Abstract 3847: APE1 mediates angiogenesis by stabilizing SMAD3 and blocking its ubiquitin induced degradation in esophageal adenocarcinoma

The incidence of oesophageal adenocarcinoma has increased markedly over the past three decades, particularly in the Western world.1 2 The cancer is considered to be a long-term complication of chronic...

The incidence rates of gastric and oesophageal adenocarcinoma are changing significantly, but little is known about specific sub-sites. To use a population-based approach to describe the trends in the site-specific incidence of oesophageal and gastric adenocarcinoma. Using the Rochester Epidemiology Project, all cases of gastric and oesophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified (n = 186). Complete in-patient and out-patient records were reviewed and site determined from pathological, surgical, endoscopic and radiological reports. Between the decades of 1971-1980 and 1991-2000, the incidence of oesophageal adenocarcinoma increased significantly from 0.4 to 2.5 per 100 000 person-years. The incidence of adenocarcinoma of the oesophagogastric junction also increased from a rate of 0.6 to 2.2 per 100 000 person-years. The incidence rate of cancer involving the gastric cardia was stable but the incidence of adenocarcinoma involving distal gastric sites declined. Combined oesophageal and oesophagogastric junction adenocarcinoma (4.7 per 1 000 000 person-years) was as common as gastric adenocarcinoma (3.4 per 100 000 person-years) in 1991-2000. The incidence rates of adenocarcinoma involving proximal gastric sub-sites do not appear to be increasing in a manner similar to those involving oesophageal sub-sites.

Background: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades and continues to rise in the Western world. The 5-year survival rate for EAC patients is less than 20% which underscores the need to better understand the underlying mechanisms to identify new therapeutic approaches. This study aimed at investigating the potential role of APE1 in regulating SMAD3 and promoting EAC progression. Methods and Results: Western blot data showed that APE1 and SMAD3 were highly expressed in EAC cell lines. APE1 silencing reduced SMAD3 nuclear expression and downregulated its downstream targets SERPINE1 and c-myc. These results were confirmed by immunofluorescence staining showing loss of nuclear accumulation of SMAD3 after APE1 knockdown. Mechanistically, immunoprecipitation and proximity ligation assays revealed a direct binding between APE1 and SMAD3 in the nucleus. Further investigation showed that APE1 binds to the C-terminal MH2 domain of SMAD3, and this binding protects SMAD3 from ubiquitin mediated proteasomal degradation by blocking its interaction with the RING finger protein, ROC1. Interestingly, APE1-redox-specific inhibition (APX2009) downregulated SMAD3 expression and the APE1 redox-deficient mutant (C65A) disrupted APE1-SMAD3 binding indicating that this regulation depends on APE1 redox activity. Conclusion: Our findings establish a role of APE1 in regulating SMAD3 in EAC. These findings provide a potential therapeutic approach for the treatment of EAC by the pharmacological inhibition of APE1. Citation Format: Farah Ballout, Heng Lu, Dunfa Peng, Wael El-Rifai. APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3964.

To evaluate the diagnostic accuracy of esophageal and cardia adenocarcinoma in the Swedish Cancer Register. Based on cancer registers, a rising incidence of esophageal and cardia adenocarcinoma has been reported in several populations, but possible influence of differences in tumor classification has not been evaluated. In a nationwide study in 1995 through 1997, all Swedish patients, born in Sweden and younger than 80 years with esophageal or cardia adenocarcinoma and half of all patients with esophageal squamous cell carcinoma, were prospectively, uniformly, and thoroughly classified. This study classification was compared with the tumor classification in the Swedish Cancer Register, which is based on routine clinical practice. The overall completeness of the Cancer Register was high (98.3%), whereas the site-specific completeness of the Register was 63% for esophageal adenocarcinoma, 74% for cardia adenocarcinoma, and 91% for esophageal squamous cell carcinoma. The incidence of esophageal adenocarcinomas was 16% higher in the study classification compared with that of the Register during the study period, whereas the incidence of cardia adenocarcinoma was 2% lower in the study classification. There is a diagnostic mismatch between esophageal and cardia adenocarcinoma in the clinical setting and, therefore, also in Cancer Registers. In etiologic and therapeutic research, this problem needs consideration, since these tumors have distinct risk factor profiles and could be subjected to different treatment strategies. The increasing incidence rate of esophageal adenocarcinoma in Sweden is unlikely to be explained by such differences in tumor classification, however.

