryos impaired gastrulation, neural tube formation, and axis elongation, processes driven by convergent extension movements that depend on the Wnt/PCP pathway,” they wrote.

For the study in adult mice, the team generated transgenic animals that specifically expressed the CagA oncoprotein in the stomach epithelial cells, in response to tamoxifen treatment. The researchers observed that CagA expression in the stomach of these adult mice caused an increase in the depth of pyloric glands—secretory glands that facilitate digestion/stomach function—and also triggered abnormal/excessive cell multiplication, which is a phenomenon remarkably observed in various types of cancers. This led to the displacement of the VANGL (Van Gogh-like) proteins VANGL1 and VANGL2 from the plasma membrane to the cytoplasm. (The VANGL family of proteins play key roles in various biological processes.) “Mice specifically expressing CagA in the stomach epithelium had longer pyloric glands and mislocalization of the tetraspanin proteins VANGL1 and VANGL2 (VANGL1/2), which are critical components of Wnt/PCP signaling,” the team pointed out. CagA expression also resulted in fewer differentiated enteroendocrine cells, which are specialized cells in the gastrointestinal tract that aid in digestion.

The investigators then separately expressed the CagA oncoprotein in cultured human gastric epithelial cells. These experiments clearly demonstrated that a small region of the CagA oncoprotein was interacting with amino acid residues from the proteins VANGL1/2, thus leading to its displacement—the phenomenon observed in the mouse model—and resulting in disruption of the Wnt/PCP pathway—a key biological “relay” that affects organismal development. “In cultured human gastric epithelial cells, the N terminus of CagA interacted with the C-terminal cytoplasmic tails of VANGL1/2, which impaired Wnt/PCP signaling by inducing the mislocalization of VANGL1/2 from the plasma membrane to the cytoplasm,” the authors stated.

The disruption of Wnt/PCP signaling by the oncoprotein CagA seems to promote gastric carcinogenesis. [Atsushi Takahashi-Kanemitsu, Juntendo University Graduate School of Medicine]

Corresponding author Masanori Hatakeyama, PhD, Laboratory Head, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, said, “Perturbation of Wnt/PCP signaling by the H. pylori CagA-VANGL interaction induces hyperplastic changes, along with impaired cell differentiation in gastric pyloric glands. This, in conjunction with other oncogenic CagA actions, may contribute to the development of gastric cancer.”

The researchers concluded that their combined results allowed them to elucidate the molecular mechanisms involved in gastric carcinogenesis induced by H. pylori, gain insights into the role of the Wnt/PCP pathway in carcinogenesis, and propose it as a potential target for clinical interventions against H. pylori cagA+ infections.  In their paper, they concluded, “The present study highlights that perturbation of Wnt/PCP signaling by H. pylori CagA-VANGL interaction induces hyperplastic changes, along with the repressed cell differentiation, in gastric pyloric glands, which may contribute to the development of gastric cancer in conjunction with other oncogenic CagA actions. This, in turn, raises the idea that the noncanonical Wnt/PCP signal pathway is a potential target for the prevention of gastric cancer development by H. pylori CagA.”

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