Risk Factor For Gastric Cancer Research Articles

"True" Helicobacter pylori infection and non-cardia gastric cancer: A pooled analysis within the Stomach Cancer Pooling (StoP) Project.

Helicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status. A pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted. The OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology. The NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

The Association of Trefoil Factors with Gastric Cancer and Premalignant Lesions: A Cross-Sectional Population-Based Cohort Study.

A lack of research on the association of trefoil factors (TFF) with gastric cancer and premalignant lesions (PML) in the general population is an important obstacle to the application of TFFs for gastric cancer screening. We aimed to analyze the association of TFFs with gastric cancer and PMLs in a general population. We evaluated 3,986 adults residing in Wuwei, China. We collected baseline characteristics and gastric cancer risk factors, including TFFs, endoscopic diagnosis, and pathologic information. Three logistic regression models were generated to analyze the association between TFFs and gastric cancer, as well as PMLs. Adjusted odds ratio (OR) and 95% confidence intervals (95% CI) were calculated to determine the strength of association. Compared with pepsinogen (PG) and anti-Helicobacter pylori immunoglobulin G antibody (Hp-IgG), TFFs had significant association with gastric cancer and PMLs after adjusting for biomarkers and risk factors (P < 0.05). The ORs (95% CI) for TFF1 (1.67; 1.27-2.20), TFF2 (2.66; 2.01-3.51), and TFF3 (1.32; 1.00-1.74) were larger than the ORs for PGI (0.79; 0.61-1.03), PGI/II (1.00; 0.76-1.31), and Hp-IgG (0.99; 0.73-1.35) in the gastric cancer group. In the intestinal metaplasia (IM) group, not only the TFF3 serum level was the highest, but also the OR (1.92; 1.64-2.25) was the highest. TFFs were associated with risk of gastric cancer and PMLs. Serum TFFs can improve the screening of high-risk populations for gastric cancer.

Helicobacter pylori–induced RASAL2 Through Activation of Nuclear Factor-κB Promotes Gastric Tumorigenesis via β-catenin Signaling Axis

Helicobacter pylori infection is the predominant risk factor for gastric cancer. RAS protein activator like 2 (RASAL2) is considered a double-edged sword in carcinogenesis. Herein, we investigated the role of RASAL2 in response to H pylori infection and gastric tumorigenesis. Bioinformatics analyses of local and public databases were applied to analyze RASAL2 expression, signaling pathways, and clinical significance. Invitro cell culture, spheroids, patient-derived organoids, and invivo mouse models wereused. Molecular assays included chromatin immunoprecipitation, co-immunoprecipitation, Western blotting, quantitative polymerase chain reaction, and immunocyto/histochemistry. H pylori infection induced RASAL2expression via a nuclear factor-κB (NF-κB)-dependent mechanism whereby NF-κB was directly bound to the RASAL2 promoter activating its transcription. By gene silencing and ectopic overexpression, we found that RASAL2 upregulated β-catenin transcriptional activity. RASAL2 inhibited protein phosphatase 2A activity through direct binding with subsequent activation of the AKT/β-catenin signaling axis. Functionally, RASAL2 silencing decreased nuclear β-catenin levels and impaired tumor spheroids and organoids formation. Furthermore, the depletion of RASAL2 impaired tumor growth in gastric tumor xenograft mouse models. Clinicopathological analysis indicated that abnormal overexpression of RASAL2 correlated with poor prognosis and chemoresistance in human gastric tumors. These studies uncovered a novel signaling axis of NF-κB/RASAL2/β-catenin, providing a novellink between infection, inflammation and gastric tumorigenesis.

AGT May Serve as a Prognostic Biomarker and Correlated with Immune Infiltration in Gastric Cancer.

PurposeAngiotensinogen (AGT), as a component of the renin–angiotensin system (RAS), is associated with multiple risk factors for gastric cancer (GC). However, the relationship between AGT and tumor-infiltrating lymphocytes in GC remains elusive.MethodsAGT expression was analyzed based on the Cancer Genome Atlas (TCGA) dataset. Kaplan–Meier curve was employed to assess the role of AGT expression in gastric patients’ prognosis. The association between AGT expression and tumor immune infiltration was further evaluated via exploring Tumour Immune Estimation Resource (TIMER) and The Gene Expression Profiling Interactive Analysis (GEPIA). We also used multiple public databases to analyse the aberrant methylation of AGT, construct protein–protein interaction (PPI) and gene ontology (GO) analyses.ResultsAGT was overexpressed in GC tissues compared with normal gastric tissues (P<0.05). High AGT expression related with poorer overall survival of patients with GC, especially in advanced GC patients. Immune infiltration analysis revealed that AGT was associated with several immune cells (including B cells, CD4+ T cells, macrophages), and AGT expression was also associated with the markers of NK cells, TAMs, Tregs, and so on (all P<0.05). Methylation analysis indicated that hypomethylation may lead to abnormal upregulation of the AGT. GO analysis showed that AGT and its related genes were enriched in systemic arterial blood pressure by hormone, regulation of blood volume by renin-angiotensin, NIK/NF-kappaB signaling, ficolin-1-rich granule and so on.ConclusionAGT could act as a promising biomarker for prognosis and immune infiltration in GC.

