Bridging metabolism and tumorigenesis: Insights from the Wnt/β-Catenin/TCF7L2 pathway in association between type 2 diabetes and colorectal adenomas

Abstract

In this editorial, we comment on the article by Gui et al published in the recent issue of the World Journal of Gastrointestinal Surgery. They retrospective study provides novel molecular insights into the link between type 2 diabetes mellitus and colorectal adenomas. By identifying elevated activation of the Wnt/β-catenin/transcription factor 7 like 2 pathways in patient tissues, the research proposes a key mechanistic bridge between metabolic dysfunction and tumorigenesis, moving beyond traditional explanations like hyperinsulinemia. While acknowledging this as an important proof-of-concept, the work is limited by its retrospective design and small sample size, leaving causality unclear. Future research should utilize prospective cohort studies to correlate Wnt pathway dynamics with colonoscopy outcomes. Functional validation is also essential, requiring in vivo diabetic models and patient-derived organoids to establish causality and refine mechanistic inquiry. Ultimately, further interdisciplinary research is needed to fully unravel the shared biology of these metabolic and neoplastic diseases.

Key Words: Type 2 diabetes mellitus; Colorectal adenomas; Wnt/β-catenin pathway; Transcription factor 7 like 2; Molecular mechanism

Core Tip: Gui et al’s recent study identifies the Wnt/β-catenin/transcription factor 7 like 2 pathways as a potential molecular link between type 2 diabetes mellitus and colorectal adenomas. Despite the retrospective design and associated limitations, the study provides mechanistic insight beyond traditional hypotheses and highlights the need for further validation.

This editorial refers to "Association between type 2 diabetes mellitus and colorectal adenoma: A retrospective study with insights into Wnt/β-Catenin/TCF7 L2 pathway activation" by Gui et al, 2026; https://doi.org/10.4240/wjgs.v18.i2.113476.

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INTRODUCTION

Recently, Gui et al[1] published in the World Journal of Gastrointestinal Surgery an article titled “Association between type 2 diabetes mellitus and colorectal adenoma: A retrospective study with insights into Wnt/β-Catenin/TCF7 L2 pathway activation”. Analysis of immunohistochemical data from clinical samples suggests that elevated activity of the Wnt/β-catenin/ transcription factor 7 like 2 (TCF7 L2) pathways may serve as a key molecular bridge linking type 2 diabetes mellitus (T2DM) and colorectal adenomas (CRA). Though limited in scale, this study shines a spotlight on a long-overlooked biological pathway connecting metabolic disorders to gastrointestinal tumors.

For a long time, epidemiological data has repeatedly suggested an increased risk of colorectal tumors in T2DM patients[2,3], but interpretations of the underlying mechanisms have largely remained at the level of macro-level hypotheses such as “hyperinsulinemia” and “chronic inflammation”[4,5]. The innovation of this study lies in its pioneering focus on the Wnt/β-catenin pathway and its key transcription factor TCF7 L2. Through immunohistochemistry, researchers visually demonstrated the activation of pathway molecules in tissues from T2DM patients with CRA, transforming abstract epidemiological associations into observable molecular pathological evidence.

A BRIEF REVIEW OF THE ASSOCIATION BETWEEN T2DM AND COLORECTAL CANCER DEVELOPMENT

Colorectal polyps and adenomas represent common precancerous lesions of colorectal cancer (CRC), with their pathogenesis and early intervention holding significant implications for CRC prevention and management. T2DM, a prevalent chronic condition affecting systemic homeostasis, has been demonstrated to be closely associated with the development of multiple malignancies[6]. A mounting body of research suggests a close association between T2DM and the development of colorectal polyps and CRC[7,8].

The elevated risk of CRC in T2DM has been extensively recognized in preliminary studies[9,10]. Wankhede et al[11] investigated the role of tumor immune status in T2DM and CRC, revealing that diabetes influences tumor development through a continuous process. Yuan et al[12] conducted a study on 4038 CRC patients, finding that those with both CRC and diabetes had a higher mortality risk compared to those without diabetes, indicating that prior diabetes increases long-term mortality in CRC patients. The predominant viewpoint is that T2DM and its degree of glycemic control are independent risk factors for CRC development[13]. However, the extant literature suggests that the impact of T2DM on CRC is subject to limitations, including gender[14].

As a metabolic effector of T2DM, hyperinsulinemia is widely recognized to play a significant role in the development of CRC in individuals with T2DM, driving the Wnt pathway in colorectal epithelial cells through multiple mechanisms thereby activating cellular carcinogenic processes[15]. Building upon the recognized link between T2DM and an increased risk of CRC, Hu et al[16] identified specific changes in plasma C-peptide levels that reflect the impact of hyperinsulinemia on CRC. Chronic inflammation and cachexia are also well-established risk factors common to T2DM and CRC[17,18]. At the molecular pathway level, Del Puerto-Nevado et al[19] conducted transcriptomic analyses linking T2DM to colon cancer, revealing that T2DM induces the upregulation of the TEA domain transcription factor/yes-associated protein-Tafazzin axis in colon tumor initiation pathways. Chang et al[20] confirmed that a high-glucose environment downregulates the collapsin response mediator protein-2 profile, thereby promoting proliferation and migration in CRC cells. Melia et al[21] proposed that cellular senescence induced by T2DM via the mitogen-activated protein kinases and nuclear factor kappaB pathways also constitutes a significant factor in the development of CRC tumors. Previous studies have demonstrated that the Wnt pathway can synergistically interact with pathways such as nuclear factor kappaB and yes-associated protein-Tafazzin[22,23], thereby influencing cancer progression. Overall, the regulatory processes governing the Wnt pathway and carcinogenesis in colorectal cells within T2DM constitute a complex interplay that warrants further investigation.

