The Toronto Upper Gastrointestinal Cleaning Score: a prospective validation study.

BACKGROUND : Assessment of mucosal visualization during esophagogastroduodenoscopy (EGD) can be improved with a standardized scoring system. To address this need, we created the Toronto Upper Gastrointestinal Cleaning Score (TUGCS). METHODS : We developed the TUGCS using Delphi methodology, whereby an international group of endoscopy experts iteratively rated their agreement with proposed TUGCS items and anchors on a 5-point Likert scale. After each Delphi round, we analyzed responses and refined the TUGCS using an 80 % agreement threshold for consensus. We used the intraclass correlation coefficient (ICC) to assess inter-rater and test-retest reliability. We assessed internal consistency with Cronbach's alpha and item-total and inter-item correlations with Pearson's correlation coefficient. We compared TUGCS ratings with an independent endoscopist's global rating of mucosal visualization using Spearman's ρ. RESULTS : We achieved consensus with 14 invited participants after three Delphi rounds. Inter-rater reliability was high at 0.79 (95 %CI 0.64-0.88). Test-retest reliability was excellent at 0.83 (95 %CI 0.77-0.87). Cronbach's α was 0.81, item-total correlation range was 0.52-0.70, and inter-item correlation range was 0.38-0.74. There was a positive correlation between TUGCS ratings and a global rating of visualization (r = 0.41, P = 0.002). TUGCS ratings for EGDs with global ratings of excellent were significantly higher than those for EGDs with global ratings of fair (P = 0.01). CONCLUSION : The TUGCS had strong evidence of validity in the clinical setting. The international group of assessors, broad variety of EGD indications, and minimal assessor training improves the potential for dissemination.

Racial and Gender Disparities Among Obese Patients With Pancreatic Cancer: A Trend Analysis in the United States.

BACKGROUND: Pancreatic cancer (PC) is the third leading cause of cancer death. Obesity can increase the risk of PC by up to 50%. Studies have shown racial and gender disparities in PC, however, there is a paucity of such information in obese PC patients. AIM: The aim of this study was to: (1) evaluate the incidence and prevalence of obesity among PC patients in the United States over the last 15 years, and (2) determine if variation exists in the demographic of obese PC patients over the last 15 years. It is hoped that this information could be used to assist in primary prevention and early detection of PC. METHODS: A population-based retrospective analysis in IBM Explorys, a pooled, national, deidentified database of 63 million patients from 300 hospitals in the United States. Patient populations were identified using SNOMED and ICD codes. Cochrane-Armitage testing was performed to analyze trends in obesity among PC. Subgroup analysis for gender, age, race, and mortality rate were assessed. RESULTS: The percentage of obese patients with PC increased over the 15-year period (2.5% to 8.5%, P <0.0001). Rates of obesity among PC patients increased among females ( P =0.0004), individuals under age 65 years ( P =0.0002), and all races, but especially for African Americans ( P =0.0007) and those in minority groups. CONCLUSION: Awareness of disparities in PC and applying targeted care to those at increased risk are essential to improve future outcomes, including increased health care access and recruitment in research studies for minority groups.

COVID-19 and Canadian Gastroenterology Trainees.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted endoscopy services and education worldwide. This study aimed to characterize the impact of COVID-19 on gastroenterology trainees in Canada. METHODS: An analysis of Canadian respondents from the international EndoTrain survey, open from April 11 to May 2 2020 and distributed by program directors, trainees, and national and international gastroenterology societies' representatives, was completed. The survey included questions on monthly endoscopy volume, personal protective equipment availability, trainee well-being and educational resources. The primary outcome was change in procedural volume during the COVID-19 pandemic. Secondary outcomes included trainee's professional and personal concerns, anxiety and burnout. RESULTS: Thirty-four Canadian trainees completed the survey. Per month, participants completed a median of 30 esophagogastroduodenoscopies (interquartile range 16 to 50) prior to the pandemic compared to 2 (0 to 10) during the pandemic, 20 (8 to 30) compared to 2 (0 to 5) colonoscopies and 3 (1 to 10) compared to 0 (0 to 3) upper gastrointestinal bleeding procedures. There was a significant decrease in procedural volumes between the pre-COVID-19 and COVID-19 time periods for all procedures (P < 0.001). Thirty (88%) trainees were concerned about personal COVID-19 exposure, 32 (94%) were concerned about achieving and/or maintaining clinical competence and 24 (71%) were concerned about prolongation of training time due to the pandemic. Twenty-six (79%) respondents experienced some degree of anxiety, and 10 (31%) experienced some degree of burnout. CONCLUSION: The COVID-19 pandemic has substantially impacted gastroenterology trainees in Canada. As the pandemic eases, it important for gastrointestinal programs to adapt to maximize resident learning, maintain effective clinical care and ensure development of endoscopic competence.

