Why Men Are at Higher Risk for Stomach Cancer

In a new study, researchers at MIT demonstrate how estrogen protects women against stomach cancer.

Stomach cancer, as well as cancers of the liver and colon, is more common in men than women. Initially, scientists thought that lifestyle choices like smoking and eating habits could explain this disparity, but current research seems to lead to another cause – basic biological differences between the sexes.

MIT’s new study, which was published online in Cancer Prevention Research, demonstrated that giving male mice estrogen greatly reduced their susceptibility to those stomach cancers known to be caused by Helicobacter pylori bacteria.

The researchers hope this new information might eventually lead to new ways to prevent these cancers.

Alexander Sheh, a postdoc in MIT’s Division of Comparative Medicine (DCM) and lead author of the paper, said: “If we can narrow in on which estrogen effect is causing this protection, we can come up with a better therapy.”

About half of the population is infected with H. pylori, which is usually symptomless. The infection itself, however, greatly increases the chance of developing gastric cancer, which is the second greatest cause of cancer deaths. The body’s immune response to the H. pylori infection can lead to a chronic inflammation of the stomach, and it is this inflammation that contributes to the development of cancer.

According to the findings from several studies, women seem to be protected from this inflammation by estrogen. For example, when estrogen is blocked by drugs such as Tamoxifen, which is used to treat breast cancer, a woman’s risk of developing gastric cancer rises. In other studies at MIT, female mice whose estrogen production ceased when their ovaries were removed became just as susceptible to stomach cancer as males, while male mice who were given estrogen became resistant to precancerous gastric lesions.

But James Fox, MIT professor of biological engineering and director of DCM, the author of these studies, is the senior author of a new study using mice genetically predisposed to develop gastric cancers. Male mice that were infected with H. pylori were given estrogen, Tamoxifen, both, or nothing; female mice, also infected, were given Tamoxifen or nothing. Since Tamoxifen blocks estrogen, researchers expected the positive effects of estrogen to diminish where it was given.

But, surprisingly, all three treated groups of males showed increased resistance to gastric cancers. Even more surprisingly, none of these mice developed cancer at all, despite their genetic background. Of an untreated control group, forty percent developed gastric cancer. Female mice receiving Tamoxifen had the same outcomes as untreated mice. This suggests to the research team that, for some reason, Tamoxifen mimics estrogen in the stomach instead of blocking it.

So how do estrogen and Tamoxifen both  protect against gastric cancer? Searching for a genetic component, the team looked at the occurrence overexpressed genes in the mice. Out of approximately 60 genes, they selected a signaling protein, CXCL1, involved in cell movement and recruitment of immune cells. It also has a human analogue, IL-8; IL-8 is frequently found to be part of the body’s immune response to H. pylori infection.

The team theorizes that a chronic H. pylori infection causes an increase in production of CXCL1 (or IL-8 in humans); since this gene’s purpose is, in part, to attract immune cells such as neutrophils and macrophages, it does so. The presence of these immune cells promotes inflammation, which lays the groundwork for cancerous growth. For reasons that are still unknown, estrogen interferes with either the recruitment or the activity of these immune cells–or both.

The MIT team are studying mice that are missing the gene for CXCL1, to see if the absence of that one protein can change the course of gastric cancers. Creating molecules that specifically block CXCL1 activity is also on the agenda.

Source: Massachusetts Institute of Technology (2011, July 14). Why men are at higher risk for stomach cancer. ScienceDaily.