Are Proton Pump Inhibitors a Risk Factor for Gastric Cancer?

Are Proton Pump Inhibitors a Risk Factor for Gastric Cancer?

Detection of secondary upper gastrointestinal tract cancer during follow-up esophagogastroduodenoscopy after gastrectomy for gastric cancer.

AimEsophagogastroduodenoscopy (EGD) may contribute to early detection of secondary cancer in the upper gastrointestinal tract although the clinical relevance of follow‐up after gastrectomy remains unclear. This study aimed to elucidate the effectiveness of follow‐up EGD by investigating the incidence of secondary cancer in any part of the upper gastrointestinal tract.MethodsData from 1438 patients who underwent curative partial gastrectomy for primary gastric cancer between 2008 and 2014 and follow‐up EGD at least once during a 5‐year follow‐up period were retrospectively reviewed. Incidence rates of remnant gastric cancer, laryngeal cancer, and esophageal cancer detected after follow‐up EGD were determined, and risk factors for secondary cancers were examined. The characteristics of clinicopathological diagnoses of secondary cancers were reviewed and compared according to the frequency of follow‐up EGD.ResultsThe average annual frequency of EGD was 0.7, while the 5‐year cumulative incidence rates of remnant gastric cancer and secondary laryngeal and esophageal cancers were 2.9% and 1.3%, respectively. Risk factors for remnant gastric cancer included heavy smoking, proximal gastrectomy, and tumor size ≥ 30 mm. All secondary cancers were resectable upon diagnosis, with endoscopically resectable cancer accounting for 81.0% of cases. Our results found a significantly higher proportion of endoscopically resectable cancers during regular follow‐up than during infrequent follow‐up.ConclusionsFollow‐up EGD can be a useful modality for detecting secondary upper gastrointestinal tract cancer, likely leading to curative treatment for secondary cancer. Focusing on patients presenting with risk factors may increase the value of follow‐up EGD after gastrectomy.

Risk factors for gastric cancer in Japan in the 2010s: a large, long-term observational study.

The numbers of Helicobacter pylori (HP)-infected individuals and deaths due to gastric cancer are decreasing in Japan. We aimed to determine whether the serological test for chronic gastritis (the ABC method) is still useful for gastric cancer risk stratification in the 2010s and to analyze risk factors for developing gastric cancer in Japan. In this prospective study, we monitored 20773 individuals for the incidence of gastric cancer from 2010 to 2019. The relationships between blood sampling results, physical examination, and lifestyle in 2010 and the cumulative incidence of gastric cancer were analyzed. A total of 19343 participants who met the study criteria were analyzed. Overall, 0.08% of participants in group A (9/11717), 0.63% in group B (28/4452), 2.05% in group C (43/2098), 1.52% in group D (1/66), and 0.30% in group E (3/1010) developed gastric cancer. Cox hazard analysis showed that age ≥ 50years; groups B, C, and D according to the ABC method; and current smoking habits were independent risk factors for gastric cancer. The hazard ratios (HRs) of the incidence of gastric cancer were 6.7 in group B and 21.7 in groups C and D, while the HRs of group E was 2.8, which was not significantly different from that of group A. The incidence of gastric cancer was not statistically significantly different between those with and without successful HP eradication in groups B, C, and D during follow-up. The ABC method was still useful for gastric cancer risk stratification in the 2010s.

Overview of epidemiological characteristics, clinical features, and risk factors of gastric cancer in Asia-Pacific region.

