Separating microbes and cancers
The role of microorganisms in the cause and maintenance of cancers has been the subject of controversy for centuries. Through the Lens of Gut-Associated Microbes and Tumors, Sepich-Poore et al. review our current understanding of the microbiota in cancer, building a “microbial awareness” framework. The authors argue that humans should be considered a meta-organism, but how our microbiota influences cancer is still not mechanistically well understood. However, advances in microbiome research are improving our understanding of immuno-oncology and are driving new diagnostic and therapeutic approaches.
Science, this number p. eabc4552
Historical accounts linking cancer and microbes date back four millennia. After the establishment of the germ theory of infectious diseases, clinical investigation of 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 dismiss the role of bacteria in cancer carcinogenesis and therapy. However, these studies provided the first crude demonstrations of cancer immunotherapy. At the same time, the viral theory of cancer flourished, fueled by the discovery in 1911 of the Rous sarcoma virus, which transformed benign tissue into malignant tumors in chickens. The decades-long search to find viruses behind every human cancer ultimately failed, and many cancers have been linked to somatic mutations. Now the field is faced with intriguing claims about the importance of microbes, including bacteria and fungi, in cancer and cancer therapy. This review critically assesses this evidence in light of modern cancer biology and immunology, outlining the roles of microbes in cancer by examining advances in proposed mechanisms, diagnostics, and modulation strategies.
Few microbes cause cancer directly, but many appear to be complicit in its growth, often acting through the host’s immune system; conversely, several have immunostimulatory properties. Mechanistic analyzes of the interactions between the gut microbiota and the immune system reveal powerful effects on antitumor immunity by modulating the activities of primary and secondary lymphoid tissue. Many of these pathways invoke cytokine signaling initiated by a Toll-like receptor, but microbial metabolic effects and antigenic mimicry with cancer cells are also important. In preclinical models, microbial metabolites also regulate somatic tumor mutation phenotypes and modulate the efficacy of the immune checkpoint inhibitor.
Emerging evidence suggests that intratumoral bacteria exist and are active, with overlapping immunohistochemical, immunofluorescence, electron microscopy, and sequencing data in approximately 10 cancers. Preliminary studies further suggest that fungi and bacteriophages contribute to gastrointestinal cancers. However, the abundance of intratumoral microbial cells is low relative to cancer cells, and knowledge of their functional repertoire and potency remains limited. Further validation of its prevalence and impact is needed in various cohorts and therapeutic settings.
The immunomodulatory effects of the host microbiota have revitalized efforts to change its composition as a form of immunotherapy. Despite extensive preclinical evidence, translation of microbiota modulation approaches in humans has yet to materialize into commercialized therapies. Synthetic biology approaches are also gaining ground, with bacterial cancer therapies designed in preclinical and clinical trial settings.
A better understanding of the roles of microbes in cancer provides the opportunity to improve each stage of the cancer care cycle, but significant challenges remain. Concerted efforts to characterize the cancer-associated microbiota among tumor, stool, and blood samples with gold standard contamination controls would greatly aid this progress. This would be analogous to the role of the Cancer Genome Atlas in characterizing the somatic mutation landscape of cancer. Currently, large-scale clinical trials are testing the efficacy of microbiota modulation approaches, ranging from dietary modifications to modified bacteria injected intratumorally. These bacterial cancer therapies, if safe and effective, could greatly expand the cancer therapeutic arsenal. Together, the integration of microbial and host-centered views of cancer can improve patient outcomes while providing a nuanced understanding of cancer host microbial evolution.
Microbial roles in cancer formation, diagnosis, prognosis, and treatment have been disputed for centuries. Recent studies have provocatively asserted that bacteria, viruses, and / or fungi are widespread among cancers, are key players in cancer immunotherapy, and can be manipulated to treat metastases. Despite these findings, the number of microbes known to directly cause carcinogenesis remains small. Critical appraisal and construction of frameworks for such evidence in light of modern cancer biology is an important task. In this review, we delineate between the causal and complicit roles of microbes in cancer and trace common themes of their influence through the host immune system, here defined as the immuno-oncology-microbiome axis. We also review the evidence for intratumoral microbes and approaches that manipulate the host gut or tumor microbiome as we project the next phase of experimental discovery.