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.
- CANCER EPIDEMIOLOGY
- CANCER IMMUNOBIOLOGY
- CANCER PREVENTION
- INTESTINAL MICROBIOLOGY
- MOLECULAR PATHOLOGY
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Correction notice This article has been corrected since it published Online First. An error with figures 2 and 3 has been corrected.
Contributors KI and TH contributed equally as co-first authors. TU, SY and SO contributed equally as co-last authors. KI and SO constructed the overall outline of the manuscript. All authors contributed to drafting, reviewing, and revising the manuscript. All authors approved the final version of the manuscript. KI and SO are responsible for the overall content as guarantors.
Funding This work was supported by U.S. National Institutes of Health (NIH) grants (R35 CA197735 to SO and R01 CA248857 to SO), and by Cancer Research UK Grand Challenge Award (OPTIMISTICC [C10674/A27140] to SO). KI was supported by grants from JSPS KAKENHI (JP22H02930), the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Ichiro Kanehara Foundation, Grant for Lung Cancer Research, Suzuki Foundation for Urological Medicine, Foundation for Promotion of Cancer Research in Japan, and the Yakult Bio-Science Foundation. TH was supported by grants from JSPS KAKENHI (JP19K08362) and the Takeda Science Foundation. TU was supported by grants from the Mishima Kaiun Memorial Foundation, Japan Society for the Promotion of Science (201960541), and Prevent Cancer Foundation. SY was supported by grants from the National Cancer Center Research and Development Fund (2020-A-4), JSPS KAKENHI (JP20H033620), Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (JP21ck0106546), Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED (JP22cm0106477); Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE) from AMED (JPama221404), United States-Japan Cooperative Medical Science Program from AMED (JP20jk0210009); AIP Accelerated Program from JST (21-191029679); Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Joint Research Project of the Institute Medical Science, the University of Tokyo, the Takeda Science Foundation, the Yasuda Medical Foundation, the Mitsubishi Foundation, and the Princess Takamatsu Cancer Research Fund. The funding source had no role in the decision to submit the manuscript to publication or preparation, review and approval of the manuscript.
Competing interests KI received research grants from Konica Minolta, Inc. and Daiichi Sankyo Co., Ltd. outside the submitted work. SB is a co-inventor on a U.S. Provisional Patent Application number 62/534,672, that covers targeting of Fusobacterium for treatment of colorectal cancer. SB has consulted for glaxosmithkline (GSK) and BiomX, and is currently on the cancer program scientific advisory board for BiomX. This study was not funded by any of these companies. No other conflicts of interest exist. The other authors declare that they have no conflicts of interest.
Provenance and peer review Not commissioned; externally peer reviewed.