Bacteria promote the development of lung tumors, study finds

MIT cancer biologists have discovered a new mechanism that lung tumors exploit to promote their own survival: these tumors alter bacterial populations in the lungs, thereby causing the immune system to create an inflammatory environment that helps tumor cells to grow .

In mice genetically engineered to develop lung cancer, those grown in a bacteria-free environment developed much smaller tumors than mice raised under normal conditions, the researchers found. In addition, the researchers were able to significantly reduce the number and size of lung tumors by treating mice with antibiotics or by blocking immune cells stimulated by the bacteria.

The researchers suggest the findings suggest several strategies for developing new treatments for lung cancer.

"This research directly links the bacterial burden in the lung to the development of lung cancer and opens many potential pathways to the interception and treatment of lung cancer," said Tyler Jacks, director of the Institute. MIT's Koch Cancer Research and lead author of the article.

Chengcheng Jin, a Koch Institute postdoctoral fellow, is the lead author of the study, which will appear in the January 31st online edition of Cell.

Connecting bacteria and cancer

Lung cancer, the leading cause of death linked to cancer, kills more than one million people worldwide each year. Up to 70% of lung cancer patients also suffer from complications of bacterial infections of the lung. In this study, the MIT team wanted to see if there was a link between the bacterial populations present in the lungs and the development of lung tumors.

To explore this potential link, the researchers studied genetically modified mice that express oncogenic Kras and lack the p53 tumor suppressor gene. These mice usually develop a type of lung cancer called adenocarcinoma in a few weeks.

Mice (and humans) usually have many harmless bacteria that thrive in their lungs. However, the MIT team found that in mice designed to develop lung tumors, the bacterial populations in their lungs had changed considerably. The overall population has increased significantly, but the number of different bacterial species has decreased. Researchers do not know exactly how lung cancers cause these changes, but they suspect one possibility is that tumors obstruct the airways and prevent the elimination of bacteria from the lungs.

This expansion of the bacterial population has induced immune cells called gamma delta T cells to proliferate and begin to secrete inflammatory molecules called cytokines. These molecules, particularly IL-17 and IL-22, create a growth and survival environment for tumor cells. They also stimulate the activation of neutrophils, another type of immune cell that releases pro-inflammatory chemicals, further strengthening the favorable environment for tumors.

"You can think of this as a feed-forward loop that forms a vicious circle to further promote tumor growth," said Jin. "Developing tumors divert existing immune cells into the lungs, exploiting them to their advantage through a mechanism dependent on local bacteria."

However, in mice born and raised in a germ-free environment, this immune response did not occur and the tumors developed by the mice were much smaller.

Block tumor growth

The researchers found that when they treated the mice with antibiotics two or seven weeks after the start of tumor growth, they decreased by about 50%. Tumors also decreased if the researchers administered mice with drugs that block gamma delta T cells or block IL-17.

Researchers believe that these drugs may be worth testing in humans, because when they badyzed human lung tumors, they found altered bacterial signals similar to those observed in mice that developed cancer. Human lung tumor samples also had an unusually high number of gamma delta T cells.

"If we can find ways to selectively block the bacteria that cause all these effects, or if we can block the cytokines that activate the gamma delta T cells or neutralize the downstream pathogenic factors, these could all be new ways. potential to treat lung cancer, "Jin said.

Many drugs of this type already exist and researchers are testing some in their mouse model in the hope of testing them later in humans. Researchers are also working to determine which strains of bacteria are elevated in lung tumors, so that they can search for antibiotics that can kill them selectively.

Provided by
Mbadachusetts Institute of Technology