The incidence of oesophageal adenocarcinoma has increased over 500% in some countries during the last three decades, but the reasons for this rise are unclear.1 The most intractable problem to...

To study the feasibility of chemoprevention of esophageal adenocarcinoma by celecoxib, a selective cyclooxygenase-2(COX-2) inhibitor using a rat model. Rats were divided into 3 groups: model group, celecoxib group, and control group. The rat surgical model was established by performing a gastrojejunostomy plus an esophagojejunostomy 5 mm distal to the gastrojejunal anastomosis. Twenty-eight weeks after surgery, all the animals were sacrificed and the pathological changes in the esophagus were examined macroscopically. COX-2 expression was analyzed by immunohistochemistry. Prostaglandin E2(PGE2) level was measured by enzyme-linked immunosorbent assay(ELISA). The incidence of Barrett's esophagus and esophageal adenocarcinoma in the model group was 84% and 57% respectively, significantly higher than those in the control group(P<0.01). The incidence of esophageal adenocarcinoma in the celecoxib-treated group was significantly lower than that in the model group(P<0.01), and no esophageal adenocarcinoma was detected in the control group. COX-2 expression was detected in 100% of reflux esophagitis, Barrett esophagus and esophageal adenocarcinoma, but not found in the normal tissue from the esophagus and the jejunum(P<0.01). The PGE2 level in the esophageal tissue in the model group was significantly higher than that in the control group(P<0.01). Rats in the celecoxib-treated group had significantly lower PGE2 level than that in the model group(P<0.01). The PGE2 levels were significantly higher in rats with cancer than those without cancer(P<0.01). Celecoxib successfully prevents the development of esophageal adenocarcinoma in a rat surgical model with mixed reflux of acid and duodenal juice and significantly decreases the risk of Barrett esophagus developing esophageal adenocarcinoma. COX-2 maybe an effective selective target of chemoprevention for esophageal adenocarcinoma.

Esophageal cancer (EC) consists of two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), each with distinct epidemiological patterns. Historically, ESCC has been the dominant subtype worldwide, especially in Asian countries. However, in recent decades, the incidence of EAC has been rising rapidly, particularly in European and American countries, reflecting significant shifts in global EC epidemiology. This study presents a comprehensive analysis of 25 years of high-quality continuous data on ESCC and EAC incidence trends across 25 countries. It highlights declining ESCC rates in most regions, rising EAC rates in Western nations, pronounced sex differences, and narrowing ESCC-to-EAC ratios. These diverse trends reveal the need to investigate region-specific risk factors and their contributions to the shifting burden of EC globally. The distinct trends of ESCC and EAC call for tailored public health strategies based on regional and histological patterns. Countries experiencing a rising burden of EAC or ESCC can implement targeted risk factor prevention and control measures to address the increasing trends. In clinical practice, a stronger focus on EAC in high-income countries and ESCC in regions, where it remains dominant, can improve early detection and treatment outcomes. Understanding these evolving patterns will aid in designing evidence-based interventions and optimizing resource allocation to reduce the global esophageal cancer burden effectively.

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana(®) immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.

Low Incidence of Esophageal Adenocarcinoma After Eradication of Helicobacter pylori in Japan

Screening and surveillance for Barrett esophagus.

To investigate the relationship between Helicobacter pylori infection and Barrett's esophagus (BE), a rat model of chronic gastroesophageal reflux with H. pylori infection was established and the degree of inflammation, incidence of BE and esophageal adenocarcinoma (EA) were evaluated. Eight-week-old male specific-pathogen-free SD rats were divided into five groups randomly: pseudo-operation group; esophagojejunum anastomosis (EJA) group; EJA with H. pylori infection group; EJA with H. pylori infection and celecoxib-treated group; EJA with celecoxib-treated group. Rats were kept for 30 weeks after surgery. Esophageal lesion was evaluated grossly and microscopically. The expression of COX-2 and CDX2 was determined by RT-PCR and immunohistochemistry staining. The level of PGE₂ was assessed by enzyme-linked immunosorbent assay. Esophageal mucosal injury in the group of EJA with H. pylori infection was decreased than that in EJA group (p < .05). The incidence of BE and EA in rats undergoing EJA with H. pylori infection was increased than in rats undergoing EJA with no statistical difference. Celecoxib treatment decreased the incidence of EA in rats undergoing EJA with H. pylori infection (p < .05). The expression of CDX2 mRNA was decreased in rats with H. pylori infection or treated with celecoxib than in the rats of pseudo-operation group (p < .05). When compared with those in rats of pseudo-operation group, the expression of COX-2 mRNA and the level of PGE₂ were upregulated in rats undergoing EJA irrespective of H. pylori infection (p < .05) and downregulated in rats treated with celecoxib (p < .05). When H. pylori colonized in esophagus, the severity of inflammation and the incidence of BE and EA were increased significantly. Higher levels of COX-2 expression and PGE₂ were detected in rats with esophageal H. pylori colonization. When H. pylori infect in stomach, it may reduce the severity of inflammation. However, when colonizes in esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA. Celecoxib administration attenuates the incidence of EA by inhibiting COX-2 expression.

Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis

A steep increase in the incidence of esophageal adenocarcinoma has been observed between 1973 and 2001, but recent trends have not been reported. Our aim was to examine recent trends in esophageal adenocarcinoma incidence. We used the Surveillance Epidemiology and End Results database of the National Cancer Institute to identify all patients who were diagnosed with esophageal adenocarcinoma between 1973 and 2006. Incidence trends were analyzed for esophageal adenocarcinoma overall and by stage using joinpoint regression. Overall esophageal adenocarcinoma incidence increased from 3.6 per million in 1973 to 25.6 per million in 2006. Incidence trend analysis, however, suggests that the increase has slowed, from an 8.2% annual increase prior to 1996 to 1.3% increase in subsequent years (P = 0.03). Stage-specific trend analyses suggest that the change in overall esophageal adenocarcinoma incidence largely reflects a plateau in the incidence of early stage disease. Its slope has changed direction, from a 10% annual increase prior to 1999 to a 1.6% decline in subsequent years (P = 0.01). The incidence of early stage esophageal adenocarcinoma seems to have plateaued. Although definitive conclusions will require additional years of data, the plateau in early stage disease might portend stabilization in the overall incidence of esophageal adenocarcinoma.

Introduction: Over the past thirty years, esophageal cancer (EC) incidence has been increasing more rapidly than any other solid neoplasm in the Western world. Globally, there is a large male predominance in both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The reasons for this gender difference and the possible role of estrogen remains unclear. We conducted an analytical epidemiological study to determine if estrogen exposure explains the male predominance in observed esophageal cancer incidence. Materials/Methods: We evaluated the Surveillance Epidemiology and End Results (SEER) cancer incidence trends from 1975 to 2008 using SEER Stat to calculate the annual percentage change (APC) in each five year age group and in EAC and ESCC by gender. Results: Male predominance in incidence rates of EC was most evident in the younger population and those with EAC histology as previously demonstrated. EAC and ESCC incidence rates both increases with aging, consistent with cancer being an age-related disease, but the male: female incidence ratio of EAC significantly decreased with aging. The rate of increase for EAC incidence in post menopausal females is greater than in any other demographic category. This increasing incidence rate in the post menopausal female was also observed in the ESCC, but to a lesser extent. The APC was negative (-1.5) between 1975-2008 only in the 50-64 age female cohort. Interestingly, the APC doubled in the last two age groupings of older females (age 65-74 = + 0.3 and age 75 and greater = + 0.7). APC rates for the males increased gradually in all their age groups (age 50-64 = +1.2, age 65-74 = +1.4, age 75+ = +1.9). Conclusions: The males’ incidence of EAC increases at a steep rate with aging and females’ incidence rates are not as steep except after age 60-64 where their incidence rate of change steeply increases. The steeper change in EAC incidence rates in the post menopausal female may explain why the male: female EAC incidence ratio decreases with age as seen nationally (SEER). The negative APC in the female 50-64 years age group may be explained by their peri-menopausal state and by the increased use of post-menopausal hormonal therapy since 1975 for this age group. Using age as a proxy for estrogen exposure, our findings suggest a hormonal component for the observed age-related, declining male to female EAC incidence rate ratios. It also confirms gender differences in incidence long observed in EC and suggests that the pre-menopausal estrogen milieu in females may serve as a protective factor against EAC. Moreover, this protective state dissipates with time in the post menopausal females where the effect of estrogen exposure dissipates. Implications: Our initial epidemiological observation of gender-age differences warrants translation into a molecular epidemiology study with the use of sophisticated biomarkers to establish the seemingly protective role of estrogen exposure in esophageal adenocarcinoma. Citation Format: Luckson N. Mathieu, Norma Kanarek, Craig Hooker, Malcolm Brock. Gender disparity in esophageal cancer incidence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2013-4802

The Effect of Obesity on Esophageal Adenocarcinoma