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Helmut Friess

Publications and source records attributed to Helmut Friess.

At least 37 records · Page 2Linked to original sources
PubMed2006

Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma.

Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release from mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small-interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria.

Apoptosis↗
PubMed2006

Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer.

AIM: To determine the role of two antiapoptotic proteins of the inhibitor of apoptosis protein family, cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2), in human pancreatic carcinogenesis. METHODS: mRNA levels were measured in pancreatic tissues and pancreatic cancer cell lines by quantitative reverse transcriptase PCR. Protein expression was assessed in pancreatic cancer cell lines by immunoblotting and in pancreatic tissues by immunohistochemistry, and correlated with pathological and survival data. RESULTS: cIAP1 expression was constantly high in non-neoplastic pancreatic tissues, in pancreatic intraepithelial neoplasia (PanIN) lesions, as well as in a subset of primary and metastatic pancreatic ductal adenocarcinomas (PDAC), and a preferential cytoplasmatic localisation was observed in the tumour tissues. cIAP1 expression was rare in a cohort of cystic tumours. cIAP2 mRNA levels were significantly higher (2.4 fold) in PDAC than in normal tissues. cIAP2 protein was overexpressed in PDAC, and was detectable in low- and high-grade PanIN lesions. Moreover, cIAP2 was often expressed in pancreatic cystic tumours. cIAP1 and cIAP2 mRNA and protein were detected in all the examined cell lines. Survival analysis revealed a shorter survival in patients with cIAP1/cIAP2-positive tumours. CONCLUSIONS: cIAP1 might contribute to the regulation of the apoptotic process in the normal and in the neoplastic pancreas, depending on its subcellular localisation. Overexpression of cIAP2 is a common and early event in the progression of pancreatic cancer, and could therefore potentially influence the important pathophysiological aspects of PDAC, such as anoikis or chemoresistance.

Adenocarcinoma↗
PubMed2006

Splenic and portal vein thrombosis in pancreatic metastasis from renal cell carcinoma.

BACKGROUND: Pancreatic metastases from previously treated renal cell carcinoma are uncommon. Surgical resection of pancreatic metastasis remains the only worthwhile modality of treatment. CASE PRESENTATION: A case where pancreatic metastasis from previously resected right sided renal cell carcinoma was resected with a subtotal left pancreatectomy is described. An unusual feature was the presence of a large splenic vein tumor thrombus extending into the portal vein with associated portal hypertension. The patient underwent an uneventful portal vein resection with primary anastomosis. CONCLUSION: This is possibly the first documented case of portal vein renal tumor thrombosis in a case of isolated pancreatic metastasis from previously operated renal cell carcinoma in published world surgical literature.

Journal Article↗
PubMed2006

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Base Sequence↗
PubMed2006

Duodenum preserving pancreatectomy in chronic pancreatitis: design of a randomized controlled trial comparing two surgical techniques [ISRCTN50638764].

BACKGROUND: Chronic pancreatitis is an inflammatory disease which is characterized by an irreversible conversion of pancreatic parenchyma to fibrous tissue. Beside obstructive jaundice and pseudocyst formation, about half of the patients need surgical intervention due to untreatable chronic pain during the course of the disease. In most of the patients with chronic pancreatitis, the head of the pancreas is the trigger of the chronic inflammatory process. Therefore, resection of pancreatic head tissue must be the central part of any surgical intervention. However, it is unclear to which extent the surgical procedure must be radical in order to obtain a favourable outcome for the patients. DESIGN: A single centre randomized controlled, superiority trial to compare two techniques of duodenum preserving pancreatic head resection. SAMPLE SIZE: 65 patients will be included and randomized intraoperatively. ELIGIBILITY CRITERIA: All patients with chronic pancreatitis and indication for surgical resection and signed informed consent. Cumulative primary endpoint (hierarchical model): duration of surgical procedure, quality of life after one year, duration of intensive care unit stay, duration of hospital stay. Reference treatment: Resection of the pancreatic head with dissection of the pancreas from the portal vein and transsection of the gland (Beger procedure). INTERVENTION: Partial Resection of the pancreatic head without transsection of the organ and visualization of the portal vein (Berne procedure). DURATION: September 2003-October 2007. ORGANISATION/RESPONSIBILITY: The trial is conducted in compliance with the protocol and in accordance with the moral, ethical, regulatory and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and the Good Clinical Practice guideline (GCP). The Center for Clinical Studies of the Department of Surgery Heidelberg is responsible for planning, conducting and final analysis of the trial.

Journal Article↗
PubMed2006

Corticosteroid co-treatment induces resistance to chemotherapy in surgical resections, xenografts and established cell lines of pancreatic cancer.

BACKGROUND: Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown. METHODS: A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Anti-apoptotic signaling in response to DEX was examined by Western blot analysis. RESULTS: In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells. CONCLUSION: These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients.

Animals↗
PubMed2006

Effects of bone sialoprotein on pancreatic cancer cell growth, invasion and metastasis.

