Microbiota-driven mechanisms at different stages of cancer development

Abstract

A myriad of microbes living together with the host constitutes the microbiota, and the microbiota exerts very diverse functions in the regulation of host physiology. Microbiota regulates cancer initiation, progression, metastasis, and responses to therapy. Here we review known pro-tumorigenic and anti-tumorigenic functions of microbiota, and mechanisms of how microbes can shape tumor microenvironment and affect cancer cells as well as activation and functionality of immune and stromal cells within the tumor. While some of these mechanisms are distal, often distinct members of microbiota travel with and establish colonization with the tumors in the distant organs. We further briefly describe recent findings regarding microbiota composition in metastasis and highlight important future directions and considerations for the manipulation of microbiota for cancer treatment.

Keywords: Cancer; Host-microbiome interactions; Mechanisms; Microbiome; Tumor microenvironment; Tumor progression.

Fig. 1

Role of gut microbiota during cancer development. Various risk factors, including viral and microbial infections, genetic predisposition, smoking, alcohol consumption, a sedentary lifestyle, obesity, and the use of medications that alter the microbiota, may promote the formation of a primary tumor. Microbiota can facilitate tumor formation via direct mutagenesis, promoting survival of tumor-initiating cells or inducing pro-tumorigenic immune responses. Microbiota further changes during cancer progression, while pro-tumor and anti-tumor bacteria directly compete with each other or with the tumor-specific microecological depletion of protective species and the bloom of pathogenic species. Transformation-induced disruption of the epithelial barrier and depletion of the mucin layer, lead to the possibility of enhanced translocation of the bacteria into the blood or lymphatic system, and the spread of microbes to distant organs and lymph nodes. Defective barriers further aid the formation of bacterial biofilms which may prevent tumor treatment or bacteria eradication. These events have a propensity to facilitate cancer progression and metastasis. Therapies aimed at changing the composition of the microbiota, including fecal microbiota transplantation, probiotics, dietary interventions, and narrow-spectrum antibiotics may be testable strategies. In addition, the use of bacteria-based nanosystems for drug delivery and bacteriophages for modulation of the microbiome may also hold a lot of promise.

Fig. 2

Pro- and anti-tumorigenic effects of microbiota. Microbiota plays a dual role in carcinogenesis. Anti-tumorigenic bacteria inhibit tumorigenesis through the following mechanisms. 1. Interbacterial competition for nutrients leads to the depletion of pathogenic bacteria. 2. Anti-cancer bacteria produce metabolites such as IPA, SCFA, and reutein that reduce cancer cell proliferation and immune response activation. 3. Anti-tumor bacteria can activate cytotoxic and helper T lymphocytes and NK cells, thereby inhibiting tumor growth. Pro-tumorigenic bacteria promote tumor development through various mechanisms.1. Pathogenic bacteria can produce toxins directly leading to DNA damage. Additionally, DNA damage can occur indirectly through the production of ROS and RNI. 2. Oncogenic bacteria produce metabolites and their effects are quite varied. The most studied to date are sBAs which can damage DNA, alter Wnt signaling, and induce and perpetuate inflammation. 3. Bacteria are involved with direct induction of inflammation including the production of pro-inflammatory and pro-tumorigenic cytokines, suppression of NK cell and T cell cytotoxicity, and activation of the Th2 and Th17 pro-tumorigenic immune responses.

Fig. 3

Mechanisms of gut microbiota translocation. Several routes contribute to microbial translocation from the gut to distal organs. Bacteria can cross the intestinal barrier as a result of local and systemic inflammation, diet-induced injury, alcohol, infection/food poisoning and dysbiosis, drug treatment, tumor formation, mucus thinning, invasive properties of bacteria, breakdown or remodeling of tight junctions by inflammatory cytokines and formation of biofilms which bring the bacteria into the immediate proximity to the epithelium to be breached. The portal vein is a key vessel connecting the intestine, pancreas, and liver and microbiota can easily enter the portal bloodstream if epithelial barrier is weakened. Alternatively, bacteria can enter the lymphatics and spread to the lymph nodes and organs via lymph flow. The last mechanism is the direct transfer of microbiota from the duodenum to the pancreas through pancreatic ducts.

Fig. 4

Microbiota in tumor progression and metastasis. The formation of metastases is a complex process that simultaneously affects several organs and circulatory systems. Bacterial translocation probably may occur as early as during pre-metastatic niche formation, at the same time with the colonization of the secondary organ by cancer cells or follow later in time by “re-infection” of growing metastasis with microbes. In the figure, we depicted the source of bacteria during the formation of metastases in the liver. Bacteria can get into the site of metastasis from the primary tumor independently through the blood and lymph flow and as part of the tumor or phagocytic immune cells. Leaky intestines are another source of bacteria in the liver. Dysbiosis is a frequent accompaniment of oncological diseases, leading to a weakening of contacts between epithelial cells and the spreading of bacteria to the site of metastasis.