Serum gastrin and Helicobacter pylori infection correlate with tumor aggressiveness and prognosis in gastric cancer

Abstract

BACKGROUND

Gastric cancer remains a leading cause of cancer-related mortality worldwide. Both Helicobacter pylori (H. pylori) infection and alterations in serum gastrin levels have been implicated in its pathogenesis. However, their associations with tumor characteristics and clinical outcomes require further clarification.

AIM

To investigate the associations of serum gastrin and H. pylori infection with pathology and prognosis in gastric cancer.

METHODS

This hospital-based cohort study included 226 gastric cancer patients undergoing surgery and 100 matched controls from January 2019 to December 2023. Serum gastrin and H. pylori status were assessed and compared. Gastric cancer patients were stratified by biomarker status to analyze associations with tumor-nodes-metastasis (TNM) stage, lymph node metastasis, and tumor differentiation. Kaplan-Meier analysis was used to evaluate disease-free and overall survival (OS). Statistical significance was set at P < 0.05.

RESULTS

Gastric cancer patients exhibited significantly higher serum gastrin levels and H. pylori infection rates than controls (P < 0.05). Among gastrin-positive patients, the proportions of advanced TNM stage (III-IV), lymph node metastasis, and poorly differentiated tumors were significantly higher than in gastrin-negative patients (P < 0.05). In contrast, H. pylori infection status showed no significant association with TNM stage, lymph node metastasis, or tumor differentiation (P > 0.05). Kaplan-Meier analysis indicated no significant difference in disease-free survival between gastrin-positive and negative patients (hazard ratio = 1.516, 95% confidence interval: 0.895-2.550), but gastrin-positive patients had significantly worse OS (hazard ratio = 2.717, 95% confidence interval: 1.311-5.633).

CONCLUSION

Gastric cancer patients have elevated serum gastrin and higher H. pylori prevalence; elevated gastrin is associated with aggressive tumor features and poorer OS, indicating prognostic value.

Key Words: Gastrin; Gastric cancer; Helicobacter pylori; Pathological characteristics; Survival curve

Core Tip: This study explores the clinical relevance of serum gastrin and Helicobacter pylori (H. pylori) infection in gastric cancer. Among 226 patients, elevated serum gastrin, but not H. pylori status, was significantly associated with advanced tumor stage, lymphatic metastasis, and poor differentiation. Notably, gastrin-positive patients had worse overall survival. These findings suggest that hypergastrinemia may serve as a biomarker of tumor aggressiveness and prognosis in gastric cancer, offering potential targets for risk stratification and therapeutic intervention.

INTRODUCTION

Gastric cancer is a common type of malignant tumor and is the third most common cause of cancer-related deaths globally. Individuals with advanced-stage stomach cancer are confronted with a poor prognosis, having a 5-year survival rate that only varies between 20% and 30%[1]. Surgical intervention continues to be the sole curative approach for treating gastric cancer. In contrast, traditional chemotherapy provides modest advantages for patients with metastatic gastric cancer, typically extending survival by around 10 months on average[2,3]. The onset and advancement of gastric cancer are complex processes that involve tumor markers, gastrointestinal hormones, and inflammatory responses[4].

Gastrin, a crucial gastrointestinal hormone primarily secreted by G-cells, plays a physiological role in gastric acid secretion and gastrointestinal growth, exerting trophic effects on the entire gastrointestinal tract[5]. The relationship between gastrin and gastric cancer has garnered considerable interest. Similar to findings in cell culture experiments, gastrin has been recognized as a factor that enhances the growth of human gastric cancer cell lines[6]. Proton pump inhibitors (PPIs), which can be used to elevate gastrin levels, have raised questions regarding the potential link between the risk of gastrointestinal cancers and PPI use. However, conclusive evidence is lacking[7]. There is a suggestion that the use of PPIs could potentially lower the risk of gastric cancer by neutralizing the effects of gastrin, which are known to be proliferative and anti-apoptotic[8,9]. Research has confirmed that high concentrations of gastrin occur in gastric cancer tissue. This correlation is linked to later stages of the disease, the presence of cancer in lymph nodes, and a prognosis that is less promising.

