Western lifestyles cause a low-grade but chronic and metabolic inflammation (or metaflammation), which might prime committed cell lineages to initiate colon tumorigenesis. At-risk individuals might include cases of early-onset colon cancer, the incidence of which has risen dramatically in the past few decades.</p

Fodde, Riccardo

Schmitt, Mark

Verhagen, Mathijs P.

English

EUR Research Repository

EUR Research Information PortalWestern lifestyle, metaflammation and the cell of origin of colon cancerPublished in:Nature Reviews Gastroenterology and HepatologyPublication status and date:Published: 01/09/2024DOI (link to publisher):10.1038/s41575-024-00964-7Document VersionPublisher's PDF, also known as Version of recordDocument License/Available under:Article 25fa Dutch Copyright ActCitation for the published version (APA):Verhagen, M. P., Schmitt, M., & Fodde, R. (2024). Western lifestyle, metaflammation and the cell of origin of colon cancer.Nature Reviews Gastroenterology and Hepatology, 21(9), 603-604. https://doi.org/10.1038/s41575-024-00964-7Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). Copyright law allows the following uses of this materialwithout prior permission:            • you may download, save and print a copy of this material for your personal use only;            • you may share the EUR portal link to this material.In case the material is published with an open access license (e.g. a Creative Commons (CC) license), other uses may beallowed. Please check the terms and conditions of the specific license.Take-down policyIf you believe that this material infringes your copyright and/or any other intellectual property rights, you may request itsremoval by contacting us at the following email address: openaccess.library@eur.nl. Please provide us with all the relevantinformation, including the reasons why you believe any of your rights have been infringed. In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/382533450Western lifestyle, metaflammation and the cell of origin of colon cancerArticle  in  Nature Reviews Gastroenterology &#38 Hepatology · July 2024DOI: 10.1038/s41575-024-00964-7CITATIONS0READS253 authors, including:Mark SchmittPhilipps University of Marburg16 PUBLICATIONS   1,054 CITATIONS   SEE PROFILERiccardo FoddeErasmus MC311 PUBLICATIONS   26,689 CITATIONS   SEE PROFILEAll content following this page was uploaded by Riccardo Fodde on 03 January 2025.The user has requested enhancement of the downloaded file.nature reviews gastroenterology & hepatologyhttps://doi.org/10.1038/s41575-024-00964-7CommentWestern lifestyle, metaflammation and the cell of origin of colon cancerMathijs P. Verhagen, Mark Schmitt & Riccardo FoddeWestern lifestyles cause a low-grade but chronic and metabolic inflammation (or metaflammation), which might prime committed cell lineages to initiate colon tumorigenesis. At-risk individuals might include cases of early-onset colon cancer, the incidence of which has risen dramatically in the past few decades.Colon cancer is thought to originate from resident stem cells — the so-called LGR5+ crypt base columnar (CBC) cells — that are located at the base of the crypts of Lieberkühn and are responsible for the daily turnover of the intestinal epithelial lining. This was first demonstrated in mouse models in which loss of the Apc tumour suppressor triggered tumour formation only when targeted in CBC stem cells and not in transient-amplifying progenitors1. More generally, somatic stem cells are considered to be the most likely origins of both solid and haema-topoietic malignancies due to their self-renewal and differentiation capacities2. In addition to the ‘bottom-up’ model of colon cancer, ‘top-down’ models in which post-mitotic, fully committed cell line-ages located at higher positions along the crypt–villus axis that can initiate tumour formation in the context of inflammation have also been proposed3,4. In a 2024 study, it was shown that the majority of colon cancers in individuals with inflammatory bowel disease (IBD) are predicted to originate from non-stem lineages5. Remarkably, a substantial percentage of non-IBD sporadic cases were also predicted to originate from differentiated cell types. Likewise, Chen et al.6 showed that conventional adenomas and sessile serrated polyps have distinct cellular origins, namely stem cells and gastric metaplasia, respectively. These studies highlight the relevance of the identity of the cell of ori-gin with respect to different cancer risks and response to therapy of colonic polyps with distinct histopathological features, environmental triggers and progression pathways. From a more methodological per-spective, whereas the identity of the cell of origin of cancer is usually established in mouse models by lineage tracing, novel developments in computational and machine-learning approaches based on single-cell omics data enable prediction of the cellular origin in patient-derived cancers (Supplementary Box 1).Ageing, Western dietary habits and chronic inflammation (IBD) undoubtedly still represent the main aetiological risk factors for colon cancer. It has been shown that Western lifestyles in general (including, among other factors, calorie-rich and vitamin-poor diets, chronic over-nutrition, obesity and sedentary behavior) can cause a chronic low-grade state of metabolic inflammation, known as metaflammation, which is possibly caused by changes in the gut microbiome7. Dysbio-sis affects gut barrier integrity, enabling harmful metabolites from commensal bacteria to enter the portal system and trigger systemic inflammation. Moreover, the Western-style diet has been shown to underlie metabolic and epigenetic reprogramming of myeloid cells and their precursors, thus establishing trained innate immunity and a state of long-lasting altered immune responsiveness to dietary cues8. Similarly, ageing, one of the main colon cancer risk factors, is also associated with intestinal mucosal immune dysfunction and low-grade but chronic inflammatory states.Taken together, these observations point to a stem versus non-stem dichotomy in the identity of the cell of origin of colon cancer as a function of the underlying aetiological risk factors