By April Garbuz, Wilton High School
New findings link estrogen to the prevention of gastric cancer. Though it is unlikely that men will be treated with estrogen in order to prevent gastric cancer, this discovery will help us learn more about how to manage immune responses and prevent some cancers. I spoke with the study's lead author, Alexander Sheh, a Postdoctoral Associate at MIT, about his estrogen research and what it might mean for cancer prevention.
How was the study conducted?
We used mice that have been genetically engineered to produce gastrin in their stomachs and infected them with bacteria that cause gastric cancer. Gastrin is a hormone used by the stomach to increase acid production, but has also been associated with increased proliferation of cells. We used Helicobacter pylori, a bacterium which is a carcinogen, to infect these mice. Previous work in our labs had shown that H. pylori infection accelerates the development of cancer.
We were interested in using this model of gastric cancer and seeing if we could prevent the development of cancer in the male mice infected with H. pylori by giving them estrogen, as we knew that estrogen played a role in protecting females from previous work. We used an anti-estrogen Tamoxifen, which blocks estrogen, to see if it would block the protective effect of estrogen.
We infected the mice with H. pylori so that they would start their progression towards gastric cancer. We treated the male mice with estrogen, Tamoxifen, a combination of both, or neither. Female mice were treated with Tamoxifen or nothing. After a total of 28 weeks of infection we assessed whether the mice had developed gastric cancer. We found that estrogen, Tamoxifen and a combination of both treatments prevented cancer in males but Tamoxifen had no effect on females. This was contrary to what we expected for Tamoxifen as we expected it to reverse the protective effects in both genders.
So we used microarrays to look at gene expression profiles in the stomach of male mice treated with placebo, estrogen or Tamoxifen. The gene expression results pointed to CXCL1, a cytokine involved in recruiting immune cells to sites of infection. CXCL1 levels have been found to be elevated in patients with cancers, but we found that estrogen treatment was able to reduce CXCL1 activity and the recruitment of immune cells.
What do the results suggest about the relationship between Helicobacter pylori and estrogen?
We are interested in how estrogen modulates immune responses and how that affects the progression to gastric cancer that H. pylori sets in motion.
Normally, H. pylori promoted disease has a snowball-like effect. The bacteria induce a response from the stomach, which recruits innate immune cells, like neutrophils and macrophages. Innate immune cells form the first line of defense to insults to the body and help organize other aspects of the body's defenses. We believe that estrogen can affect how the body reacts to H. pylori, downplaying the ineffective immune response and preventing the body from damaging itself.
What property of estrogen protects against gastric cancer?
Estrogen helps regulate immune responses in women. Increased levels of estrogen seem to reduce pro-inflammatory signals in the body by eliciting the production of distinct types of T regulatory cells and T helper 2 (Th2) cells. In this study we tried to exploit this fact as we know that H. pylori induces a strong T helper 1 response from mice, which is a pro-inflammatory response.
Our study showed that estrogen had effects even further upstream as it affected the development of the tumor microenvironment, that is the combination of chemical mediators at the site of tumor origin that aid the progression of cancer.
Do the findings suggest that estrogen could protect against other infections?
Others have no doubt looked at the role of estrogen in other infections. Our particular findings do suggest a possible mechanism by which estrogen can protect the body from damage due to chronic infections that the body is not well-equipped to eradicate on its own. Other chronic inflammatory agents such as hepatitis B and C viruses and liver flukes can also promote these states where the body damages itself while not actually resolving the infection. However, in infections that can be resolved by the immune system, treatment with estrogen might actually allow the infection to persist.
Is it likely that will men be treated with estrogen to prevent gastric cancer?
It’s unlikely that doctors would prescribe estrogen to men as a preventative treatment for gastric cancer. However if we can learn more about the mechanisms involved, we hope to discover ways to better manage the immune response in order to prevent cancers mediated by inflammation and other inflammatory mediated diseases involving the brain and heart.
How will these results be applied to other research? What is the next step?
What we showed is that estrogen was able to skew the tumor microenvironment by decreasing CXCL1 levels which were associated with protection. We hypothesize that the decrease in CXCL1 levels and neutrophils affected the tumor microenvironment which influences the development of the response to H. pylori. So we'll focus on trying to determine what CXCL1 is doing in our model system and whether we can modulate its effects.