As a common infection of the gastric mucosa, Helicobacter pylori (H. pylori) infection can lead to gastritis and other gastric disorders, including gastric ulcer and gastric cancer[10]. The resulting chronic inflammation and H. pylori infection are pivotal in the genesis and advancement of gastric cancer. This infection can lead to an upregulation of gastrin secretion, producing excessive gastric acid. Consequently, the gastric mucosa becomes irritated and damaged, increasing the risk of gastritis, gastric ulcer, and gastric cancer. Several factors contribute to how H. pylori stimulates gastrin release, including increased stimulation of inflammatory cytokines and local pH changes caused by H. pylori’s urease production. These factors collectively promote gastrin release within the gastric antrum. Conversely, gastrin release decreases after eradication or suppressing H. pylori infection[11]. H. pylori infection and gastrin may synergistically contribute to gastric cancer development, given that research has shown H. pylori infections accelerate gastric carcinogenesis in insulin-gastrin transgenic mice[12]. However, there is a paucity of clinical evidence regarding the biological roles and mechanisms of H. pylori and gastrin in the pathological progression and prognostic regression of gastric cancer. Therefore, this research endeavors to explore the relationship between circulating gastrin levels, clinical and H. pylori infection, and pathological characteristics among gastric cancer patients.

MATERIALS AND METHODS

Study population

This was an observational study with two arms (gastric cancer patients and matched healthy controls) and no intervention. No changes were made to the study design after initiation. A single-center hospital setting, 226 patients who had surgical management of gastric cancer at People’s Hospital of Longhua District between January 2019 and December 2023. In addition, a control group of 100 individuals who underwent general physical health check-ups during the same period who were matched for age and gender. Of the gastric cancer patient group, 108 were female and 118 were male, with a mean age of 62.36 ± 12.03 years. Tumor classification followed histopathological confirmation based on World Health Organization criteria.

Inclusion and exclusion criteria

Inclusion criteria: (1) Meeting the relevant diagnostic criteria outlined in the standardized diagnostic and treatment guidelines for gastric cancer (trial implementation); (2) Ages ranging from 18 to 80 years, irrespective of gender; (3) First surgical treatment with confirmed diagnosis through surgical resection and pathological examination; and (4) Absence of other digestive system diseases.

Exclusion criteria: (1) History of cancer recurrence after treatment; (2) Presence of concurrent malignant tumors; (3) Severe liver or kidney dysfunction; (4) Projected life expectancy of under six months; (5) Prior receipt of radiotherapy or other anticancer treatments before enrollment; (6) Diagnosis of systemic inflammatory disease, cirrhosis or chronic liver failure, or abnormal renal function; and (7) Coexistence of psychiatric or neurological conditions that would impede cooperation with the completion of the tests.

Gastrin measurement

Peripheral venous blood samples of 3 to 5 mL were taken prior to surgery from fasting subjects with newly diagnosed gastric cancer, and blood samples from subjects in the control group were collected when they presented for physical examination. Blood samples were then processed by spinning them at 3000 revolutions per minute for 10 minutes in a centrifuge to isolate the serum. Serum gastrin was assessed using radioimmunoassay methods, and positive serum gastrin was defined as values greater than 17.65 pmol/L. To avoid potential confounding, all subjects in both groups were asked to discontinue PPIs or potassium-competitive acid blockers (PCABs) at least 14 days before sample collection.

Information regarding regular use of PPI or PCAB was collected through medical interviews. Of the 226 gastric cancer patients, 72 (31.9%) had a history of regular PPI/PCAB use, and 65 (28.8%) reported use within the past month. To mitigate confounding effects on serum gastrin, all participants were instructed to discontinue PPI/PCAB therapy for at least 14 days prior to blood sample collection, and compliance was confirmed verbally at the time of testing. The sample size was determined based on the availability of eligible gastric cancer patients and matched controls during the study period; no formal power calculation was performed. Laboratory staff analyzing serum gastrin and H. pylori status were blinded to clinical outcomes.

