Advancing early detection of gastric cancer through serum cytokine profiling

Abstract

Gastric carcinoma (GC) is one of the most common and deadly cancers worldwide, ranking fifth in incidence and third in cancer-related mortality. Despite significant advancements in surgical techniques and chemotherapy, the overall prognosis for GC remains poor, primarily due to late-stage diagnosis. Current diagnostic tools, such as endoscopy and biopsy, are invasive and are often utilized only after symptoms arise, leading to missed opportunities for early intervention. Traditional serum tumour markers, such as carcinoembryonic antigen and carbohydrate antigen 19-9, demonstrate limited sensitivity and specificity, particularly in the disease's early stages. GC often diagnosed at advanced stages due to a lack of early, specific biomarkers. Chronic inflammation plays a significant role in gastric carcinogenesis, particularly in cases of Helicobacter pylori-associated gastritis. Pro-inflammatory cytokines have gained attention as potential non-invasive serum biomarkers for early diagnosis and disease monitoring. In recent years, numerous studies have explored the potential of serum cytokines-such as interleukin (IL)-6, tumour necrosis factor-alpha, IL-8 and interferon-gamma-as biomarkers for detecting gastric cancer. Future research integrating cytokine profiling with imaging, endoscopic, or genomic data may revolutionize how we screen and manage GC.

Key Words: Gastric carcinoma; Cytokines; Interleukin-6; Interleukin-8; Interleukin-10; Tumour necrosis factor-alpha; Interferon-gamma; Biomarkers; Inflammation; Diagnosis

Core Tip: Ren et al’s study produced some main findings that suggest serum pro-inflammatory cytokines may serve as potential biomarkers for the diagnosis of gastric carcinoma (GC). This study reveals that patients with GC have significantly elevated levels of interleukin (IL)-1β, IL-6, IL-8, and interferon-γ compared to healthy individuals. Notably, the receiver operating characteristic curve analysis demonstrates that IL-1β, IL-6, and IL-8 show exceptional potential in distinguishing GC patients, with area under the curve values exceeding 0.7. Furthermore, a positive correlation was found between the serum levels of IL-1β and IL-6 and both the T stage and N stage of the disease. These insights encourage further exploration and offer hope for advancements in gastric cancer diagnostics. In addition to this, there are several limitations to consider. One major limitation is the relatively small sample size, as well as the potential bias introduced by collecting data from a single center. Furthermore, the study did not evaluate the dynamic changes in pro-inflammatory cytokines at various stages of GC. Lastly, it is worth noting that the samples were collected over an extended period, nearly one year.

TO THE EDITOR

Gastric cancer remains one of the most challenging malignancies in oncology, ranking as the third leading cause of cancer-related deaths worldwide[1]. The insidious nature of this disease, often presenting with nonspecific symptoms in early stages, contributes to its poor prognosis and high mortality rates[2]. The combination of T, N, and M classifications allows for the staging of gastric cancer from stage I to stage IV, each with specific therapeutic recommendations and prognostic implications. For instance, early-stage tumours (stage I) may be treated with curative surgical resection, while advanced-stage disease (stage IV) typically requires systemic therapy or palliative care. Therefore, accurate tumour-node-metastasis (TNM) staging is essential for risk stratification and evidence-based management of gastric cancer. The TNM classification system is the international standard for assessing cancer spread, particularly in gastric carcinoma (GC). Developed by the American Joint Committee on Cancer and the Union for International Cancer Control, it provides a clear framework for staging, prognosis, treatment selection, and outcome comparison[3,4]. In this system, the "T" component indicates the depth of primary tumour invasion, ranging from Tis (carcinoma in situ) to T4b (direct invasion of nearby structures). The "N" category measures regional lymph node metastasis, from N0 (no involvement) to N3b (involvement of 16 or more lymph nodes). The "M" component shows the presence (M1) or absence (M0) of distant metastases[4,5]. The T, N, and M classifications stage gastric cancer from stage I to stage IV, each with specific treatment implications. Early-stage tumours may be treated with surgery, while advanced-stage cases often require systemic therapy or palliative care. Accurate TNM staging is crucial for the effective management of gastric cancer[2].