and, in particular, of chronic inflammation. This notion also touches on the controversy around the ‘bad luck’ cancer hypothesis and the role of stem cell self-renewal rates in establishing cancer risk9. We hypothesize that in the conventional bad luck cases, somatic APC mutations occur under homeostatic conditions in the rapidly dividing CBC stem cells, thereby initiating the classic adenoma–carcinoma sequence (Fig. 1). On the other hand, in the context of chronic inflammation, differentiated cell lineages re-enter the cell cycle through dedifferentiation or trans-differentiation mechanisms and, on subsequent epigenetic or genetic alterations (for example, BRAF oncogenic mutations and the CpG island methylator phenotype), acquire tumour-initiating features5,6. The distinct identities of the cell of origin and the presence or absence of an inflammatory environment likely result in different carcinoma types with specific progression behaviour and response to therapy.In the past few decades, the incidence of colorectal cancer (CRC) in individuals under 50 years of age, often referred to as young-onset CRC or early-onset CRC (EO-CRC), has dramatically increased, especially in Western, industrialized countries, and is expected to account for 11% of colon cancers worldwide and for up to one-third of cases in the USA alone by 2030 (ref. 10). Notably, the clinicopathological features of EO-CRC seem to be distinct from cases diagnosed at later ages11. As CRC population screening programmes in most countries target older individuals (≥50 years of age), the majority of EO-CRC cases will go undetected and be diagnosed at late disease stages10. Therefore, it is plausible to assume that, in view of the prevalence of EO-CRC in industrialized countries, Western lifestyle factors linked to improve-ments in economic prosperity, such as obesity, antibiotic use, low physical activity and diet, might represent important aetiological determinants. However, the molecular and cellular mechanisms that underlie EO-CRC are largely unknown, as are its specific aetiological risk factors. According to preliminary data, accelerated ageing was shown to be more common in recent birth cohorts in association with increased incidence of early-onset solid tumours12. As biological age can be accelerated by diet, inflammation, lack of physical activity and other environmental stress factors, it is plausible to assume that EO-CRC cases are also initiated in specific, possibly non-stem cell line-ages through reprogramming mechanisms similar to those observed in the context of serrated polyps and in the context of inflammation. In  Check for updatesnature reviews gastroenterology & hepatology4. Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).5. Verhagen, M. P. et al. Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation. Nat. Genet. 56, 1456–1467 (2024).6. Chen, B. et al. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell 184, 6262–6280.e26 (2021).7. Christ, A., Lauterbach, M. & Latz, E. Western diet and the immune system: an inflammatory connection. Immunity 51, 794–811 (2019).8. Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175.e14 (2018).9. Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).10. Spaander, M. C. W. et al. Young-onset colorectal cancer. Nat. Rev. Dis. Primers 9, 21  (2023).11. Vuik, F. E. R., Nieuwenburg, S. A. V., Nagtegaal, I. D., Kuipers, E. J. & Spaander, M. C. W. Clinicopathological characteristics of early onset colorectal cancer. Aliment Pharmacol. Ther. 54, 1463–1471 (2021).12. Accelerated aging may increase the risk of early-onset cancers in younger generations. AACR https://www.aacr.org/about-the-aacr/newsroom/news-releases/accelerated-aging-may-increase-the-risk-of-early-onset-cancers-in-younger-generations/ (2024).Competing interestsThe authors declare no competing interests.Additional informationSupplementary information The online version contains supplementary material available at  https://doi.org/10.1038/s41575-024-00964-7.the coming years, computational analysis of multi-omics platforms of patient-derived colon cancer cohorts combined with more ‘smoking gun’ experimental evidence from lineage tracing in mouse models will elucidate the mechanisms that underlie the cellular origin of colon cancer and its consequences for malignant progression and response to therapy.Mathijs P. Verhagen1, Mark Schmitt2 & Riccardo Fodde    1 1Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands. 2Institute of Pharmacology, University  of Marburg, Marburg, Germany.   e-mail: r.fodde@erasmusmc.nlPublished online: xx xx xxxxReferences1. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).2. Bajaj, J., Diaz, E. & Reya, T. Stem cells in cancer initiation and progression. J. Cell Biol. 219, e201911053 (2020).3. Shih, I.-M. et al. Top-down morphogenesis of colorectal tumors. Proc. Natl Acad. Sci. USA 98, 2640–2645 (2001).'Bad luck' routeInflammatory routeCBC-like CRC• APC-initiated (WNT-ON)• More frequently adenomatous• More common in patients  >50 years of ageMetaflammation CRC• BRAF- and/or CIMP-initated?• More frequently serrated• More common in EO-CRC  and/or WSD-associated    cases?1st hitAdditionalmutationsBottom-upTop-downCommitted IEC Reprogrammed IECLGR5+ CBC mCBC-derived IECMutated reprogrammed IECWestern lifestylesmCBCInflammationFig. 1 | Two alternative paths to colon cancer. Schematic illustration of two alternative routes to colon cancer, namely the ‘bad luck’ and ‘metaflammation’ paths. Although somatic mutations leading to the constitutive activation of WNT signalling (WNT-ON; for example, in APC or CTNNB1) in the ‘bad luck’ route occur in resident intestinal stem cells and eventually result in the conventional colon carcinoma observed in the majority of (older) patients, in the context of metaflammation due to Western lifestyles, dedifferentiation of committed lineages to acquire stem cell features and the consequent accumulation of somatic gene mutations underlie the alternative inflammatory route. CBC, crypt base columnar; CIMP, CpG island methylator phenotype; CRC, colorectal cancer; EO-CRC, early-onset CRC; IEC, intestinal epithelial cell; mCBC, mutated CBC; WSD, Western-style diet.View publication stats