Colorectal Cancer, Age, and Obesity-Related Comorbidities: A Large Database Study.

BACKGROUND AND AIMS: The association between obesity and colorectal cancer (CRC) is well established in older individuals, but evidence is limited in the younger population. The study aims to analyze the relationship of obesity and its related comorbidities in early-onset CRC (E-CRC) and compare it to late-onset CRC (L-CRC). METHODS: A retrospective, cross-sectional study was performed on average-risk individuals ≥ 20 years who were active patients in the commercial database, IBM Watson Health Explorys in the last 5 years. Individuals with CRC were compared to those without CRC across different age groups (20-39, 40-49, and 50-74 years). Individuals with CRC diagnosed < 50 years (E-CRC) were compared to those with CRC between 50 and 74 years (L-CRC). Variables included sex, smoking, obese BMI, diabetes mellitus type 2 (DM2), hypertension (HTN), and hyperlipidemia (HLD). Since Explorys aggregates population-level, de-identified data, approval from institutional review board was not required. RESULTS: Among 37,483,140 individuals, 162,150 cases of sporadic CRC were identified. Compared to the general population, obesity and HLD were independent risk factors for CRC across all age groups; DM2, HTN, and smoking were independent risk factors for CRC in men of all age groups and women with L-CRC. Compared to L-CRC, individuals with E-CRC had lower percentages of obesity-related comorbidities. CONCLUSION: In E-CRC, obesity, DM2, HTN, HLD, and smoking are independent risk factors for CRC among men; obesity and HLD are independent risk factors for CRC in women. These subgroups may benefit from a personalized screening approach to detect early-onset CRC.

Disparities in Colorectal Cancer Screening Practices in a Midwest Urban Safety-Net Healthcare System.

AIMS: Although colorectal cancer screening (CRC) using stool-based test is well-studied, evidence on fecal immunochemical test (FIT) patterns in a safety-net healthcare system utilizing opportunistic screening is limited. We studied the FIT completion rates and adenoma detection rate (ADR) of positive FIT-colonoscopy (FIT-C) in an urban safety-net system. METHODS: We performed a retrospective cross-sectional chart review on individuals ≥ 50 years who underwent CRC screening using FIT or screening colonoscopy, 09/01/2017-08/30/2018. Demographic differences in FIT completion were studied; ADR of FIT-C was compared to that of screening colonoscopy. RESULTS: Among 13,427 individuals with FIT ordered, 7248 (54%) completed the stool test and 230 (48%) followed up a positive FIT with colonoscopy. Increasing age (OR 1.01, CI 1.01-1.02), non-Hispanic Blacks (OR 0.87, CI 0.80-0.95, p = 0.002), current smokers (OR 0.84, CI 0.77-0.92, p < 0.0001), those with Medicaid (OR 0.86, CI 0.77-0.96, p = 0.006), commercial insurance (OR 0.85, CI 0.78-0.94, p = 0.002), CCI score ≥ 3 (OR 0.82, CI 0.74-0.91, p < 0.0001), orders by family medicine providers (OR 0.87, CI 0.81-0.94, p < 0.0001) were associated with lower completion of stool test. Individuals from low median household income cities had lower follow-up of positive FIT, OR 0.43, CI 0.21-0.86, p = 0.017. ADR of FIT-C was higher than that of screening colonoscopy. CONCLUSION: Adherence to CRC screening is low in safety-net systems employing opportunistic screening. Understanding demographic differences may allow providers to formulate targeted strategies in high-risk vulnerable groups.