In spite of decreasing the overall incidence of gastric cancer (GC), it remains one of the most common and deadly cancers worldwide. The incidence and mortality rate of GC is very different in the world. Geographical differentiation is one of the most distinctive characteristics of GC. Effective prevention and early diagnostic strategies are the most important public health interventions in GC, as a common malignancy worldwide. Notably, the preventive strategies require understanding the risk factors associated with GC for identifying high-risk groups that may require screening for prevention. Therefore, up-to-date statistics on GC occurrence and outcome are essential for the primary prevention of the disease. We conducted this review based on the current epidemiology knowledge of GC to provide an update perspective of GC in Asia-Pacific region. Based on the findings of this study, incidence and mortality rate of GC in Asia-Pacific region shows a great heterogeneity. Gastric carcinogenesis arises as a consequence of a complex interaction between host and environmental factors. In addition to screening and eradication of Helicobacter pylori (H. pylori) infection, it seems that the main cause of GC is an undesirable lifestyle in this region. Therefore, it is necessary to improve the lifestyle and the community awareness about GC risk factors and healthy lifestyle education.

Advanced gastric cancer detected during regular follow-up after eradication of Helicobacter pylori.

Helicobacter pylori (H. pylori) is an important risk factor for gastric cancer and is a recognized carcinogen. Although eradication of H. pylori reduces the incidence of gastric cancer, cases can still occur after eradication therapy. A number of such cases have been reported, and their early clinicopathological characteristics are becoming clearer. Some reports mention that endoscopic diagnosis of gastric cancer may be difficult after eradication therapy, because the cancer is covered by non-cancerous epithelium. However, there are few reports on advanced gastric cancer after eradication therapy, and its characteristics remain poorly understood. In view of the predicted increase in frequency of advanced gastric cancer after eradication therapy in the near future, it is important to be aware of these cases. In this report, we describe three cases of advanced gastric cancer detected during routine follow-up after eradication.

Prevalence estimates of Helicobacter species infection in pancreatic and biliary tract cancers.

Background Helicobacter pylori infection is a well‐established risk factor for gastric cancer and has been linked to other gastrointestinal diseases, including pancreatic and biliary tract cancers; however, the relevance of enterohepatic non‐H. pylori helicobacters to the pathophysiology of these diseases remains unclear.Materials and MethodsWe estimated the prevalence of two enterohepatic non‐H. pylori helicobacters (Helicobacter hepaticus and Helicobacter bilis) in the framework of a hospital‐based case‐control study involving 121 patients with biliary tract cancer, pancreatic cancer, or other gastrointestinal diseases. Bile and blood samples were collected from the patients undergoing endoscopic retrograde cholangiopancreatography. The presence of H. bilis, H. hepaticus, and other Helicobacter spp. was examined using bacterial culture, PCR‐based detection, and serological tests.ResultsCulture of Helicobacter spp. from biliary brush samples was unsuccessful. Approximately 13.0% (15/115) of the bile samples collected from patients with a variety of gastrointestinal cancers, including pancreatic and biliary tract cancers, tested positive for one of the enterohepatic non‐H. pylori helicobacter species as determined by PCR. Specifically, H. bilis and H. hepaticus DNA were detected in 11 and 4 bile samples, respectively. Approximately 20%–40% of the patients tested positive for serum non‐H. pylori helicobacter IgG antibodies. The seroprevalence of H. bilis and H. hepaticus in the patients without evidence of H. pylori infection appeared to be higher in the pancreatic cancer group than in the control group.ConclusionOur findings suggest a role for Helicobacter spp., especially H. bilis and H. hepaticus, in the etiology of pancreatic and biliary tract cancers.

Racial Differences in Helicobacter pylori Prevalence in the US: A Systematic Review.

Helicobacter pylori remains an important risk factor for noncardia gastric cancer and a spectrum of disease from H. pylori infection to gastric cancer. As a step toward improved clinical strategies for gastric cancer prevention, we assessed racial differences in prevalence of H. pylori from studies across the United States. This systematic review provides a comprehensive evaluation of the literature regarding racial differences in H. pylori in the United States. MEDLINE, Embase, and Web of Science database searches were performed through May 26, 2021. Ultimately, 25 studies that reported H. pylori infection prevalence by race were included. All studies included in the review documented higher H. pylori prevalence in Blacks and Hispanics than in whites. The ratio of H. pylori prevalence for Blacks compared to non-Hispanic whites ranged from 1.3 to 5.4, and the ratio for Hispanics compared to non-Hispanic whites ranged from 1.8 to 4.4. Of the 5 studies that examined H. pylori CagA prevalence by race, 4 found higher prevalence among Blacks and Hispanics compared to whites, with CagA prevalence ranging from 19% to 77% in whites, 62% to 90% in Blacks, and 64% to 74% in Hispanics. In this review, across 25 studies, varying in underlying population, time period, and geographic location, Blacks and Hispanics appeared to have a higher prevalence of H. pylori infection than whites. This increased prevalence of H. pylori among populations also at a higher risk of gastric cancer is relevant in the clinical setting for decision-making related to H. pylori testing and gastric cancer prevention.