Bone sialoprotein (BSP) is an acidic glycoprotein that plays an important role in cancer cell growth, migration and invasion. The expression, localization and possible function of BSP in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were analyzed by QRT-PCR, laser capture microdissection, DNA microarray analysis, immunoblotting, radioimmunoassays and immunohistochemistry as well as cell growth, invasion, scattering, and adhesion assays. BSP mRNA was detected in 40.7% of normal, in 80% of CP and in 86.4% of PDAC samples. The median BSP mRNA levels were 6.1 and 0.9copies/microl cDNA in PDAC and CP tissues, respectively, and zero copies/microl cDNA in normal pancreatic tissues. BSP was weakly present in the cytoplasm of islet cells and ductal cells in 20% of normal pancreatic tissues. BSP was localized in the tubular complexes of both CP and PDAC, as well as in pancreatic cancer cells. Five out of 8 pancreatic cancer cell lines expressed BSP mRNA. Recombinant BSP (rBSP) inhibited Capan-1 and SU8686 pancreatic cancer cell growth, with a maximal effect of -46.4+/-12.0% in Capan-1 cells and -45.7+/-14.5% in SU8686 cells. rBSP decreased the invasion of SU8686 cells by -59.1+/-11.2% and of Capan-1 cells by -13.3+/-3.8% (P<0.05), whereas it did not affect scattering or adhesion of both cell lines. In conclusion, endogenous BSP expression levels in pancreatic cancer cells and low to absent BSP expression in the surrounding stromal tissue elements may indirectly act to enhance the proliferation and invasion of pancreatic cancer cells.

Carcinoma, Pancreatic Ductal↗
PubMed2006

Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis.

A central feature of all solid tumor growth is the presence of neovascularization. The CXC chemokines GRO-gamma/CXCL3, ENA-78/CXCL5, and IL-8/CXCL8 have profound angiogenic potential mediated through the CXCR2 receptor. The aim of the present study was to evaluate the expression of the angiogenic chemokines in three human pancreatic cancer cell lines and to determine the role of these proteins in pancreatic cancer angiogenesis. Secreted CXC protein levels in the supernatant of the cell lines were analyzed by ELISA. A rat corneal micropocket model was used to determine the angiogenic potential of these secreted CXC chemokines in vivo. ELISA confirmed expression of all three tested CXC chemokines in the supernatant of two cell lines. In the corneal micropocket assay, neovascularization was induced using pelleted supernatant of all three-cell lines. Using an anti-CXCR2 antibody, neovascularization was significantly inhibited in the high expressing BxPC-3 cell line samples. In addition, the expression of ENA-78/CXCL5 and IL-8/CXCL8 has been evaluated in human pancreatic cancer tissue samples by using immunohistochemistry in order to further investigate the potential role of CXC chemokines in pancreatic cancer angiogenesis and tumorigenesis.

Animals↗
PubMed2006

FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.

The expression and localization of FXYD domain containing ion transport regulator 3 (FXYD3), a transmembrane protein that acts as a chloride channel or chloride channel regulator, was analyzed in pancreatic tissues derived from donors and patients suffering from chronic pancreatitis (CP) or pancreatic ductal adenocarcinoma (PDAC) as well as in pancreatic cancer cells using QRT-PCR, laser-capture microdissection and microarray analysis, in situ hybridization and immunohistochemistry. FXYD3 antisense expressing T3M4 pancreatic cancer cells were generated and compared to control cells using anchorage-dependent and independent growth assays, and xenotransplantation into nude mice. FXYD3 mRNA levels were 3.4-fold increased in PDAC tissues compared to donor specimens (p = 0.006), and 3.9-fold increased in microdissected cancer cells compared to normal pancreatic ductal cells (p = 0.02). FXYD3 was localized in the tubular complexes and PanIN lesions of both CP and PDAC, as well as in pancreatic cancer cells. Downregulation of FXYD3 by stable antisense transfection increased significantly the doubling time of T3M4 pancreatic cancer cells from 44 +/- 2 hr to 55 +/- 12 hr (p = 0.02). Nude mice transplanted with antisense transfected cells displayed a significant increase in tumor doubling time from 3.3 days +/- 1.0 to 4.3 days +/- 0.43 (p = 0.058). Anchorage-independent growth and sensitivity to 5-fluorouracil, gemcitabine and cisplatin as well as to MgCl(2) were not dependent on the level of FXYD3 expression. In conclusion, overexpression of FXYD3 in pancreatic cancer may contribute to the proliferative activity of this malignancy.

Adenocarcinoma↗
PubMed2006

Stapler hepatectomy is a safe dissection technique: analysis of 300 patients.