H. pylori determination

All patients underwent a carbon-14 urea breath test (¹⁴C-UBT) prior to surgery to assess active H. pylori infection. To minimize false-negative results, patients were instructed to discontinue antibiotics and bismuth compounds for at least 30 days and PPIs for 14 days prior to testing. After overnight fasting, patients ingested a ¹⁴C-urea capsule, and exhaled samples were collected after 25 minutes for analysis using a liquid scintillation counter. An activity level ≥ 100 disintegrations per minute (dpm) was defined as positive for H. pylori infection. Thus, only current infection was assessed. Based on retrospective chart review, 38 gastric cancer patients (16.8%) and 20 control subjects (20%) had documented history of eradicated H. pylori infection, though these individuals were not excluded or separately analyzed due to incomplete eradication records. We acknowledge that this may have led to misclassification and potentially affected the associations observed.

However, it is important to note that the UBT only detects current infection status and does not account for past infections or eradication history. Endoscopic biopsy with histology or additional serological testing (e.g., anti-H. pylori immunoglobulin G antibodies) was not performed. Additionally, no detailed inquiry was made regarding prior H. pylori eradication therapy. Therefore, patients were categorized into H. pylori-positive and negative groups based solely on UBT results, which may not comprehensively reflect their true infection status or history. This limitation is acknowledged and considered in the interpretation of the results.

Postoperative follow-up

Postoperative follow-up assessments were conducted until January 2025, incorporating outpatient or inpatient reviews and telephone callbacks. The follow-up protocol encompassed monitoring disease-free survival (DFS) and overall survival (OS).

Analysis of PPI/PCAB use and serum gastrin

To evaluate whether long-term PPI or PCAB use influenced serum gastrin levels and confounded the association with tumor characteristics, we conducted a stratified and adjusted analysis. Based on medication history, patients were categorized into three groups. (1) No use group: No history of PPI/PCAB use; (2) Past use group: History of regular use but none in the past month; and (3) Recent use group: Use within the past month. Serum gastrin levels were compared across the three groups using one-way ANOVA. To assess whether PPI/PCAB use confounded the relationship between gastrin levels and tumor grade, we performed multivariable logistic regression with tumor grade as the dependent variable and serum gastrin and PPI group as independent variables.

Statistical analysis

The survival curves were derived from the survival package within the R programming language. Data analysis was carried out using version 23.0 of the SPSS statistical software. Numerical data were presented as the mean ± SD, and the independent samples t-test was used to evaluate the differences between the two groups. DFS and OS were depicted using Kaplan-Meier survival curves. Discrepancies between the two groups were assessed employing the Log-rank test. Serum gastrin levels were compared across the three groups using one-way ANOVA. To assess whether PPI/PCAB use confounded the relationship between gastrin levels and tumor grade, we performed multivariable logistic regression with tumor grade as the dependent variable and serum gastrin and PPI group as independent variables. Each test was conducted with a two-tailed approach, the threshold for statistical significance established at P < 0.05.

RESULTS

Quantitative detection of gastrin and H. pylori

The levels of gastrin and H. pylori were quantitatively measured and compared. The gastrin level in the gastric cancer group was 26.02 ± 5.93 pmol/L, and the H. pylori quantitative detection was 275.42 ± 42.36 dpm. The gastrin level was 14.02 ± 4.10 pmol/L, and the H. pylori quantitative detection was 163.36 ± 39.63 dpm in the control group (Table 1). Gastrin levels and H. pylori positivity were markedly elevated among gastric cancer patients as opposed to the control group (P < 0.01 for all comparisons).

