Microbiota as a mediator of cancer progression and therapy

Abstract

Complex and intricate circuitries regulate cellular proliferation, survival, and growth, and alterations of this network through genetic and epigenetic events result in aberrant cellular behaviors, often leading to carcinogenesis. Although specific germline mutations have been recognized as cancer inducers, the vast majority of neoplastic changes in humans occur through environmental exposure, lifestyle, and diet. An emerging concept in cancer biology implicates the microbiota as a powerful environmental factor modulating the carcinogenic process. For example, the intestinal microbiota influences cancer development or therapeutic responses through specific activities (immune responses, metabolites, microbial structures, and toxins). The numerous effects of microbiota on carcinogenesis, ranging from promoting, preventing, or even influencing therapeutic outcomes, highlight the complex relationship between the biota and the host. In this review, we discuss the latest findings on this complex microbial interaction with the host and highlight potential mechanisms by which the microbiota mediates such a wide impact on carcinogenesis.

Fig 1

The microbiota regulates the balance between health and disease. A combination of external factors can influence microbial composition, including host genetics, diet, lifestyle, and environmental factors. These perturbations in the microbiota shift the balance between healthy and carcinogenesis.

Fig 2

Interplay among the microbiota, host immunity, and CRC. The intestinal microbiota induces a variety of host immune responses (brown arrows) including cytokine production, PRRs, inflammasomes, and autophagy, all of which contribute to cancer development. The microbiota induces the proinflammatory cytokines IL-23, IL-17A, and IL-17C, which promote CRC. The PRRs Nod2 and Aim2 and the Nlrp6 inflammasome protect against tumor-igenesis by regulating epithelial proliferation and may contribute to eubiosis. Nlrp3 suppresses metastatic growth to the liver, a phenotype which is unaffected by antibiotics. The autophagy gene Atg7 promotes tumorigenesis in an Apc model by promoting proliferation and decreasing the antitumor CD8+ T cell response. CRC, colorectal cancer; IL, interleukin; PRR, pattern recognition receptor. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig 3

Interaction between bacteria and anticancer drugs. The microbiota influences anticancer drug efficacy and toxicity through direct or indirect mechanisms. Bacterial β-glucuronidases convert SN-38G to active SN-38, leading to the toxic effect of CPT-11. Microbiota can generate barrier-protective metabolites such as butyrate and activate TLR2/drug efflux response to attenuate CPT-11 and MTX toxicity, respectively. B. fragilis (via Treg response) and B. cepacia can ameliorate CTLA-4-blockade–induced intestinal inflammation. On the other hand, bacteria profoundly influence the efficacy of chemotherapeutics via a metabolic route. Microbial-driven ROS production by tumor-associated inflammatory cells promotes the antitumor effect of oxaliplatin and cisplatin. A. shahii induces TNF production by tumor-associated myeloid cells, which contributes to the antitumor effect of CpG-ODN. Efficacies of CTX, CTLA-4 blockade, and PD-L1 blockade can be enhanced by specific and distinct bacteria. CpG-ODN, CpG-oligonucleotide; CPT, irinotecan; CTLA, cytotoxic T-lymphocyte–associated protein 4; MTX, methotrexate; ROS, reactive oxygen species; TLR, toll-like receptor; TNF, tumor necrosis factor.

Fig 4

Gut microbiota regulates carcinogenesis at various levels. Perturbations in the healthy microbiota lead to dysbiosis, increasing the number of procarcinogenic bacteria that can have local or long-distance effects. Healthy microbiota can biotransform anticancer therapeutic drugs, impacting their toxicity and efficacy. In addition, cancer therapeutics can function synergistically with the immune system to inhibit cancer.