Bacteria in tumors may spur resistance to chemotherapy

Microbes that reside in tumors can inactivate the chemotherapy used to treat the cancer, a process that might well explain drug resistance in these tumors, according to results of a recent study published in the journal Science. But investigators also found that adding antibiotics to chemotherapy could nullify this resistance and thereby provide effective treatment against these cancers.

“Here we demonstrate that bacteria are a component of the…tumor microenvironment,” wrote Ravid Straussman, MD, PhD, and his team in the Department of Molecular Cell Biology at Weizmann Institute of Science, in Rehovot, Israel. “Regardless of whether bacteria are involved in tumor pathogenesis or exist as opportunistic residents, they may play a critical role in mediating resistance to chemotherapy.”

This study, led by PhD student Leore Geller in Dr. Straussman’s lab, got its start when the researchers observed that the colorectal and pancreatic cancer cell lines they were studying appeared to be more resistant to the chemotherapeutic drug gemcitabine. Further tests revealed that a bacterial enzyme (cytidine deaminase, found primarily in Gammaproteobacteria) was able to metabolize gemcitabine into its inactive form. This means the bacteria have the potential to confer resistance to the chemo drug.

The researchers found that the bacteria were present within the tumor environment, and even in the tumor cells themselves. “Because the topic is so new, we first used different methods to prove that there really were bacteria inside the tumors,” Dr. Straussman said. “Then we decided to look at the effect that these bacteria might have on chemotherapy."

To do so, the researchers performed experiments in mice with colon cancer tumors. First, they injected the mice with the bacteria to colonize the tumors. Then they gave the mice chemotherapy with gemcitabine; in addition, some of the mice also received an antibiotic (ciprofloxacin).

“Antibiotic-treated mice displayed a marked antitumor response to gemcitabine, whereas control-treated mice displayed rapid tumor progression,” they noted.

Next, the researchers wanted to determine whether the bacteria also exist in human tumors. They analyzed more than 100 samples taken from tumors of pancreatic cancer patients, as well as 20 samples from organ donors with a normal pancreas. Bacterial DNA was found in 75% of the pancreatic cancer samples but in only 15% of normal pancreas controls. More than half of the species identified were Gammaproteobacteria, most of which were from Enterobacteriaceae and Pseudomonadaceae families.

To confirm that these bacteria could bring about gemcitabine resistance, the researchers cultured bacteria from fresh tumors of pancreatic cancer patients and found that 93% rendered human colon carcinoma cell lines fully resistant to gemcitabine.

“Collectively, our results indicate that pancreatic ductal adenocarcinomas contain bacteria that can potentially modulate tumor sensitivity to gemcitabine,” Dr. Straussman and colleagues concluded. “The presence of bacteria in human tumors may paradoxically result in drug concentrations that are lower in the tumor than in other organs.”

But, the authors added, these results also raise the “tantalizing possibility” that chemotherapy given with antibiotics could improve the therapeutic efficacy against this lethal cancer. Further research is needed to find out if it will.