Dalbir S. Sandhu

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

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. (HEPATOLOGY 2008.)

The Tumor Suppressor Function of Human Sulfatase 1 (SULF1) in Carcinogenesis

IntroductionHuman 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.DiscussionThe 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.ConclusionStrategies targeting SULF1 or the interaction between SULF1 and the related sulfatase 2 will potentially be important in developing novel cancer therapies.

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 FGFs potential role as a prognostic marker in clinical practice, as well as its potential as a therapeutic target in HCC. (Hepatology 2014;59:1166–1173)

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.

Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis, diagnosis and identification of treatment targets

Cholangiocarcinomas (CCs) are highly lethal malignant tumours arising from the biliary tract epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its typically late clinical presentation and the lack of effective non‐surgical therapeutic modalities. The overall survival rate, including resected patients is poor, with less than 5% of patients surviving 5 years, a rate which has not changed significantly over the past 30 years. Although CC is a relatively uncommon tumor, interest in this disease is rising as incidence and mortality rates for intrahepatic cholangiocarcinoma are increasing markedly worldwide. A variety of risk factors, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis have been described. However, for most CCs the cause is unknown, and affected individuals have no history of exposure to, or association with, known risk factors. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations in the form of promoter region hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes reported to be methylated in CC to date and their putative roles in cholangiocarcinogenesis. Future directions in the study of methylated genes and their potential roles as diagnostic and prognostic markers are also discussed.

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.

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.

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 GSK3β and SULF2 expression is associated with a decreased apoptotic index in human HCCs.

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.

Sa1951 Collagenous Gastroduodenitis: A Case Report and Review of Literature

Introduction: Isolated collagenous gastroduodenitis (CGD) with no colonic involvement is an extremely rare entity with only 2 cases reported in the literature. We report a case of isolated CGD presenting as nausea, vomiting, abdominal pain and profound weight loss. Case: A 63-year-old African American woman presented with two-year history of nausea, vomiting, upper abdominal pain and sixty pounds weight loss. There was no history of diarrhea, gastrointestinal (GI) bleeding or skin changes. Prior evaluation, including esophagogastroduodenoscopy, colonoscopy with biopsies and a video-capsule endoscopy only revealed gastric mucosal edema. Celiac serologies were negative and a gluten free diet failed to improve her symptoms. She was hospitalized for severe malnutrition and total parenteral nutrition (TPN) was started. Laboratory evaluation revealed Hemoglobin of 12.4g/dl, albumin 2.6g/dl, positive antinuclear antigen (1:640), and positive anti SCL-70 antibody. Push enteroscopy showed inflammatory changes in the stomach and the small bowel (SB) wall mucosa appeared edematous and nodular. Biopsies revealed inflammatory changes and thickened collagen table consistent with CGD. She was started on oral prednisone, mycophenolate mofetil (MMF), and high dose proton pump inhibitors. Prednisone was eventually tapered off and the TPN was discontinued. At 4 months, repeat push enteroscopy showed normal looking SB mucosa. Biopsies revealed no collagen table. She has regained her baseline weight and is currently maintained only on MMF. Discussion: Collagenous gastroenteritides are characterized by marked subepithelial collagen deposition with mucosal inflammatory infiltrate. Isolated collagenous gastritis presents with anemia, weight loss, dyspepsia and epigastric pain. Endoscopy shows thickened and nodular mucosa, erosions, and ulcerations. Diagnosis is made by histology, with increased subepithelial collagen band thickness to at least 10 μm and inflammatory cell response with predominant mononuclear infiltrate in the lamina propria. GI involvement in scleroderma can also present similarly, however, endoscopic findings are more consistent with gastric antral vascular ectasia (GAVE) and histology is characterized by mucosal capillary dilatation with fibromuscular hyperplasia. The histological features in our case typify CGD and were not consistent with GI scleroderma. A variety of therapies for CGD have been tried including corticosteroids, Bismuth subsalicylate, Mesalazine, and hypoallergenic diets. Steroids can lead to clinical improvement, however, endoscopic or histological improvement has not been documented. The uniqueness in our case is significant clinical, endoscopic and histologic response to steroid and MMF therapy. With increased awareness and reporting of such cases, diagnostic and management strategies may be better elucidated.