Table 1 Gastrin and Helicobacter pylori quantitative assays, mean ± SD.

	n	Gastrin level (pmol/L)	Helicobacter pylori quantitative assays (disintegrations per minute)
Gastric cancer group	226	26.02 ± 7.93	275.42 ± 62.36
Control group	100	16.02 ± 4.10	163.36 ± 59.63
t		18.09	12.99
P value		< 0.001	< 0.001

Relationship between gastrin and pathological features

Based on the serum gastrin level, the gastric cancer group was divided into a gastrin-negative group (≤ 17.65 pmol/L) and a gastrin-positive group (> 17.65 pmol/L), which consisted of 90 and 136 cases, respectively. The rate of gastrin positivity was 60.18%. An examination of the clinicopathological features of gastric cancer across the two groups was undertaken, with the outcomes detailed in Table 2. Among the gastrin-negative patients, 39 cases were in stage III-IV, 51 were in tumor-nodes-metastasis (TNM) stage I-II, 21 had lymph node metastasis, 23 had low differentiation, and 67 had middle and high differentiation. Among the gastrin-positive patients, 86 cases were in stage III-IV, 50 were in TNM stage I-II, 52 had lymph node metastasis, 54 had low differentiation, and 82 had middle and high differentiation. Patients in the gastrin-positive group had notably higher rates of lymph node metastasis, TNM stage III-IV, and poorly differentiated tumors than the gastrin-negative group, with each difference achieving statistical significance (P < 0.05 for each comparison).

Table 2 Relationship between gastrin and pathologic features.

	Gastrin-negative	Gastrin-positive	χ2	P value
n	90	136
TNM staging			9.637	0.002
I-II	51	50
III-IV	39	86
Lymphatic metastasis			5.899	0.015
No	69	84
Yes	21	52
Degrees of differentiation			5.265	0.022
Medium-high differentiation	67	82
Low differentiation	23	54

TNM: Tumor-nodes-metastasis.

Relationship between pathological features and H. pylori infection

Gastric cancer patients were divided into two categories: Those with H. pylori infection and those without, determined by the detection of H. pylori, which comprised 173 and 53 cases, respectively. The H. pylori-positive rate was 76.55%. The comparison of gastric cancer’s clinicopathological traits between the two groups is depicted in Table 3, presenting the findings. Among the H. pylori-negative patients, 28 cases were in stage III-IV, 18 had lymph node metastasis, 25 were in TNM stage I-II, 22 had low differentiation, and 31 had middle and high differentiation. Among the H. pylori-positive patients, 96 cases were in stage III-IV, 77 were in TNM stage I-II, 56 had lymph node metastasis, 56 had low differentiation, and 117 had middle and high differentiation. No significant statistical disparities were observed when comparing the two groups’ TNM stage, lymph node involvement, and differentiation grade (P > 0.05 for all comparisons).

Table 3 Relationship between Helicobacter pylori infection and pathologic features.

	Helicobacter pylori-negative	Helicobacter pylori-positive	χ2	P value
n	53	173
TNM staging			0.208	0.648
I-II	25	77
III-IV	28	96
Lymphatic metastasis			0.109	0.741
No	35	117
Yes	18	56
Degrees of differentiation			1.614	0.204
Medium-high differentiation	31	117
Low differentiation	22	56

TNM: Tumor-nodes-metastasis.

As shown in Table 3, patients were categorized into H. pylori-positive and negative groups based on ¹⁴C-UBT results. Comparison of pathological features between these groups revealed no statistically significant differences in TNM staging (χ² = 0.208, P = 0.648), presence of lymphatic metastasis (χ² = 0.109, P = 0.741), or degree of differentiation (χ² = 1.614, P = 0.204). These findings indicate that UBT-defined H. pylori status did not meaningfully correlate with key indicators of tumor severity, suggesting potential limitations in the diagnostic classification based solely on current infection.