Impact of COVID-19 on endoscopy trainees: an international survey.

BACKGROUND AND AIMS: Although coronavirus disease 2019 (COVID-19) has affected endoscopy services globally, the impact on trainees has not been evaluated. We aimed to assess the impact of COVID-19 on procedural volumes and on the emotional well-being of endoscopy trainees worldwide. METHODS: An international survey was disseminated over a 3-week period in April 2020. The primary outcome was the percentage reduction in monthly procedure volume before and during COVID-19. Secondary outcomes included potential variation of COVID-19 impact between different continents and rates and predictors of anxiety and burnout among trainees. RESULTS: Across 770 trainees from 63 countries, 93.8% reported a reduction in endoscopy case volume. The median percentage reduction in total procedures was 99% (interquartile range, 85%-100%), which varied internationally (P < .001) and was greatest for colonoscopy procedures. Restrictions in case volume and trainee activity were common barriers. A total of 71.9% were concerned that the COVID-19 pandemic could prolonged training. Anxiety was reported in 52.4% of respondents and burnout in 18.8%. Anxiety was independently associated with female gender (odds ratio [OR], 2.15; P < .001), adequacy of personal protective equipment (OR, 1.75; P = .005), lack of institutional support for emotional health (OR, 1.67; P = .008), and concerns regarding prolongation of training (OR, 1.60; P = .013). Modifying existing national guidelines to support adequate endoscopy training during the pandemic was supported by 68.9%. CONCLUSIONS: The COVID-19 pandemic has led to restrictions in endoscopic volumes and endoscopy training, with high rates of anxiety and burnout among endoscopy trainees worldwide. Targeted measures by training programs to address these key issues are warranted to improve trainee well-being and support trainee education.

Risk of de-novo inflammatory bowel disease among obese patients treated with bariatric surgery or weight loss medications.

BACKGROUND: An association between bariatric surgery and development of de-novo inflammatory bowel disease (IBD) has been observed. AIM: To evaluate further the association among bariatric surgery, weight loss medications, obesity and new-onset IBD. METHODS: Using Explorys, a population-based Health Insurance Portability and Accountability Act compliant database, we estimated the prevalence of de-novo IBD among patients treated with bariatric surgery (Roux-en-Y gastrojejunostomy, laparoscopic sleeve gastrectomy or gastric banding) (n = 60 870) or weight loss medications (orlistat, phentermine/topiramate, lorcaserin, bupropion/naltrexone and liraglutide) (n = 193 790) compared with obese controls (n = 5 021 210), between 1999 and 2018. RESULTS: The prevalence of de-novo IBD was lower among obese patients exposed to bariatric surgery (7.72 per 1000 patients) or weight loss medications (7.22 per 1000 patients) compared with patients with persistent obesity not exposed to these interventions (11.66 per 1000 patients, P < 0.0001). The risk reduction for de-novo IBD was consistent across bariatric surgeries and weight loss medications with the exception of orlistat which was not associated with a reduction in risk for de-novo IBD compared with the persistent obese control cohort. CONCLUSION: Obese patients undergoing treatment with bariatric surgery or weight loss medications are at a lower risk for developing de-novo IBD compared with persistently obese controls not exposed to these interventions. These data suggest that obesity and ineffective management of obesity are risk factors for de-novo IBD. Further research is needed to confirm these observations and understand potential mechanisms.

Stop Blaming the Weatherman! A Retrospective Study of Endoscopy Show Rates at a Midwest Urban Safety-Net Hospital.