Given the close link between T2DM and colorectal tumor mechanisms, research has begun to explore the therapeutic potential of diabetes medications for CRC. Metformin exerts a downregulatory effect on the Wnt3a/β-catenin pathway function[24], potentially counteracting CRC by altering gut microbiota and inhibiting polyp growth[25,26], though some trials indicate no significant impact on CRC incidence with combined metformin therapy[27]; Conversely, a meta-analysis by Sun et al[28] on glucagon-like peptide-1 receptor agonists and cancer suggested that glucagon-like peptide-1 receptor agonists may increase the risk of developing CRC. Lactoferrin, a potential therapeutic agent for diabetes, demonstrated potent inhibitory effects on colon cancer progression under hyperglycemic conditions[29]. Whether the mechanism of action of therapeutic drugs is associated with the Wnt/β-catenin pathway requires more explorations.

Multiple studies emphasize that T2DM influences both the development and prognosis of CRC, with numerous shared mechanisms between the two conditions. However, further research is required to elucidate their interactions at a microscopic level. Additionally, the clinical translation of prior research findings and the innovative development of more effective therapeutic approaches leveraging the interplay between T2DM and CRC are areas that require further exploration.

LIMITATIONS OF THE STUDY

As acknowledged by the authors, the retrospective nature of the study and the small sample size represent its primary limitations. Whether the elevated expression demonstrated by immunohistochemistry is a cause or a consequence remains to be clarified. Does T2DM directly drive the activation of the Wnt pathway in the colonic epithelium, or do both share a common genetic background? Answering these questions requires: Retrospective cohort studies should not stop at validating associations but should strive to explore influencing trends and serve the cohort studies and development of dynamic predictive models. Ideal studies should include T2DM patients at various stages (newly diagnosed, undergoing treatment, and with differing glycemic control), and establish matched non-diabetic control groups[30]. Beyond baseline serum measurements of Wnt pathway-related proteins, repeated assessments at fixed intervals (e.g. every 1-2 years) should be conducted and strictly synchronized with regular colonoscopic follow-ups (documenting adenoma onset timing, quantity, and pathological characteristics)[31]. This process will help identify which specific biomarkers (such as β-catenin, TCF7 L2 target gene expression, and serum Wnt ligands) hold the greatest clinical utility[32,33], and determine whether these biomarkers can distinguish colitis induced by T2DM from sporadic colitis. This design addresses core questions: Does longitudinal variation in Wnt pathway activity precede and predict adenoma development? Is its predictive efficacy independent of traditional risk factors (e.g. age, gender, body mass index diabetes duration)[34,35]? Resolving this issue will facilitate the integration of Wnt pathway biomarkers or targeted therapies into existing clinical practice to prevent CRC in patients with T2DM[36]. Meanwhile, the activation of the Wnt pathway and development of T2DM may exhibit demographic and clinical heterogeneity[37,38], conducting multicenter collaborative studies with stratified statistical analysis of influencing factors ensures both sample diversity and the generalizability of conclusions, while accumulating data for subsequent development of non-invasive risk stratification tools to supplement existing risk assessment models. Functional experimental validation requires simulating clinical scenarios in vivo and in vitro models while introducing precise interventions: (1) Forward simulation observational studies. At the animal level, db/db or high-fat diet combined with low-dose streptozotocin-induced T2DM mouse models can be selected[39]. At different stages of the diabetic disease course, analyses changes in Wnt pathway-related proteins and TCF7 L2 target gene expression in colonic crypts[40], and observe spontaneous or carcinogen-induced tumor formation; (2) Reverse intervention and validation analysis. In diabetic models, intervene in the Wnt/TCF7 L2 pathway via gene knockout, small-molecule inhibitors, or specific drugs to observe whether adenoma development can be prevented or delayed[41-43]; and (3) Organoid experiments provide more refined mechanistic insights. Organoids derived from human colonic stem cells cultured under varying glucose concentrations, insulin levels, or diabetic patient serum allow direct observation of metabolic stress's effects on Wnt signaling and cellular fate[44,45].

CONCLUSION

Despite its limitations, this study represents an important proof-of-concept effort. It ingeniously stitches together fragmented knowledge from two vast disease domains - the genetic susceptibility to diabetes and the classical carcinogenesis pathways of CRC - to propose a concise and compelling scientific hypothesis. It reminds us that in the era of comorbidities, medical research requires more cross-disciplinary thinking. Future research on the T2DM-CRA association should move beyond statistical correlations to delve into their shared biological underpinnings. The Wnt/β-catenin/TCF7 L2 pathway may represent only the first piece of this complex puzzle, but following its revealed pathways holds promise for developing more precise risk prediction tools and effective cross-disease prevention strategies.