Relationship between gastrin and prognosis

Post-discharge surveillance of patients within the gastric cancer cohort was conducted to document DFS and OS. Follow-up periods ranged from a minimum of 6 months to a maximum of 24 months, with a median follow-up time of 16 months. The DFS was illustrated with the Kaplan-Meier survival analysis, depicted in Figure 1. Throughout the follow-up, 18 disease progressions were noted among gastrin-negative patients, and 39 among gastrin-positive patients. Kaplan-Meier survival analysis showed no substantial difference in DFS between individuals with positive and negative gastrin status [hazard ratio = 1.516, 95% confidence interval (CI): 0.895-2.570]. The OS was described using Kaplan-Meier survival curves, as shown in Figure 2. During the follow-up period, six deaths occurred in the gastrin-negative patients, and 24 deaths occurred in the gastrin-positive patients. Kaplan-Meier analysis showed that the OS of gastrin-positive patients was inferior to that of gastrin-negative patients (hazard ratio = 2.717, 95%CI: 1.311-5.633).

Figure 1 Kaplan-Meier analysis comparing disease-free survival between gastrin-positive and gastrin-negative gastric cancer patients. No statistically significant difference was observed (hazard ratio = 1.516; 95% confidence interval: 0.895-2.570; P > 0.05). HR: Hazard ratio; CI: Confidence interval; GAS: Gastrin.

Figure 2 Kaplan-Meier curve for overall survival Kaplan-Meier analysis comparing overall survival between gastrin-positive and gastrin-negative gastric cancer patients. Gastrin-positive patients showed significantly worse overall survival (hazard ratio = 2.717; 95% confidence interval: 1.311-5.633; P < 0.01). HR: Hazard ratio; CI: Confidence interval; GAS: Gastrin.

Logistic regression for gastrin positivity

PPI use was independently associated with elevated gastrin levels (Table 4). No statistically significant association between histologic type and tumor location.

Table 4 Logistic regression for gastrin positivity.

Predictor	Coefficient (β)	P value	95%CI (lower, upper)	Interpretation
PPI use (yes)	1.567	0.037	(0.095, 3.039)	PPI use significantly increases odds of high gastrin
Helicobacter pylori (positive)	–0.401	0.39	(-1.317, 0.514)	Not statistically significant
Tumor location (body)	0.291	0.562	(-0.694, 1.276)	Not significant
Tumor location (esophagogastric junction)	0.286	0.569	(-0.697, 1.268)	Not significant
TNM stage (III-IV)	–0.143	0.738	(-0.983, 0.696)	Not significant

TNM: Tumor-nodes-metastasis; CI: Confidence interval; PPI: Proton pump inhibitor.

Association between gastrin levels and H. pylori infection

Boxplot analysis suggested a trend toward higher serum gastrin levels in patients with H. pylori-positive status compared to H. pylori-negative individuals (Figure 3). However, statistical comparison using Welch’s t-test revealed no significant difference between the two groups (mean ± SD: 25.28 ± 6.02 pmol/L vs 24.51 ± 5.86 pmol/L, respectively; t = -1.15, P = 0.251).

Figure 3 Association between gastrin levels and Helicobacter pylori infection. H. pylori: Helicobacter pylori.

PPI/PCAB use and serum gastrin

Of the 226 gastric cancer patients, 72 (31.86%) had a history of regular PPI or PCAB use, including 65 (28.76%) who used these medications within the past month. Gastrin levels were significantly elevated in both the past and recent PPI use groups compared to patients with no history of use (F = 39.71, P < 0.0001). Multivariable logistic regression revealed that serum gastrin level remained independently associated with higher tumor grade (adjusted odds ratio = 1.015 per pmol/L increase, 95%CI: 1.002-1.027, P = 0.021) after adjusting for PPI/PCAB use. Neither past use (P = 0.708) nor recent use (P = 0.824) of PPI/PCABs showed a significant association with tumor grade.

Harms or unintended effects

No adverse events, harms, or unintended effects related to study procedures (including blood sampling, ¹⁴C-UBT, or follow-up assessments) were observed or reported in either the gastric cancer or control groups. While serum gastrin levels were elevated in patients with a history of PPI or PCAB use, this biochemical finding is expected and not classified as a harm. The use of PPI/PCAB medications was retrospectively assessed for its confounding effect on gastrin levels, and no patients experienced clinically significant side effects attributable to PPI/PCAB withdrawal during the 14-day washout period. Additionally, the diagnostic procedures (e.g., radioimmunoassay, UBT) were non-invasive or minimally invasive and conducted under standard clinical protocols. Therefore, the study was not associated with any direct physical or psychological harm to participants.

