Recently, there has been considerable buzz around the potential cancer-causing effects of aspartame. However, when placed in the context of the WHO International Agency for Research on Cancer's (IARC) classification, which designates aspartame as a "class 2b carcinogen". Nonetheless, compared to the unequivocally class 1 carcinogen Helicobacter pylori (Hp), the concern over aspartame's impact seems relatively minor. Particularly, Helicobacter pylori (Hp) strains that are cytotoxin-associated gene A protein (CagA)-positive greatly promote gastric cancer.
A recent study conducted by researchers from Juntendo University in Japan, published in Science Signaling, has shed light on the latest mechanism underlying CagA's role in gastric carcinogenesis. The study reveals that CagA can disrupt the Wnt/PCP signaling pathway by interacting with VANGL1/2 proteins, thereby stimulating the proliferation of pyloric basal cells in the stomach while inhibiting their differentiation. Coupled with other pro-cancer effects of CagA, this mechanism potentially accelerates the development of gastric cancer.
The term "PCP" refers to "planar cell polarity," which encompasses the overall polarity of cells within a specific plane. This phenomenon offers directional cues to cells and participates in vital physiological processes such as tissue morphogenesis, embryonic development, and organ formation. Pertinently, the dysregulated activation of body hair arrangement in Drosophila is connected to cancer development, and the PCP pathway is modulated by non-classical Wnt signaling.
However, at the outset of the study, the Juntendo University team did not directly correlate CagA's cancer-promoting actions with the Wnt/PCP pathway. To unravel this connection, the researchers conducted experiments involving African clawed toad embryonic cells expressing CagA and examined its impact on embryonic development. These experiments unveiled that CagA disrupts neural tube closure, causing a form of congenital malformation. This disruption is attributed to the influence of CagA on the convergent extension movements (CEMs) of cells regulated by the Wnt/PCP pathway.
The team then replicated these findings using human gastric mucosal epithelial cells, highlighting how the N-terminus of CagA proteins interacts with VANGL1/2 proteins, causing their displacement from their regular positions. Since VANGL1/2 proteins are crucial regulatory agents in the Wnt/PCP pathway, this interaction provides insight into how CagA affects the pathway.
The involvement of the Wnt/PCP signaling pathway in the carcinogenesis of gastric mucosal epithelial cells is known to encourage cancer cell invasion and metastasis after cancer develops. Consequently, the impact of the CagA protein's role comes into focus.
Again, the spotlight turns to VANGL1/2 proteins. Immunohistochemical analysis of mouse stomachs revealed an abnormal expression of VANGL1/2 proteins on the plasma membrane's surface of pyloric gland basal cells. This abnormal expression was observed to shift when CagA was specifically expressed in the mice's stomachs.
The influence of CagA extended beyond this observation. In comparison to normal mice, those with stomach-specific CagA expression exhibited significantly enlarged (darkened) pyloric glands, increased cell numbers, accelerated proliferation, and consistent changes akin to cancerous cells, all while displaying a decline in enteroendocrine cell markers.
The researchers noted that the morphological impact of CagA on pyloric glands could be associated with other oncogenic mechanisms, possibly prompting a subset of pyloric gland basal cells with stem cell attributes to become cancerous. Consequently, this process expedites the progression of gastric cancer. As such, the study concludes that future gastric cancer treatments should contemplate intervening in the Wnt/PCP pathway.