INTRODUCTION
Gastric cancer is a prevalent and lethal malignancy of the digestive system that imposes a significant burden on patients and their families[1]. Gastric cancer ranks as the fourth most prevalent malignancy and the fifth leading cause of cancer-related mortality globally. Despite recent research indicating a favourable decline in its incidence and mortality rates, gastric cancer continues to pose a formidable public health challenge that necessitates unwavering attention[2]. Risk factors for gastric cancer include Helicobacter pylori (H. pylori) infection, age, high salt intake and dietary habits[3]. Among these factors, H. pylori infection is the main factor in gastric cancer development[4]. Notably, a randomized study conducted in a high-risk East Asian area demonstrated that targeted intervention against H. pylori significantly decreased the risk of gastric cancer[5]. Upon infecting the human host, H. pylori produces noxious substances and metabolites that elicit chronic inflammation within the gastric mucosa, a pivotal event in the multistep progression towards gastric cancer[6].
Furthermore, dietary practices, such as the excessive consumption of high-temperature foods, particularly those prepared through frying, barbecuing, or prolonged meat cooking, as well as nitrite-laden foods, are closely linked to the incidence of gastric cancer[7-9]. Notably, barbecued meat generates polycyclic aromatic hydrocarbons, such as acrylamide and heterocyclic amines, which possess mutagenic and carcinogenic properties in animals, thereby promoting the initiation and progression of gastric cancer[10]. Moreover, the enigmatic pathogenesis of gastric cancer, coupled with the fact that the majority of cases are diagnosed at an advanced stage, significantly compromises patient survival and quality of life[11].
Advanced glycation end products (AGEs) are complex chemical entities that are generated in living organisms via nonenzymatic reactions between free amino groups of macromolecules (proteins, amino acids, lipids, and nucleic acids) and the aldehyde moieties of reducing sugars[12]. This intricate cascade involves condensation, structural rearrangement, cleavage, and oxidative modifications, ultimately yielding a repertoire of stable end products termed AGEs[13]. The genesis of AGEs is a protracted and cumulative process that intensifies with advancing age and is further expedited in diabetic individuals experiencing hyperglycaemic conditions due to elevated blood glucose levels[14]. The accumulation of AGEs within biological systems has deleterious effects on cellular and tissue integrity, ultimately decreasing organ function and predisposing individuals to chronic diseases[15]. Consequently, AGEs have garnered significant interest within the realms of biology and medicine owing to their intricate associations with a broad spectrum of chronic illnesses, malignancies, and their accompanying complications. Notably, previous investigations have suggested that the overexpression of the receptor for AGEs (RAGE) in ovarian cancer could serve as a valuable biomarker for monitoring tumour progression and prognosis, underscoring the clinical significance of AGEs in disease pathogenesis[16]. Senavirathna et al[17] reported that abnormal accumulation of AGEs damages the cell proteome and promotes an AGEs-RAGE-driven proinflammatory signaling cascade.
The investigation of AGEs holds paramount importance in elucidating the underlying mechanisms of gastric cancer pathogenesis and fostering the development of innovative therapeutic strategies. By implementing targeted interventions aimed at mitigating the formation and accumulation of AGEs, we can aspire to prevent or delay the onset and progression of gastric cancer. As research on AGEs progresses, we anticipate the discovery of more potent interventions that will significantly reduce the incidence and mortality rates associated with gastric cancer, thereby safeguarding human health and well-being.
A REFLECTION ON AND FUTURE PERSPECTIVES FOR AGES RESEARCH IN GASTRIC CANCER
AGEs, which are produced by nonenzymatic glycosylation reactions, are ubiquitous in both human metabolic processes and food processing[18]. Although the origins of foodborne and nonfoodborne AGEs differ, they elicit equivalent detrimental effects. For example, methylglyoxal-H1 (MG-H1) is derived from in vitro foodborne pathogens, and compound methionine leucine (CML) impacts metabolic processes within the body[19]. CML and compound methionine leucine are predominantly found within red blood cells, and their levels remain unchanged regardless of dietary intake, suggesting endogenous production within the body[20]. Conversely, MG-H1 is derived primarily from dietary sources[21]. The accumulation of AGEs is associated with diabetic gastrointestinal motility disorders. Yu et al[22] found that advanced glycosylation end products interfere with the expression of markers of gastric smooth muscle contraction via the AGEs/RAGE/NF-kB pathway. Therefore, whether AGEs are ingested through food or accumulate in the gastrointestinal tract due to dietary habits, they may contribute to the risk of gastric cancer. The seminal work by Brownlee[23] indicated that biochemical alterations in receptors regulate AGEs levels. The intracellular generation of AGEs precursors initiates inflammatory infiltration by modifying intracellular proteins, the extracellular matrix, and plasma proteins, altering their structures and receptor interactions. Furthermore, the accumulation of the extracellular matrix disrupts matrix-matrix and matrix-cell interactions, impeding intercellular communication and fostering cancer development. The increase in AGEs promotes the activation of the RAGE axis, subsequently triggering a myriad of signaling cascades, including the JAK/STAT and AKT/mTOR pathways[24]. The activation of the RAGE axis promotes the development of key processes in oncology, such as genomic instability and aberrant interference with inflammatory processes[25]. Given the structural and functional attributes of AGEs and RAGE, the pursuit of small-molecule inhibitors or eliminators targeting these entities has emerged as a promising research direction. By inhibiting or eradicating their activities, we can potentially unravel novel and efficacious avenues for the prevention and treatment of chronic diseases and cancer.
