The Role of Visfatin in Gastric and Esophageal Cancer: From Biomarker to Therapeutic Target

Abstract

Background: Gastric and esophageal cancers are among the most lethal malignancies worldwide, necessitating improved biomarkers and therapeutic targets to improve patient outcomes. Visfatin, also known as nicotinamide phosphoribosyltransferase (NAMPT), is a metabolic enzyme and adipokine with emerging significance in cancer progression. It has been implicated in tumor cell proliferation, angiogenesis, immune modulation, and chemotherapy resistance, yet its clinical relevance in upper gastrointestinal (GI) cancers remains unclear. This review aims to explore visfatin's biochemical properties, its role in the pathogenesis of upper GI cancers, and its implications for potential therapeutic interventions. Methods: A comprehensive review of the literature was conducted to evaluate the role of visfatin in gastric and esophageal cancer. We analyzed studies investigating visfatin expression in tumor tissues, blood, and adipose tissue, its prognostic significance, and its potential as a therapeutic target. Preclinical and clinical studies evaluating visfatin inhibitors were also reviewed. Results: Visfatin promotes tumor progression through the activation of key oncogenic pathways leading to increased angiogenesis, epithelial-mesenchymal transition (EMT), and immune suppression. Elevated visfatin levels are associated with advanced tumor stage, reduced response to chemotherapy, and poor prognosis in both gastric and esophageal cancers. Therapeutic agents targeting visfatin, such as the inhibitor FK866, have shown promising results in reducing tumor proliferation by >50%, improving chemoresistance, and restoring antitumor immunity in preclinical studies. However, clinical translation remains limited due to toxicity concerns and the need for more targeted therapies. Conclusions: Visfatin is a promising biomarker and potential therapeutic target in gastric and esophageal cancer. However, its precise role and mechanisms require further investigation. The standardization of measurement techniques and large-scale clinical studies is needed to validate its prognostic and predictive value. Future research should focus on optimizing visfatin-targeted therapies, particularly in the context of obesity-associated malignancies and chemoresistant tumors.

Keywords: biomarkers; esophageal cancer; gastric cancer; therapeutic targets; upper gastrointestinal cancer.

Figure 1

Suggested and established roles of intracellular and extracellular NAMPT in upper gastrointestinal cancer pathogenesis. Intracellular NAMPT within cancer cells maintains NAD levels (established mechanism) essential for cancer cell metabolism and survival. Suggested intracellular functions (dashed arrows) include promoting chemoresistance under hyperglycemic conditions via the altered expression of resistance-related proteins (Sirt1, P-gp, Topo-IIα) and facilitating EMT through the increased expression of transcription factors (TWIST1, VIM, SNAI1). Extracellular NAMPT, secreted into the tumor microenvironment, has several suggested roles (dashed arrows), including the promotion of angiogenesis and lymphangiogenesis (VEGF-C, MEK1/2-ERK, NF-κB signaling), the modulation of immune responses (CD36, NEAT1, PRDM1, PTGS2, PD-1 on CD8+ T cells), ECM remodeling (MMP-2, MMP-9), extracellular adenosine-mediated immunosuppression, and the stimulation of tumor cell proliferation (hTERT, resistin). Solid arrows denote proven mechanisms, while dashed arrows represent mechanisms that are currently suggested but require further validation (Created in BioRender.com on 20 March 2025).