BACKGROUND: Weather patterns are well-known to affect human health and behavior and are often arbitrarily blamed for high no-show rates (NSRs). The NSR for outpatient gastrointestinal procedures ranges from 4% to 41% depending on the population and procedure performed. Identifying potential causes will allow for the optimization of endoscopy resource utilization. AIM: The aim of this study was to evaluate the effects of a day of the year and weather conditions have on NSRs for outpatient endoscopic procedures at a safety-net hospital in Cleveland, Ohio, United States. METHODS: A 12-month, retrospective cohort study of the NSR for outpatient endoscopic procedures was performed using local weather data from January 1, 2017 to December 31, 2017. Data was assessed by analysis of variance/t test, and the χ test was used to analyze weather impact on NSR. RESULTS: A total of 7935 patients had an average overall NSR of 11.8%. Average NSR for esophagogastroduodenoscopies (EGDs) were 9.9%, colonoscopies 12.3%, and advanced endoscopy procedures 11.1%. The NSR was highest in April (15.3%, P=0.01) and lowest in September (9.0%, P=0.04). There is a greater likelihood of procedural no-show for colonoscopies compared with EGDs when mean temperatures were at or below freezing (P=0.02) and with snowfall (P=0.03). NSR were also high for EGDs on federal holidays (25%, P=0.03) and colonoscopies on days following federal holidays (25.3%, P<0.01). Day of the week, wind speed, presence of precipitation, wind chill, the temperature change from the prior day, and temperature (high, low, and mean) had no significant impact on NSR. CONCLUSIONS: Our study demonstrates that scheduling adjustments on federal holidays, days when temperatures are below freezing, and snowfall may improve department resource utilization. These data, along with other variables that affect NSR for endoscopic procedures, should be taken into consideration when attempting to optimize scheduling and available resources in a safety-net hospital.

Current Trends in the Management of Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) characterized by heartburn and/or regurgitation symptoms is one of the most common gastrointestinal disorders managed by gastroenterologists and primary care physicians. There has been an increase in GERD prevalence, particularly in North America and East Asia. Over the past three decades proton pump inhibitors (PPIs) have been the mainstay of medical therapy for GERD. However, recently there has been an increasing awareness amongst physicians and patients regarding the side effects of the PPI class of drugs. In addition, there has been a marked decline in the utilization of surgical fundoplication as well as a rise in the development of nonmedical therapeutic modalities for GERD. This review focuses on different management strategies for GERD, optimal management of refractory GERD with special focus on available endoluminal therapies and the future directions.

Underwater endoscopic mucosal resection: an alternative treatment for large colorectal polyp removal.

BACKGROUND: Large sessile/flat colonic polyps are traditionally removed by lift polypectomy. Underwater endoscopic mucosal resection (UEMR) is a novel technique where air is suctioned out and replaced by water to decompress the colon so that the flat lesions assumes a more polypoid shape facilitating its removal with the standard snare resection. We report the feasibility and safety in our series of patients utilizing this technique. METHODS: A retrospective, observational study of all patients who underwent removal of large colonic polyps (>10 mm) over a period of 3 years (January 2012 to January 2015) at a tertiary care center by UEMR were included in the study. RESULTS: A total of 102 polyps were removed in 93 adult patients using UEMR. The mean age of patients was 64.7±9.7 years. The average number of polyps per patient was 1.84±1.3 with a range of 1-7. The range of the polyp size was 10 to 60 mm. The mean size of the polyp was 20.4±9.4 mm, median size 26.9±9.4 mm. Ninety-two (90.2%) were removed in piecemeal fashion and ten (9.8%) were removed en bloc. Delayed bleeding occurred in seven (9.7%) patients. CONCLUSIONS: In this largest series on UEMR, we report the feasibility and safety of this procedure. Future randomized trials comparing this technique versus standard lift polypectomy technique will further elucidate the benefit of one over other.

Fibroblast growth factor signaling in liver carcinogenesis.