DISCUSSION

Gastric cancer, a relatively common tumor of the digestive system, is a significant public health threat. It is the fourth most common cancer and the third leading cause of cancer death worldwide[13]. Gastric cancer arises from malignant neoplastic transformation of epithelial cells in the gastric mucosa and is multifactorial in origin, including dietary factors, infections, and genetic predisposition. Despite advancements in therapeutic management, the disease continues to have an unsatisfactory five-year survival rate[14]. Given that H. pylori-associated carcinogenesis can persist after bacterial eradication, a more robust classification system, dividing patients into currently infected, previously infected (eradicated), and never infected, is methodologically superior. However, due to the lack of serologic testing and incomplete eradication histories, we were unable to stratify patients accordingly in this study. Our study assessed and compared gastrin and H. pylori levels in healthy persons and patients with gastric cancer. We found the gastrin levels were significantly elevated, with 60% of cases positive for gastrin, in addition to a significant amount of H. pylori infection, with a positivity rate of 76.55%. Several factors, including gastric acid, gastrin-releasing peptide, amino acids, and hormones during gastrin synthesis, translation, post-translational processing, sequestration, and secretion, modulate gastrin levels in blood. In addition, gastrin also influences the expression of genes that modulate gastric parietal cell function regulation and stimulates their self-secretion of peptides, such as transforming growth factors[15]. Previous research has demonstrated heterogeneous gastrin expression in precancerous lesions and high gastrin levels in gastric cancer. Therefore, gastrin has clinical relevance as a significant indicator for differentiating early gastric cancer and precancerous lesions[16]. While we instructed patients to stop either PPIs or PCABs at least 14 days before blood sample collection, we cannot completely disregard the potential residual pharmacologic effects on serum gastrin levels, which may have affected measurements of serum gastrin[17]. The prevalence of H. pylori infection varies geographically and across different populations. However, the overwhelming majority of studies report the prevalence of H. pylori infection in patients with gastric cancer between 60% and 80%, which supports our study’s findings[18]. A 15-year cohort study that followed the risk of gastric cancer in 2405 male patients infected with H. pylori demonstrated a 4.8-fold greater risk of morbidity than patients without H. pylori infection[19]. Further, the diagnostic utility of H. pylori for gastrin was investigated in a cohort of healthy individuals to determine whether the gastric cancer and precancerous states could be detected. H. pylori were detected in 84.82% of the individuals in this cohort. While infection rates were significantly lower in the healthy cohort than in precancerous lesions or gastric cancer patients, the serum gastrin in the gastric cancer participants showed a significant elevation compared to control groups and precancerous lesions. Gastrin levels progressively increased with disease[20]. Although long-term and recent PPI/PCAB use were associated with higher serum gastrin levels, these medications did not independently predict tumor grade. After adjusting for PPI/PCAB exposure, serum gastrin remained significantly associated with tumor aggressiveness, indicating that the observed relationship was not solely attributable to acid suppressant use. These findings strengthen the validity of gastrin as a potential biomarker in gastric cancer independent of acid suppression therapy. Future studies should continue to control for medication history and consider dose-duration effects.

A limitation of the study is the absence of stratification by prior H. pylori eradication status, which might also have caused heterogeneity in the test results and the interpretation of the associations. Additionally, it is essential to mention that while the UBT is an excellent diagnostic modality, it ultimately captures events of previously eradicated infections and does not differentiate between those who were never infected and those who were[21]. Therefore, perhaps our study could not optimally characterize H. pylori and its association with gastric cancer.

This study illuminated the complex relationship between gastrin levels and clinicopathological factors in gastric cancer, which may provide some insight into the mechanisms at play in gastric cancer and clinical implications. Gastrin-positive patients had a significantly higher incidence of lymph node metastasis, poorly differentiated tumors, and advanced TNM stages (III-IV), which may indicate a direct correlation between the pathological progression of the gastric cancer and higher gastrin release.