AGEs, which are hallmarks of chronic hyperglycaemia in individuals with diabetes, are implicated in enhanced biofilm formation[26]. The generation and accumulation of AGEs are to some extent linked to the invasion, spread, metastasis and prognosis of gastric cancer cells. AGEs can induce processes such as oxidative stress, the inflammatory response, and apoptosis, thereby promoting gastric cancer development and progression[27,28]. High-mobility group box 1 (HMGB1), a RAGE-cognate ligand, is upregulated in gastric cancer cells, promoting their proliferation and growth. Notably, H. pylori infection potentiates HMGB1 expression and AGEs accumulation, stimulating gastric epithelial inflammation and ultimately carcinogenesis[29,30]. Intriguingly, HMGB1, via RAGE-mediated mechanisms, facilitates the release of autophagic gastric cancer cells, supporting their survival and decreasing their chemosensitivity[12].
AGEs have emerged as pivotal players in gastric cancer progression, engaging receptors such as RAGE and toll like receptor to activate diverse signaling pathways that stimulate gastric cancer cell proliferation, migration, and invasion[31]. This RAGE-dependent intracellular signaling orchestrates the activation of activator protein-1, cAMP-responsive element binding protein, and other transcription factors, ultimately transcriptionally activating cancer-promoting genes[16,32]. In addition to these direct effects, AGEs profoundly modulate the metabolic processes and energy supply mechanisms of gastric cancer cells, further exacerbating their neoplastic progression[12]. Indeed, AGEs intricately disrupt the homeostatic metabolic pathways of gastric cancer cells through multifaceted interactions with cellular molecules, culminating in a perturbation of energy production and allocation dynamics[33,34]. This metabolic imbalance not only undermines the viability of gastric cancer cells but also promotes their malignant transformation and proliferation, resulting in a more aggressive disease phenotype.
In the future, exploring the intricate relationship between AGEs and gastric cancer will necessitate a multifaceted approach. First, a meticulous investigation into the precise mechanisms underlying the involvement of AGEs in gastric carcinogenesis and progression is imperative to elucidate their role in modulating the biological behaviour of gastric cancer cells. Second, unravelling the intricate interplay between AGEs and other gastric cancer-associated factors will enhance our understanding of the intricate processes driving gastric cancer initiation and progression. Last, the development of targeted interventions aimed at modulating AGEs, including strategies to reduce their formation and inhibit their receptor binding, holds immense potential for offering novel insights and therapeutic avenues for gastric cancer prevention and treatment. Collectively, the presented findings indicate that the intricate relationship between AGEs and gastric cancer is a compelling research frontier and that further research on this topic could provide profound insights into the mechanistic underpinnings of AGEs in gastric carcinogenesis and progression to pave the way for innovative strategies to combat this disease.
CONCLUSION
Previous investigations have focused predominantly on traditional risk factors such as H. pylori infection and dietary habits. In contrast, our study innovatively elucidates the pivotal role of AGEs, which are emerging biomarkers, in the initiation and progression of gastric cancer. These findings not only enrich our understanding of the underlying mechanisms of gastric cancer but also highlight a novel strategy for its prevention and management.
First, our work systematically consolidates the intricate relationship between AGEs and gastric cancer through meticulous analysis, fostering a more coherent and exhaustive research landscape in this domain. Second, by integrating the latest scientific advancements, we delve into the contribution of AGEs receptors to gastric cancer pathogenesis, offering a fresh perspective for future investigations into the AGE–gastric cancer nexus.
Moreover, we introduce a novel preventative strategy aimed at mitigating the formation and accumulation of AGEs, which represents a theoretically ground-breaking approach while also presenting tangible prospects for gastric cancer prevention and treatment. Our findings underscore the pivotal role of AGEs in gastric cancer aetiology, thereby establishing a solid theoretical foundation for its prevention and management strategies. Moreover, these findings highlight the feasibility and promise of developing AGE-targeted interventions to reduce the incidence and mortality rates of gastric cancer. Notably, the pivotal involvement of both AGEs and their receptor RAGE in gastric cancer progression-related processes, including cell growth, invasion, and metastasis, underscores their importance. Furthermore, RAGE has emerged as a potential prognostic biomarker in gastric cancer patients, emphasizing the need for further exploration, particularly in East Asia, where the incidence of gastric cancer is high. To fully elucidate the specific roles of AGEs and RAGE in gastric cancer, additional research endeavours and investments are warranted.
Future endeavours should emphasize conducting comprehensive clinical trials to advance the therapeutic application of AGEs and RAGE in gastric cancer, promising breakthroughs in oncological treatment. Such studies will propel gastric cancer research and enhance human health by providing novel therapeutic avenues. By elucidating the roles of AGEs and RAGE, we aim to improve patient outcomes and alleviate the disease burden.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade D
Novelty: Grade B, Grade D
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade B, Grade C
P-Reviewer: Otsuka Y S-Editor: Luo ML L-Editor: A P-Editor: Zhao YQ