Fibroblast growth factors, or FGFs, are a large family of polypeptide cytokines exhibiting a pleiotropy of functions, from cell growth to angiogenesis, wound healing, and tissue repair. This review broadly covers the genetics and protein expression of the FGF family members and the signaling pathways involved in FGF-mediated growth regulation. We emphasize the role of FGFs in the pathogenesis of hepatocellular carcinoma (HCC), including their effects on regulation of the tumor microenvironment and angiogenesis. Finally, we present current views on FGF's potential role as a prognostic marker in clinical practice, as well as its potential as a therapeutic target in HCC.

Viral hepatitis among Somali immigrants in Minnesota: association of hepatitis C with hepatocellular carcinoma.

OBJECTIVE: To study the frequencies of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and their associations with hepatocellular carcinoma (HCC) in immigrant Somalis seen at Mayo Clinic in Rochester, Minnesota. PATIENTS AND METHODS: We determined the frequencies of HBV and HCV infection and HCC in immigrant Somalis seen at Mayo Clinic from July 1, 1996, through October 31, 2009. Non-Somali Olmsted County residents served as controls. RESULTS: For Somali males and females, age-adjusted proportions (per 1000 population) were 209 and 123 for hepatitis B surface antigen (HBsAg), 644 and 541 for hepatitis B core antibody (HBcAb), and 99 and 66 for anti-HCV. The comparative proportions in non-Somalis were 20 and 9 for HBsAg, 126 and 97 for HBcAb, and 32 and 17 for anti-HCV. Hepatitis C virus RNA confirmed that 68 of 73 Somalis (93.2%) and 261 of 282 non-Somalis (92.6%) with positive anti-HCV test results had active HCV infection. Of 30 Somali patients with HCC, 22 (73.3%) tested anti-HCV positive (odds ratio [OR], 31.3; 95% confidence interval [CI], 13.0-75.5; P<.001; compared with anti-HCV-negative Somalis), 5 (16.7%) were HBsAg positive (OR, 1.4; 95% CI, 0.5-3.7; P=.53), and 18 (60.0%) were HBcAb positive (OR, 1.8; 95% CI, 0.8-4.2; P=.16). Viral hepatitis was diagnosed coincident with HCC in 9 of 20 patients (45.0%) with HCV-associated HCCs. Only 4 of 24 cases of HCC (16.7%) were detected during surveillance. CONCLUSION: Both HBV and HCV occurred frequently in this sample of Somali immigrants. However, HCV was the major risk factor for HCC. Screening Somali immigrants for HCV infection may enhance the prevention, early detection, and optimal treatment of HCC.

Sulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors.

BACKGROUND: Sulfatase 2 (SULF2), an extracellular heparan sulphate 6-O-endosulphatase, has an oncogenic effect in hepatocellular carcinoma (HCC) that is partially mediated through glypican 3, which promotes heparin-binding growth factor signalling and HCC cell growth. SULF2 also increases phosphorylation of the anti-apoptotic Akt kinase substrate GSK3ß and SULF2 expression is associated with a decreased apoptotic index in human HCCs. METHODS: We investigated the functional and mechanistic effects of SULF2 on drug-induced apoptosis of HCC cells using immunohistochemistry, Western immunoblotting, gene transfection, real-time quantitative polymerase chain reaction, MTT and apoptosis assays and immunocytochemistry. RESULTS: The increased expression of SULF2 in human HCCs was confirmed by immunohistochemistry and immunoblotting. Treatment with inhibitors of MEK, JNK and PI3 kinases decreased the viability of SULF2-negative Hep3B HCC cells and induced apoptotic caspase 3 and 7 activity, which was most strongly induced by the PI3K inhibitor LY294002. Forced expression of SULF2 in Hep3B cells significantly decreased activity of the apoptotic caspases 3 and 7 and induced resistance to LY294002-induced apoptosis. As expected, LY294002 inhibited activation of Akt kinase by PI3K. Conversely, knockdown of SULF2 using an shRNA construct targeting the SULF2 mRNA induced profound cell growth arrest and sensitized the endogenously SULF2-expressing HCC cell lines Huh7 and SNU182 to drug-induced apoptosis. The effects of knockdown of SULF2 on HCC cells were mediated by decreased Akt phosphorylation, downregulation of cyclin D1 and the anti-apoptotic molecule Bcl-2, and upregulation of the pro-apoptotic molecule BAD. CONCLUSION: The prosurvival, anti-apoptotic effect of SULF2 in HCC is mediated through activation of the PI3K/Akt pathway.