This highlights that the unique sample composition might impact generalizability and should be studied more[22]. Furthermore, prognostic evaluations were conducted to understand the impact of gastrin on gastric cancer outcomes, using the key endpoints of progression and mortality. Notably, a negative correlation was noted in the association of serum gastrin levels and cumulative OS, which suggests that elevated gastrin release led to worse prognosis for gastric cancer patients and is an independent prognostic indicator of poor outcomes.

These findings support and highlight the potential use of serum gastrin as a diagnostic marker but suggest its usefulness for risk stratification and treatment planning. It is plausible that clinicians should factor gastrin into their assessment with traditional pathological and imaging evaluations, consider gastrin measurements in the management strategy, and evaluate better personalized management plans. Future studies in gastrin-targeted therapies may offer opportunities in precision oncology, particularly in patients with aggressive tumor phenotypes with high gastrin profiles, but this is only hypothetical.

Mechanistic evidence based on in vitro modelled studies also provided insight into tumor-promoting effects with gastrin. The experimental data demonstrated that gastrin promoted Michael Fay’s[23] gastric cancer cell lines (AGS and MKN1) by stimulating cellular proliferation, encouraging migration, and anti-apoptotic modelling properties. For example, by activating the mixed-spectrum kinase 3/c-Jun protein amino-terminal kinase 1 pathway by binding to the cholecystokinin B receptor among other downstream pathways, there was an increase in the migratory capacity of AGSE, the human gastric cancer cell line[24]. Additionally, gastrins binding to the gastrin receptor on the AGS-P, another gastric cancer cell line, promoted a similar notable increase in intracellular calcium ions, resulting in increased cellular growth rates[25]. Furthermore, strong evidence from diverse studies indicated that genes related to the gastrin receptor, with upregulated expression, also significantly enhanced metastatic behaviors in gastric cancer cells, increasing the invasiveness in neighboring tissues and distant organs, and contributing to metastasis.

A key limitation of this study is the classification of H. pylori infection status based solely on the UBT. While UBT is highly sensitive and specific for detecting active infection, it does not identify past infections or successful eradication. Without combining serologic testing or detailed eradication history, potential misclassification bias cannot be excluded, and this may have affected the observed associations between H. pylori status and gastric cancer characteristics. The binary classification into H. pylori-positive and negative based solely on UBT does not differentiate between patients with prior eradicated infection and those never infected. The lack of serologic antibody data and eradication history limited our ability to classify subjects into the recommended three categories: Current, previous, and never infected. Future studies should adopt a multimodal diagnostic approach including UBT, anti-H. pylori immunoglobulin G, and detailed medical history to improve classification accuracy. Moreover. the findings of this study support the association between elevated serum gastrin levels and gastric cancer aggressiveness, as evidenced by higher rates of advanced TNM stage, lymph node metastasis, and poor differentiation in gastrin-positive patients. While these results suggest a potential role for gastrin in tumor progression, it is important to note that the therapeutic implications of targeting gastrin remain speculative due to the lack of clinical or in vivo validation. Current evidence is limited to in vitro studies demonstrating gastrin’s proliferative effects on gastric cancer cell lines, and further research is needed to determine whether gastrin inhibition would translate into meaningful clinical benefits without compromising physiological functions such as gastric acid secretion and mucosal repair. Therefore, while gastrin may serve as a prognostic biomarker, its viability as a therapeutic target requires additional investigation through preclinical and clinical studies.

CONCLUSION

To summarize, the comprehensive findings from this study underscore the significance of high serum gastrin concentrations in individuals with gastric cancer, illuminating their close association with tumor aggressiveness and dismal prognoses. Moreover, the mechanistic elucidation of gastrin’s tumor-promoting effects in gastric cancer cell lines provides valuable insights into the underlying biological processes governing disease progression. Collectively, these findings enhance our understanding of the intricate interplay between gastrin and gastric cancer, paving the way for potential therapeutic interventions and prognostic stratification in clinical practice.