Comparison of the gastric biopsy results of Afghan refugees and Turkish people

Helicobacter pylori- (H. pylori) infection is one of the effective factors in the development of gastric premalignant lesions, and it is known that socioeconomic conditions are closely related to H. pylori infection. Our aim was to show whether there were differences regarding H. pylori infection and gastric histopathological findings between humans who had to manage an exhausting escape out of their own country and residents of a coastal town in the black sea region of Turkey. Endoscopic findings of Turkish and Afghan patients who underwent gastroscopy for various reasons, gastric biopsies, and their histopathological results (H. pylori, intestinal metaplasia, and gastric atrophy) and some biochemical parameters were retrospectively screened from the hospital online data system. A total of 222 patients, 41 Afghan and 181 Turkish, were included in the study. There were no significant differences regarding age and gender of the patients between the groups. The percentage of the patients with intestinal metaplasia and H. pylori infection was higher in the group of the Afghan patients than in Turkish patients. Afghan refugees had similar rates of atrophic gastritis (23.1% versus 21.5%; p=0.834), when compared to resident controls. Risk factors of gastric cancer include the presence of H. pylori infection, atrophic gastritis, and intestinal metaplasia. This study supports the knowledge that socioeconomic factors such as low economic conditions and poor health infrastructure are one of the major causes of widespread global H. pylori infection status.

Metabolic Syndrome as a Risk Factor for Gastric Cancer by Gender.

The article's abstract is not available.

Identifying the Profile of Helicobacter pylori-Negative Gastric Cancers: A Case-Only Analysis within the Stomach Cancer Pooling (StoP) Project.

The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1,325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.

Risk factors for cancer-specific survival in elderly gastric cancer patients after curative gastrectomy.

BACKGROUND/OBJECTIVESThis study aimed to investigate cancer-specific survival (CSS) and associated risk factors in elderly gastric cancer (EGC) patients.SUBJECTS/METHODSEGC patients (≥ 70 yrs) who underwent curative gastrectomy between January 2013 and December 2017 at our hospital were included. Clinicopathologic characteristics and survival data were collected. Receiver operating characteristic (ROC) analysis was used to extract the best cutoff point for body mass index (BMI). A Cox proportional hazards model was used to determine the risk factors for CSS.RESULTSIn total, 290 EGC patients were included, with a median age of 74.7 yrs. The median follow-up time was 31 (1–77) mon. The postoperative 1-yr, 3-yr and 5-yr CSS rates were 93.7%, 75.9% and 65.1%, respectively. Univariate analysis revealed risk factors for CSS, including age (hazard ratio [HR] = 1.08; 95% confidence interval [CI], 1.01–1.15), intensive care unit (ICU) admission (HR = 1.73; 95% CI, 1.08–2.79), nutritional risk screening (NRS 2002) score ≥ 5 (HR = 2.33; 95% CI, 1.49–3.75), and preoperative prognostic nutrition index score < 45 (HR = 2.06; 95% CI, 1.27–3.33). The ROC curve showed that the best BMI cutoff value was 20.6 kg/m2. Multivariate analysis indicated that a BMI ≤ 20.6 kg/m2 (HR = 2.30; 95% CI, 1.36–3.87), ICU admission (HR = 1.97; 95% CI, 1.17–3.30) and TNM stage (stage II: HR = 5.56; 95% CI, 1.59–19.43; stage III: HR = 16.20; 95% CI, 4.99–52.59) were significantly associated with CSS.CONCLUSIONSLow BMI (≤ 20.6 kg/m2), ICU admission and advanced pathological TNM stages (II and III) are independent risk factors for CSS in EGC patients after curative gastrectomy. Nutrition support, better perioperative management and early diagnosis would be helpful for better survival.

Helicobacter Pylori infection among Iranian patients with normal upper gastrointestinal endoscopy.

Background: Helicobacter pylori infection can be a risk factor for non-cardia gastric cancer. In the present study, we aimed to assess the rate of Helicobacter pylori infection, its virulence factor and precancerous lesion among over 50 years old, dyspeptic patients with normal endoscopy.Methods:A total of 620 patients over 50 years of age with dyspepsia that referred to Shahid Sadoughi Hospital, Yazd, Iran from December 2018 to January 2019 were evaluated. One hundred fifty patients with normal appearance endoscopy were selected, and six gastric biopsy specimens were taken from each subject. Data were analyzed using chi-square and logistic regression tests.Results:A total of 150 patients with mean age of 65.8±11.9 years old participated in this study. Sixty-three (42%) patients were males. Thirty-four (22.6%) patients had precancerous lesions. Ninety (60%) patients had positive PCR results for H. pylori. H. pylori infection test was positive in 24 (70.6%) patients with precancerous lesion. Sixty-six (57%) patients without the precancerous lesions (116 cases) were positive for H. pylori.Conclusion:There was no a significant difference in the rate of H. pylori infection and its genotype distribution was between patients with and without the precancerous lesions.