Additive effect of apicidin and doxorubicin in sulfatase 1 expressing hepatocellular carcinoma in vitro and in vivo.

BACKGROUND/AIMS: There are limited chemotherapy options for hepatocellular carcinoma (HCC). The heparin-degrading endosulfatase SULF1 functions as a liver tumor suppressor. We investigated the effects of the histone deacetylase inhibitor apicidin in combination with doxorubicin in SULF1-expressing HCC cells in vitro and in SULF1-expressing xenografts in nude mice. METHODS: We evaluated the effects of apicidin alone or combined with doxorubicin on apoptosis, caspase activity, and phosphorylation of Erk and Akt in SULF1-transfected Huh7 and Hep3B cells in vitro and in vivo. RESULTS: Apicidin induced HCC cell apoptosis and caspase activation in a dose- and time-dependent manner. Apicidin-induced caspase activation was significantly inhibited by the caspase inhibitor Z-Vad-fmk. Apicidin also decreased phosphorylation of both Erk and Akt. Expression of constitutively-active Mek1 and Akt significantly decreased apicidin-induced apoptosis. The combination of doxorubicin with apicidin significantly increased the anti-tumor effect in the SULF1-expressing Huh7 and Hep3B cells as compared to either apicidin or doxorubicin alone, both in vitro and in vivo. CONCLUSIONS: The combination of a histone deacetylase inhibitor with doxorubicin may be a novel and promising therapeutic modality for HCCs, particularly for SULF1-expressing HCCs.

Treatment options for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is frequently diagnosed at advanced stages and has a high mortality rate. With improved survival of patients with cirrhotic liver disease and increased prevalence of chronic hepatitis C viral infections, a rise in the number of HCC cases is being reported worldwide. Early diagnosis and treatment can significantly improve the prognosis of patients with HCC. Although surgical resection is an important potentially curative therapy for liver tumors, in appropriately selected patients, liver transplantation has been shown to achieve excellent survival rates for a solid tumor. Locally ablative and locoregional therapies in the form of percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization and transcatheter arterial radioembolization (TheraSphere) are viable options in patients with unresectable HCC. Unfortunately, the role of systemic therapy has been very limited in the treatment of these patients. Novel treatment options based on an improved understanding of the molecular pathogenesis of HCC are being explored. These targeted molecular therapies are aimed at growth factors and their receptors, intracellular signal transduction and cell cycle control. A substantial improvement in outcomes of intermediate and advanced stage HCC is expected with the advent of these targeted therapies, used in combination with surgical or locoregional therapies. Recent positive results from a large Phase III study of the receptor tyrosine kinase inhibitor, sorafenib, hold great promise in the treatment of HCC.

Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.

Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage at which there are limited treatment options. Two recently identified human heparin-degrading endosulfatases, named sulfatase 1 (SULF1) and sulfatase 2 (SULF2), have been found to be involved in liver carcinogenesis. SULF1 and SULF2 desulfate cell surface and extracellular matrix heparan sulfate proteoglycans and modulate heparin-binding growth factor signaling in multiple cancers, including HCCs. SULF1 inhibits HCC tumor cell growth in vitro and in nude mice in vivo, partially through effects on gene expression mediated through histone H4 acetylation. While SULF1 is downregulated in the majority of HCC cell lines and approximately 30% of primary HCCs, SULF2 is upregulated in almost all HCC cell lines and in 60% of primary HCCs. In contrast to the tumor suppressor effect of SULF1, expression of SULF2 activates MAPK and Akt pathways, promotes HCC cell growth in vitro and in vivo, and is associated with decreased survival of HCC patients. Targeting SULF2 or the interaction between SULF2 and SULF1 may lead to novel therapeutics for the treatment of HCCs.

