Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science

Abstract

Cancer is generally regarded as a localised disease, with the well-established role of the tumour microenvironment. However, the realm of cancer goes beyond the tumour microenvironment, and cancer should also be regarded as a systemic and environmental disease. The exposome (ie, the totality of exposures), which encompasses diets, supplements, smoking, alcohol, other lifestyle factors, medications, etc, likely alters the microbiome (inclusive of bacteria, viruses, archaea, fungi, parasites, etc) and immune system in various body sites and influences tumour phenotypes. The systemic metabolic/inflammatory status, which is likely influenced by exposures and intestinal physiological changes, may affect tissue microenvironment of colorectum and any other organs. Germline genomic factors can modify disease phenotypes via gene-by-environment interactions. Although challenges exist, it is crucial to advance not only basic experimental research that can analyse the effects of exposures, microorganisms and microenvironmental components on tumour evolution but also interdisciplinary human population research that can dissect the complex pathogenic roles of the exposome, microbiome and immunome. Metagenomic, metatranscriptomic and metabolomic analyses should be integrated into well-designed population research combined with advanced methodologies of artificial intelligence and molecular pathological epidemiology. Ideally, a prospective cohort study design that enables biospecimen (such as stool) collection before disease detection should be considered to address reverse causation and recall biases. Robust experimental and observational research together can provide insights into dynamic interactions between environmental exposures, microbiota, tumour and immunity during carcinogenesis processes, thereby helping us develop precision prevention and therapeutic strategies to ultimately reduce the cancer burden.

Keywords: CANCER EPIDEMIOLOGY; CANCER IMMUNOBIOLOGY; CANCER PREVENTION; INTESTINAL MICROBIOLOGY; MOLECULAR PATHOLOGY.

Figure 1.

Cancer as a microenvironmental, systemic, and environmental disease. Tumour generates its intrinsic microenvironment, where tumour cells interact with immune cells, microbes, and other cells as well as non-cellular components. Notably, there are no clear boundaries of the tumour microenvironment, which rather blends into tissue outside of the tumour. Systemic conditions, especially systemic immunity, affect the local tumour microenvironment and contribute to tumourigenic processes. The exposome, which encompasses diets, alcohol, medications, lifestyle factors, etc., influences tumour phenotypes by modulating systemic conditions and the tumour microenvironment. Microbes, which may exist in the tumour microenvironment, in distant organs, or around the human body, potentially influence tumour phenotypes directly or indirectly by modulating the host’s local and systemic antitumour immunity.

Figure 2.

Multi-level perspectives of cancer-microbe associations. Tumour cells, microbes, and immune cells are major constituents of the tumour microenvironment. Cancer may metastasise to other organs. Microbiota, especially the gut microbiota, influences cancer phenotypes via systemic host-tumour-microbiome interactions. The exposome (e.g., diets, smoking, alcohol, supplements, medications, obesity, physical inactivity) influences tumour phenotypes and clinical outcomes of cancer patients via its complex effects on tumour cells, tumour microenvironment, and systemic conditions.

Figure 3.

Analytical framework of molecular pathological epidemiology (MPE) in cancer-microbiome research. MPE research examines associations of an exposure of interest with the development and consequence of tumour subtypes with specific microbial / immune features, potentially providing evidence for complex interactions between exposome and tumour during cancer development and progression. Notably, the “tumour” in this figure may be a benign (premalignant) or malignant tumour, which can be analysed for its microbial, immune, and other characteristics.

Figure 4.

Roadmap of transdisciplinary cancer-microbiome research from a discovery phase to a translation phase and a final implementation phase for targeted cancer prevention and treatment. The exposome represents the totality of exposures (including but not limited to diets, drugs, and smoking), which can be examined individually or collectively in relation to cancer development and progression. In contrast to research on non-neoplastic diseases, cancer research is characterised by the availability of tumour tissue specimens for examinations of the microenvironment where tumour cells, immune cells, and microorganisms form a dynamic interactive network. Tumour tissue research plays a key role in discovering and validating new insights into the mechanism through which microorganisms may influence cancer initiation and progression by interacting with the exposome and immune cells. FMT, faecal microbiota transplantation.