Uncovering Microbes' Role in Tumor Progression

The average person consists of approximately 10 trillion cells, with another 100 trillion from the microbes colonizing the gastrointestinal and respiratory tracts and skin. Of late, these tiny residents, particularly bacterial species—collectively called the microbiota—have received increasing scientific scrutiny.

“Our microbiota is extremely important in forging robust immune responses to infections,” explains José Conejo-Garcia, MD, PhD, leader of the tumor microenvironment and metastasis program at The Wistar Institute in Philadelphia, PA. “We'd like to understand how these bacteria influence a systemic disease like cancer.” He recently showed that, together, the microbiota and Toll-like receptor (TLR) 5 may drive molecular events affecting the progression of certain tumors.

TLR5 recognizes microbe-specific molecules and activates the innate immune system, the body's first line of defense. However, roughly 7.5% of the general public harbors a single-base polymorphism in the TLR5 gene, reducing signaling through TLR5 by up to 80%.

Conejo-Garcia and his team examined models of cervical and ovarian cancers, as well as sarcoma, in TLR5-sufficient and TLR5-deficient mice. They observed that TLR5 signaling led to a dramatic spike in the levels of IL6—an inflammatory cytokine—and myeloid-derived suppressor cells (MDSC). Mobilized MDSCs provoked γδ T cells into producing galectin-1, a protein that suppresses antitumor immune activity, thereby accelerating tumor progression in these models.

After the microbiota was eliminated with antibiotics, “all the phenotypes associated with malignant progression were no longer evident,” Conejo-Garcia says. “We think interactions between the microbiota and TLR5 produce a perfect storm of inflammatory events that promote tumor growth.”

The researchers discovered quite the opposite in mice bearing mammary tumors: tumor growth was more aggressive in TLR5-deficient animals than in TLR5-sufficient animals, and driven by a different inflammatory cytokine, IL17. “Certain tumors produce more IL6, and its levels go through the roof in the presence of functional TLR5,” Conejo-Garcia says. “However, other tumors produce far less IL6, and IL17—which is systemically higher when TLR5 is nonfunctional—may dominate inflammation in this setting.”

Depleting these mice of their microbiota once again eliminated differences in tumor progression. “TLR5-positive and TLR5-negative mice have distinct bacterial repertoires,” says Melanie Rutkowski, PhD, an associate staff scientist at Wistar and the study's first author. “So in our mammary tumor model, the upregulation of IL17 and subsequent growth-inducing inflammation could be due to the different microbiota forged by TLR5's absence.”

Using data from The Cancer Genome Atlas, the researchers carried out survival analyses of 199 patients with ER-positive breast cancer and 315 ovarian cancer patients, all with known TLR5 status. Ovarian cancer is associated with high IL6 levels, and the researchers found more long-term survivors (6 years post-diagnosis) among patients with the TLR5 polymorphism. ER-positive breast cancer, meanwhile, is associated with low IL6 levels; correspondingly, patients with functional TLR5 had better long-term survival.

“These initial analyses corroborate what we've found in mice,” Conejo-Garcia says, “but we need bigger, independent patient cohorts, along with fecal samples for microbiota profiling. The hope is that someday we'll know enough about the bacteria residing within us to control tumor-promoting inflammation by manipulating or even resetting the microbiota.”