Diagnosis and management of cholangiocarcinoma.

Cholangiocarcinoma (CC) is a rare yet frequently fatal tumor that causes significant morbidity and mortality due to late presentation. Radiology is the mainstay of CC diagnosis; however, advances in understanding the pathogenesis of CC, including the role of oncogenes, inflammation-mediated genomic instability, and interleukin-6/STAT-3 signaling pathways, may allow development of new diagnostic and prognostic markers and targets for CC therapy. Although surgical resection is the standard of care for resectable CC, liver transplantation has shown excellent results in selected patients. The use of chemotherapy and radiotherapy are currently limited by marginal response rates, toxicity, and biliary complications. Locally ablative therapies in the form of transcatheter arterial chemoembolization and radioembolization are under investigation. Molecular therapies (eg, epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor antagonists) and immunotherapy using diabodies are also under investigation for treatment of unresectable CC.

Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma.

UNLABELLED: It has been shown that the heparin-degrading endosulfatase, sulfatase 1 (SULF1), functions as a liver tumor suppressor, but the role of the related sulfatase, sulfatase 2 (SULF2), in liver carcinogenesis remains to be elucidated. We investigated the effect of SULF2 on liver tumorigenesis. Expression of SULF2 was increased in 79 (57%) of 139 hepatocellular carcinomas (HCCs) and 8 (73%) of 11 HCC cell lines. Forced expression of SULF2 increased HCC cell growth and migration, whereas knockdown of SULF2 using short hairpin RNA targeting SULF2 abrogated HCC cell proliferation and migration in vitro. Because SULF1 and SULF2 desulfate heparan sulfate proteoglycans (HSPGs) and the HSPG glypican 3 (GPC3) is up-regulated in HCC, we investigated the effects of SULF2 on GPC3 expression and the association of SULF2 with GPC3. SULF2-mediated cell growth was associated with increased binding of fibroblast growth factor 2 (FGF2), phosphorylation of extracellular signal-regulated kinase and AKT, and expression of GPC3. Knockdown of GPC3 attenuated FGF2 binding in SULF2-expressing HCC cells. The effects of SULF2 on up-regulation of GPC3 and tumor growth were confirmed in nude mouse xenografts. Moreover, HCC patients with increased SULF2 expression in resected HCC tissues had a worse prognosis and a higher rate of recurrence after surgery. CONCLUSION: In contrast to the tumor suppressor effect of SULF1, SULF2 has an oncogenic effect in HCC mediated in part through up-regulation of FGF signaling and GPC3 expression.

The tumor suppressor function of human sulfatase 1 (SULF1) in carcinogenesis.

INTRODUCTION: Human sulfatase 1 (SULF1) was recently identified and shown to desulfate cellular heparan sulfate proteoglycans (HSPGs). Since sulfated HSPGs serve as co-receptors for many growth factors and cytokines, SULF1 was predicted to modulate growth factor and cytokine signaling. DISCUSSION: The role of SULF1 in growth factor signaling and its effects on human tumorigenesis are under active investigation. Initial results show that SULF1 inhibits the co-receptor function of HSPGs in multiple receptor tyrosine kinase signaling pathways, particularly by the heparin binding growth factors--fibroblast growth factor 2, vascular endothelial growth factor, hepatocyte growth factor, PDGF, and heparin-binding epidermal growth factor (HB-EGF). SULF1 is downregulated in the majority of cancer cell lines examined, and forced expression of SULF1 decreases cell proliferation, migration, and invasion. SULF1 also promotes drug-induced apoptosis of cancer cells in vitro and inhibits tumorigenesis and angiogenesis in vivo. CONCLUSION: Strategies targeting SULF1 or the interaction between SULF1 and the related sulfatase 2 will potentially be important in developing novel cancer therapies.