The microbiome and human cancer

BACKGROUND

Historical reports linking cancer and microbes date back to four millennia ago. After the establishment of the germ theory of infectious diseases, clinical research on microbial influences on cancer began in 1868, when William Busch reported spontaneous tumor regressions in patients with Streptococcus pyogenes infections. Over the next century, poor reproducibility, erroneous microbiological claims and severe toxicity led many to disregard the role of bacteria in carcinogenesis and cancer therapy. However, these studies provided the first crude demonstrations of cancer immunotherapy. At the same time, the viral theory of cancer flourished, spurred on by the 1911 discovery of the Rous sarcoma virus, which transformed benign tissue into malignant tumors in chickens. The decades-long quest to find viruses behind every human cancer has failed, and many cancers have been linked to somatic mutations. Now, the field is finding intriguing claims about the importance of microbes, including bacteria and fungi, in cancer and cancer therapy. This review critically evaluates this evidence in the light of modern cancer biology and immunology, outlining the roles of microbes in cancer, examining advances in the proposed mechanisms, diagnoses and modulation strategies.

ADVANCES

Few microbes cause cancer directly, but many appear to be complicit in its growth, usually acting through the host’s immune system; conversely, several have immunostimulating properties. Mechanistic analyzes of the interactions of the intestinal microbiota with the immune system reveal powerful effects on anti-tumor immunity through the modulation of the activities of the primary and secondary lymphoid tissue. Many of these pathways invoke cytokine signaling initiated by the Toll-like receptor, but microbial metabolic effects and antigenic mimicry with cancer cells are also important. In preclinical models, microbial metabolites also regulate the somatic mutation phenotypes of the tumor and modulate the efficacy of the immune control point inhibitor.

New evidence suggests that intratumor bacteria exist and are active, with superimposed immunohistochemistry, immunofluorescence, electron microscopy and sequencing data on about 10 types of cancer. Preliminary studies also suggest that fungi and bacteriophages contribute to gastrointestinal cancer. However, the abundance of intratumoral microbial cells is low in relation to cancer cells, and knowledge of their functional repertoire and potency remains limited. Additional validation of its prevalence and impact is required in several cohorts and therapeutic settings.

The immunomodulatory effects of the host’s microbiota have reinvigorated efforts to change its composition as a form of immunotherapy. Despite extensive preclinical evidence, the translation of microbiota modulation approaches in humans has not yet materialized in commercial therapies. Synthetic biology approaches are also gaining momentum, with therapies designed for bacterial cancer in preclinical and clinical trial settings.

PANORAMA

A better understanding of the functions of microbes in cancer offers an opportunity to improve each stage of the cancer treatment cycle, but there are still major challenges. Combined efforts to characterize the cancer-associated microbiota among tumor, stool and blood samples with gold-standard contamination controls would help tremendously in this progress. This would be analogous to the role of the Cancer Genome Atlas in characterizing the somatic mutation of cancer. Large-scale clinical trials are currently testing the effectiveness of microbiota modulation approaches, ranging from diet modifications to bacteria modified by intratumor injection. Such therapies against bacterial cancer, if safe and effective, could expand the arsenal of cancer therapy tremendously. Altogether, the integration of the host-centered and microbial views of cancer can improve patient outcomes, while providing a differentiated understanding of the evolution of host-microbial cancer.