Can bacteria that cause food-borne illness be used to fight cancer? Ongoing research suggests this is the case.
“There has long been interest in using genetically engineered microbes to target and destroy cells within solid tumors,” said Roy Curtiss, III, PhD, University Professor of Microbiology and Director, Center for Infectious Diseases and Vaccinology and Center for Microbial Genetic Engineering, the Biodesign Institute, Arizona State University. His group has been working on turning Salmonella into a cancer-fighting machine.
The idea that bacterium can be used as an anticancer agent dates back to the turn of the century. In 1890, William B. Coley, MD, a surgeon at what is now known as Memorial Sloan-Kettering Cancer Center, observed that cancer patients who developed bacterial infections after surgery had better outcomes than those who did not. Dr. Coley developed Coley’s toxins, mixtures of dead bacteria that were used to treat cancer patients. While the treatment was controversial, different formulas of Coley toxins were made by several drug companies in the United States and used in cancer patients until the early 1950s. At that point, better forms of cancer treatment became available.
In recent years, there has been a re-emergence of interest in using bacteria to kill cancer. In the March/April issue of mBio, an American Society for Microbiology online-only, open access journal, researchers show that genetically modified Salmonella can be used to kill cancer cells. Salmonella enterica Serovar Typhimurium has been shown to not only colonize solid tumors, but also to exhibit an antitumor effect. However, in order to use Salmonella as a weapon against cancer in humans, researchers must find a balance between allowing it to kill the cancer and be safe for the patient. The bacteria, commonly known for causing severe food poisoning, can lead to sepsis and death in humans.
In the new study, researchers from Germany and the United States teamed up to modify the lipopolysaccharide structure (LPS) of the Salmonella strain to make the bug less toxic. LPS, found in the outer membrane of bacteria, is one of the major inducers of sepsis, a life-threatening infection. The researchers used genetic engineering to delete genes involved in the synthesis of the LPS, and then tested various modified Salmonella strains to see how they performed in test tube studies with human cancer cells and in tumor bearing mice. They identified a particular mutant strain that was the most effective at killing cancer cells and shrinking tumors, and also unable to cause disease. However, this mutant strain was less able to colonize the tumors, although being most effective in killing tumor cells when getting there.
To address this problem, the researchers then added another genetic modification, an inducible arabinose promoter. The modification allowed the Salmonella to be injected in the mouse in a form that would not harm normal, healthy cells, was effective at colonizing tumors, and after entering cancer cells, would turn toxic. "This transition from a benign, invasive Salmonella that doesn't hurt normal cells to the toxic type occurs very rapidly (time wise) in the tumor due to the very rapid growth and cell division that occurs when Salmonella enters a tumor," said Dr. Curtiss. In a normal cell, Salmonella grows very slowly, dividing once or twice in a 24-hour period, but in a tumor, the bacteria divide every hour.
The researchers believe their study is a significant step in developing a strategy that will help in the overall means of using Salmonella as part of a cancer therapy. The investigational therapy would probably be used in conjunction with chemotherapy and radiation therapy, once it gets to human trials, according to the scientists.