The recently published article by Ren et al[6], provides compelling evidence for the role of serum pro-inflammatory cytokines as biomarkers in diagnosing GC. This research offers new hope for earlier detection strategies. What makes this study particularly significant is its focus on translational applicability. Translational applicability refers to the process of turning findings from basic or preclinical research into interventions, diagnostics, or therapeutic strategies that are relevant to clinical practice. It emphasizes the practical utility of scientific discoveries in improving patient care, bridging the gap between experimental observations (e.g., in vitro or animal models) and their implementation in human medicine. In an era where precision medicine and early detection are priorities in oncology, identifying serum-based markers that reflect the tumour microenvironment and a systemic immune response is crucial for clinical practice. Inflammatory cytokines are measurable, cost-effective, and relatively easy to obtain in routine settings, presenting a realistic opportunity for enhancing early detection, especially in high-risk populations.

THE CRITICAL NEED FOR BETTER DIAGNOSTIC TOOLS

The current diagnostic landscape for gastric cancer heavily relies on invasive procedures such as endoscopy and tissue biopsy, which are often delayed due to the non-specific nature of early symptoms[2]. Traditional tumour markers like carbohydrate antigen 19-9 have shown limited sensitivity and specificity for gastric cancer, particularly in the early stages. In addition, other biomarkers-including interleukin (IL)-6, carcinoembryonic antigen (CEA) and microRNA21 (miR21)-have been proposed for the early detection and monitoring of GC. In preclinical and clinical studies, miR21 has emerged as a promising circulating biomarker, with metaanalyses demonstrating moderate sensitivity (approximately 0.665) and high specificity (approximately 0.831) for GC diagnosis-significantly outperforming CEA[7]. One validation study of 50 GC patients vs healthy controls reported approximately 88% sensitivity and 80% specificity for serum miR21[8]. On the other hand, microRNAs (miRNAs), long non-coding RNAs, and circular RNAs show variability in their expression due to tumour heterogeneity, patient-related factors, technical detection challenges, and the lack of large-scale clinical validation. These issues hinder their reliable application in clinical settings. To address this, Ren et al[6] conducted a study using untargeted metabolomics to investigate changes in serum metabolic profiles among GC patients. The goal was to identify potential serum biomarkers for GC diagnosis and to analyse the relationship between the concentrations of differentially expressed metabolites and disease severity in these patients. The translational applicability of these biomarkers hinges on further validation in large multicenter studies, reproducibility across analytical platforms, and integration into cost-effective, clinically viable assays. Only those biomarkers meeting these criteria can move from bench findings to reliable tools in routine clinical workflows.

INFLAMMATION AS A WINDOW INTO CARCINOGENESIS

The relationship between chronic inflammation and cancer development has been well-established[9], with gastric cancer serving as a prime example of this pathophysiological connection. Chronic gastritis, often initiated by Helicobacter pylori(H. pylori) infection[10], creates a pro-inflammatory microenvironment that promotes cellular transformation and tumor progression[11]. The authors' focus on serum pro-inflammatory cytokines as potential biomarkers represents a logical extension of our understanding of gastric carcinogenesis[2].

STUDY INSIGHTS AND CLINICAL IMPLICATIONS

This case-control study's approach to systematically evaluate serum cytokine profiles offers several advantages over single biomarker strategies. The multi-cytokine panel approach may capture the complex inflammatory signature associated with gastric cancer more comprehensively than individual markers[12]. If validated, such a diagnostic panel could potentially: (1) Enable earlier detection before symptoms manifest; (2) Provide a non-invasive screening tool for high-risk populations; (3) Facilitate monitoring of treatment response; and (4) Assist in risk stratification for surveillance programs.

