Metabolic and hormonal remodeling of colorectal cancer cell signaling by diabetes

Abstract

The existence of molecular links that facilitate colorectal cancer (CRC) development in the population with type 2 diabetes (T2D) is supported by substantial epidemiological evidence. This review summarizes how the systemic metabolic and hormonal imbalances from T2D alter CRC cell metabolism, signaling and gene expression as well as their reciprocal meshing, with an overview of CRC molecular subtypes and animal models to study the diabetes-CRC cancer links. Metabolic and growth factor checkpoints ensure a physiological cell proliferation rate compatible with limited nutrient supply. Hyperinsulinemia and hyperleptinemia in prediabetes and excess circulating glucose and lipids in T2D, overcome formidable barriers for tumor development. Increased nutrient availability favours metabolic reprogramming, alters signaling and generate mutations and epigenetic modifications, through increased reactive oxygen species and oncometabolites. The reciprocal control between metabolism and hormone signaling is lost in diabetes. Excess adipose tissue at the origin of T2D, unbalances adipokine (leptin / adiponectin) secretion ratios and function and disrupts the Insulin/IGF axes. Leptin/adiponectin imbalances in T2D are believed to promote proliferation and invasion of CRC cancer cells and contribute to inflammation, an important component of CRC tumorigenesis. Disruption of the Insulin/IGF axes in T2D targets systemic and CRC cell metabolic reprogramming, survival and proliferation. Future research to clarify the molecular diabetes-CRC links will help to prevent CRC and reduce its incidence in the diabetic population and must guide therapeutic decisions.

Remodelling of colorectal cancer cell signaling by microbiota and immunity in diabetes

“…In support of epidemiological data, analysis of 976 colonoscopies showed that T2D patients exhibit a higher incidence of polyps and higher-grade dysplasia/ carcinoma (even higher in uncontrolled diabetes) when compared to nondiabetic patients (Miłek et al 2019). Although T2D is associated to higher grade CRC, it has not been associated to particular molecular subtypes of CRC (CMS) as summarized (Gutiérrez-Salmerón et al 2021). However, clinical adoption of CMS-based classification (integrating biological layers) to guide CRC prognosis and treatment is hampered by practical obstacles such as the influence of where the tumour samples are taken, availability of bioinformatic procedures, and the need for clinical trials to confirm their predictive value for therapy response (Buikhuisen et al 2020).…”

“…However, most MAIT cells are recruited after the tumour is formed making it unlikely that MAIT-dependent inflammation initiates sporadic CRC. The localized inflammatory tumour microenvironment, with increased ROS that favour mutations and epigenetic changes, may lead to tumour progression (Gutiérrez-Salmerón et al 2021). Cytokines produced inside the tumour, mainly by TILs (IL17) and TAMs (TNFA, IL6, TGFB, IL10, VEFG) and outside the tumour (in blood and/or neighbouring WAT) in T2D patients, may have an adjuvant effect on tumour progression (Landskron et al 2014) (Fig.…”

“…Cancer cells may be allografted or CRC might be chemically or genetically induced in T2D mouse models. Alternatively, diabetes can be induced in CRC mice models, see Gutiérrez-Salmerón et al (2021). These models are complicated and time-consuming but it is necessary to understand the interactions between T2D and CRC.…”

“…The molecular mechanisms that link both diseases include direct impact of T2D on cancer cells and indirect effects mediated by T2D impact on the immune response and microbiome, which will, in turn, impact tumour development. The direct effects of metabolic and hormonal alterations of T2D on CRC cells are reviewed in Gutiérrez-Salmerón et al (2021) Here, we review the potential impact for CRC of T2D-linked immune and microbiome alterations.…”

Adipositas und Krebs

“…Beim kolorektalen Karzinom steigt die Leptinexpression von der normalen Kolonmukosa über das Adenom zum Adenokarzinom stark an, was darauf schließen lässt, dass es in die Mehrschrittkarzinogenese involviert ist. Aus translationalen Studien wird deutlich, dass Leptin direkt mit einem erhöhten Risiko, an einem kolorektalen Karzinom zu erkranken, und einem aggressiveren Phänotyp korreliert ist, wie Daten zu einem verminderten remissionsfreien Überleben zeigen [26].…”