Fetuin-A:adiponectin ratio (FAR) as a critical biomarker in obesity-induced colorectal cancer?

Obesity is one of the burning lifestyle-related health problems of the current generation, affecting more than one-third of the global population. Obese individuals face a severe risk of various cancers, particularly concerning colorectal cancer (CRC), which has an extremely low survival rate among affected patients [1]. In fact, obesity is linked to 4%–8% of global cancer cases, and obese cancer patients face a 17% higher risk of mortality [2]. A recent report examined the relationship between obesity and four obesity-related cancers, namely cancers of the colon, rectum, pancreas, and kidney [2]. The study analyzed cancer incidence data from 42 countries and found positive correlation coefficients of 0.27 and 0.33 for colon cancer and rectal cancer, respectively [2]. Obesity-related CRC is associated with chronic low-grade inflammation, which may promote the progression of colorectal neoplasia through the inflammation–dysplasia–tumor sequence, particularly in early-onset cases. [3]. The risk of CRC in overweight/obese women under 50 years old has doubled, and a high-fat diet (HFD) consumed by a mother can lead to CRC in both mother and foetus [4]. Obesity modulates the CRC microenvironment, where the fat components are readily taken up by the tumor but not the CD8⁺ T cells, thereby blocking tumor infiltration and blunting cancer immunotherapy [5]. In fact, HFD causes metabolic dysregulation by gut microbiota, increases the levels of lysophosphatidic acid, and promotes colorectal tumorigenesis [6, 7]. Similarly, the increase in the levels of palmitic acid in the blood caused by an HFD, which then leads to the activation of Toll-like receptor 4 (TLR4) in the colonic tissue, promotes growth, inflammatory pathogenesis, and CRC metastasis, and is directly associated with poor survival rates in patients with CRC [8]. Among the events, obesity-induced and/or obesity-associated pro-inflammatory milieu is majorly signaled by the adipokine, called fetuin-A or alpha-2-Heremans-Schmid glycoprotein (AHSG), whose serum level is positively correlated with visceral adipose tissue mass and body mass index (BMI, >30 kg/m²). Fetuin-A binds to TLR4 to induce inflammation-mediated fatty colon, interacts with membrane annexins (II and VI), and activates the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway to promote the proliferation of CRC cells. In contrast, adiponectin, a 30-kDa adipokine secreted by the adipocytes, prevents obesity through anti-inflammatory and hypolipidemic actions, and low adiponectin levels are associated with obesity, other inflammatory diseases, and poor prognosis across multiple cancer subtypes, including CRC [8]. Individuals with the highest serum levels of adiponectin possess around 60% less risk of CRC. Exogeneous adiponectin treatment was found to restrict cell growth, survival, migration, oxidative stress, and cytokine expression in CRC cells (Caco-2 and HCT-116) [9]. Moreover, a significant increase in serum adiponectin level was found after successful chemotherapy and radiotherapy in CRC patients [10]. Although the underlying mechanistic circuit behind obesity-induced CRC remains partially understood, the available reports indicate fetuin-A and adiponectin as the possible key mediators. We have summarized how high fetuin-A:adiponectin ratio (FAR) is most likely to trigger CRC in obese patients (Figure 1). In this inaugural bioinformatics study, we found that the expression profiles of fetuin-A and adiponectin were antagonistically correlated with obesity and CRC. This inference is supported by the transcriptomics data (Figure 1a,b), gene correlation analysis (Figure 1c), and immunohistochemical study (Figure 1d) across normal/control and tumor tissues. FAR appears to be an important fate-deciding factor of the survival of CRC patients (Figure 1e). Collectively, fetuin-A induces carcinogenic effects in CRC by establishing multiple signaling cross-talks, activating the TLR4–NF-κB pathway, and inducing inflammation-driven tumorigenesis and angiogenesis, whereas adiponectin has the opposite effect (Figure 1f).

Now, the important question is how critically FAR can be used as an efficacious prognostic/clinical biomarker for obesity-induced CRC in humans. Interestingly, FAR has already shown its potential as a diagnostic biomarker for obesity, hyperglycemia, insulin resistance, and subclinical atherosclerosis in type 2 diabetes mellitus, obesity-associated sepsis, and myelodysplastic syndrome in obese patients [11, 12]. Moreover, human AHSG and ADIPOQ genes lie next to each other on chromosome 37 and possess better diagnostic feasibility. Additionally, mutations in ADIPOQ and AHSG genes are also susceptibility factors for obesity, which may also be an important factor for obesity-induced CRC. Thus, fetuin-A levels adjusted by adiponectin appear to serve as a performance indicator. High FAR values could predict high fetuin-A-mediated inflammation to dysplasia and high risk of CRC, while low FAR values indicate a high adiponectin, low inflammation, and low risk of CRC. In fact, this is the first proposal of FAR in the context of any form of human cancer or CRC, specifically in obesity-induced CRC. Taken together, the serum FAR satisfies the clinical requirements of a crucial prognostic biomarker for obesity-induced CRC. Further use of FAR in clinical settings will help us to clarify the mechanisms linking FAR to chemotherapeutic treatment outcomes in obesity-induced CRC, and therefore, FAR should be incorporated into the population-based cross-sectional studies assessing CRC prevalence in obese subjects. This knowledge may facilitate the recognition of FAR as a prognostic biomarker that enables rapid, accurate, and timely detection, thereby advancing the treatment of obesity-induced CRC—a distinct subtype of colorectal cancer.

Chandrani Fouzder: Conception; writing. Subhadip Mukhopadhyay: Conception; writing. Aditi Banerjee: Conception; writing. Suprabhat Mukherjee: Conception; writing.

The authors declare no conflicts of interest.

The authors have nothing to report.