METHODOLOGICAL CONSIDERATIONS

While the study design appears robust, several factors warrant consideration when interpreting these findings. The characteristics of both case and control groups significantly impact the generalizability of results, as factors such as H. pylori status, co-existing gastric pathology, and demographic variables can influence cytokine levels[10]. Pro-inflammatory cytokines can be elevated in various conditions including other malignancies, autoimmune disorders, and infections[11], making careful consideration of these potential confounders essential for clinical application. Furthermore, the stability of cytokine measurements, sample processing protocols, and inter-laboratory variability are crucial factors that need standardization before clinical implementation as inconsistencies in these areas could significantly impact the reliability and reproducibility of results.

FUTURE DIRECTIONS AND CLINICAL TRANSLATION

The promising results of this study open several avenues for future research. The investigation of serum pro-inflammatory cytokines as gastric cancer biomarkers represents a significant step forward in our quest for better diagnostic tools. Previous studies have demonstrated that using a combination of multiple serum proteins as a single panel can enhance sensitivity or specificity compared to individual biomarkers[13]. In this study, a panel consisting of IL-1β, IL-6, IL-8, and interferon-gamma (IFN-γ) for the diagnosis of GC was examined. The results indicated that the area under the curve value for this panel increased to 0.888, suggesting that it holds significant promise as a biomarker for identifying patients with GC.

As we continue to unravel the complex relationship between inflammation and cancer[14], studies like this one provide hope that we may soon have more effective tools for early gastric cancer detection. The ultimate goal–improving survival rates through earlier diagnosis–remains within reach as we build upon these important findings[15].

Large-scale, multi-center validation studies are needed to confirm these findings across diverse populations and clinical settings to establish their universal applicability. Additionally, prospective studies tracking cytokine changes over time could provide insights into disease progression and treatment monitoring[16]. Integration of cytokine profiles with other emerging biomarkers such as circulating tumor DNA and exosomal markers may enhance diagnostic accuracy through multi-modal approaches. Furthermore, advanced analytical approaches including machine learning applications could optimize cytokine panel composition and improve predictive algorithms, potentially leading to more precise and personalized diagnostic strategies.

CHALLENGES AND CONSIDERATIONS

Despite the promising findings, several challenges remain before clinical implementation. The economic feasibility of cytokine panel testing needs evaluation compared to current diagnostic approaches to ensure cost-effectiveness. Extensive validation and regulatory review will be required for clinical adoption, as regulatory bodies will demand robust evidence of safety and efficacy. Most importantly, demonstration of improved patient outcomes, not just diagnostic accuracy, will be essential for widespread clinical acceptance and integration into standard care protocols.

CONCLUSION

This study reinforces the growing body of evidence that serum pro-inflammatory cytokines hold considerable promise as non-invasive biomarkers for the early detection and monitoring of GC. The significant elevation of cytokines such as IL-1β, IL-6, IL-8, and IFN-γ in patients with gastric cancer, as well as their correlation with TNM staging parameters, underscores their diagnostic and prognostic relevance. Beyond the diagnostic potential, the clinical applicability of cytokine profiling lies in its simplicity, cost-effectiveness, and feasibility for integration into routine screening programs-especially in high-risk populations. When used alongside conventional diagnostic modalities and emerging molecular markers such as circulating tumor DNA or miRNAs, cytokine panels may enhance the sensitivity and specificity of early cancer detection strategies. Nevertheless, the transition of these findings into clinical practice necessitates large-scale, multicenter validation studies to confirm their reproducibility across diverse populations and laboratory settings. Future studies should also focus on standardizing sample processing protocols, assessing longitudinal cytokine dynamics during treatment, and evaluating the utility of cytokine-based algorithms in risk stratification and therapeutic response monitoring. In conclusion, serum cytokine profiling represents a promising, translationally relevant approach to address the longstanding challenge of early gastric cancer diagnosis. With further validation and integration into clinical workflows, it has the potential to substantially improve patient outcomes by enabling timely intervention, personalized care, and more effective surveillance strategies.