Knowledge of Gastric Cancer Risk Factors, Warning Symptoms, and Screening Among the General Population in Makkah, Saudi Arabia

Knowledge of Gastric Cancer Risk Factors, Warning Symptoms, and Screening Among the General Population in Makkah, Saudi Arabia

Associations Between Autoimmune Conditions and Gastric Cancer Risk Among Elderly Adults in the United States.

Pernicious anemia (PA) is a risk factor for gastric cancer. Other autoimmune conditions may also contribute. In a case-control study, we evaluated 47 autoimmune conditions among 39,125 gastric cancers and 200,000 cancer-free controls. Six conditions were associated with increased gastric cancer risk (range of adjusted odds ratios: 1.28-1.93, P < 0.05): PA, membranous nephropathy, primary biliary cirrhosis, pure red cell aplasia, primary sclerosing cholangitis, and Graves disease. PA was associated with 8 other autoimmune conditions (adjusted odds ratios: 1.57-4.54, P < 0.05). Autoimmune conditions associated with gastric cancer or PA may reflect effects of autoimmune gastritis or other carcinogenic pathways.

Long non-coding RNA CERS6-AS1 plays a prognostic role in promoting the progression of gastric cancer

ABSTRACT This study aims to investigate the potential clinical function of long non-coding RNA CERS6-AS1 (lncRNA CERS6-AS1) integrated miR-567 in gastric cancer. The expression of CERS6-AS1 in gastric cancer tissues was detected through RT-qPCR in contrast to the normal tissues. The correlation between the expression of lncRNA CERS6-AS1 and the characteristics of clinical data was analyzed. Kaplan-Meier curve was used to assess the survival analysis, while Cox proportional hazards model multivariate analysis was performed to evaluate the prognostic risk factors of gastric cancer to verify the prognostic possibility of CERS6-AS1. The expression of CERS6-AS1 in different gastric cancer cells was detected, being the development of gastric cancer cells after knockdown CERS6-AS1 studied using CCK-8, Transwell migration, and invasion detection methods. The targeting effect and interaction between CERS6-AS1 and miR-567 through biological analysis and luciferase activity detection. The expression of lncRNA CERS6-AS1 was elevated in gastric cancer tissues and cells. The results of this study demonstrate that the condition of gastric cancer patients was related to the expression of CERS6-AS1, and therefore CERS6-AS1 might be a prognostic factor for the progression of gastric cancer. In addition, the ability of gastric cancer cells to proliferate, migrate and invade could be reduced by knockdown CERS6-AS1. After CERS6-AS1 knockdown, the expression level of miR-567 in gastric cancer tissues decreased, while the expression level of miR-567 increased. In conclusion, lncRNA CERS6-AS1 might promote the progression of gastric cancer and had the potential as a prognostic marker of gastric cancer.

Nicotine stimulates IL-8 expression via ROS/NF-κB and ROS/MAPK/AP-1 axis in human gastric cancer cells

Nicotine, a major alkaloid found in tobacco, is a significant risk factor for gastric cancer. IL-8, a pleiotropic cytokine, plays a vital role in cancer cell metastasis. The role of nicotine in IL-8 expression and the underlying mechanism is currently unknown. Here, we examined the effects of nicotine on IL-8 expression and explored the potential mechanisms in gastric cancer cells. We found that nicotine increases IL-8 expression. Specific inhibitor and mutagenesis studies showed that ROS and MAPK (Erk1/2, p38) were involved in this process. Deletion and site-directed mutagenesis studies indicate the involvement of transcription factor NF-κB and AP-1. ROS and ROS/MAPK (Erk1/2, p38) functioned as the upstream signaling molecules in the activation of NF-κB and AP-1, respectively. AGS gastric cancer cells pretreated with nicotine stimulate angiogenesis in the tumor microenvironment, partially abrogated by silencing IL-8 in AGS cells. In this study, we found that nicotine induces IL-8 expression via ROS/NF-κB and ROS/MAPK (Erk1/2, p38)/AP-1 axis in gastric cancer cells, thus stimulating endothelial cell proliferation and angiogenesis in the tumor microenvironment.