BACKGROUND: In many surgical procedures, stapling devices have been introduced for safety and to reduce the overall operative time. Their use for transection of hepatic parenchyma is not well established. Thus, the feasibility of stapler hepatectomy and a risk analysis of surgical morbidity based on intraoperative data have been prospectively assessed on a routine clinical basis. MATERIALS AND METHODS: From October 1, 2001, to January 31, 2005, a total of 416 patients underwent liver resection in our department. During this period endo GIA vascular staplers were used for parenchymal transection in 300 cases of primary (22%) and metastatic (57%) liver cancer, benign diseases (adenoma, focal nodular hyperplasia [FNH], cysts) (14%), gallbladder carcinoma (2%), and other tumors (5%). There were 193 (64%) major resections (i.e., removal of three segments or more) and 107 minor hepatic resections. Additional extrahepatic resections were performed in 44 (15%) patients. RESULTS: Median values for operative time and intraoperative hemorrhage were 210 minutes and 700 ml, respectively. Further, transfusion of RBC and FFP was needed in 17% and 11% of patients, respectively. A postoperative ICU stay for >2 days was required in 18% of patients. The median postoperative hospital stay was 10 days (IQR 8-14 days). The most frequent surgical complications were bile leak (8%), wound infection (3%), and pneumothorax (2%). In 7% of cases after stapler hepatectomy a relaparotomy was necessary. Treated medical complications were pleural effusion (7%), renal insufficiency (5%), and cardiac insufficiency (3%). Risk assessment revealed that both operative time and indication for resection had significant impact on surgical morbidity. Mortality (4%) and morbidity (33%) were comparable to other high-volume centers performing conventional liver resection techniques. CONCLUSION: In conclusion, stapler hepatectomy can be used in a routine clinical setting with a low incidence of surgical complications.

Aged↗
PubMed2006

Management of pain in small duct chronic pancreatitis.

Small duct chronic pancreatitis (CP) is defined by a nondilated main pancreatic duct, and the morphological and clinical features of chronic pancreatitis with pain are the most prominent symptoms. Current treatment strategies are based on pain history and the location and extent of disease. Traditionally, radical pancreatic resectional procedures have been carried out for small duct CP, especially with an associated head mass of uncertain aetiology. Based on the information from five randomized trials, the duodenum-preserving pancreatic head resection and its modifications have proven to provide excellent long-term pain relief and to be superior to more radical operations. Therefore, these procedures can be considered the standard for small duct CP with head dominant disease. The longitudinal V-shaped excision of the ventral pancreas combines extensive drainage and a limited resection and offers good pain relief in diffuse small duct CP. However, long-term results and larger series are awaited for definite conclusions. Thoracoscopic splanchnicectomy and endosonography-guided celiac plexus blocks require controlled trials before their routine use. This article provides an overview about the current and evidence-based pain management in small duct CP.

Chronic Disease↗
PubMed2006

Pancreatic regeneration in chronic pancreatitis requires activation of the notch signaling pathway.

Chronic pancreatitis as an inflammatory process characterized by morphological changes, pancreatic dysfunction, and pain. During pancreatic injury and repair the Notch signaling pathway is reinstated. The current study analyzed this pathway in chronic pancreatitis and characterized its influence on fibrogenesis. Real-time quantitative PCR and immunohistochemistry were used for expression studies. Notch activation was determined by a specific luciferase-HES-1-reporter gene constructs. Cells were stimulated with alcohol, glucose, bile acids, and steroids. Notch-2, -3, and -4 mRNA, were overexpressed in chronic pancreatitis specimens. The ligands Jagged-1, -2, and Delta-1 were highly overexpressed. Jagged-1 and Notch receptors were observed in nerves, regenerating exocrine cells, and endocrine cells. Delta staining was present in ductal but not in acinus cells and not in nerves. Activation of Notch signaling was detectable upon cell stimulation with glucose, steroids, and bile acids. High glucose levels were further associated with increased collagen-I production. The Notch pathway is reactivated during chronic pancreatitis. Among the stimuli activating the Notch pathway are steroids, high glucose levels, and bile acids. These findings suggest a possible role of the Notch pathway during pancreatic regeneration since Jagged-1 inhibits inducible collagen-1 production, suggesting a new mechanism of tissue repair in this disease.

Animals↗
PubMed2006

Clinical results of surgery for retroperitoneal sarcoma with major blood vessel involvement.

PURPOSE: The study was conducted to evaluate the clinical results of resection for retroperitoneal soft tissue sarcoma (STS) with vascular involvement. METHODS: The study group consisted of consecutive patients (mean age, 52 years) who underwent surgery for retroperitoneal STS with vascular involvement. The procedures were performed between 1988 and 2004. Vessel involvement by STS was classified as type I, artery and vein; type II, only artery; type III, only vein; and type IV, neither artery nor vein (excluded from the analysis). Patient data were prospectively gathered in a computerized database and retrospectively analyzed. RESULTS: Of 141 patients with retroperitoneal STS, 25 (17.7%) underwent surgery for tumors with vascular involvement. The most common vascular involvement pattern was vein only (type III) at 64%. Arterial and vein (type I) and arterial only (type II) involvement were observed in 16% and 20% of the cases, respectively. STS originating from the vessel wall (primary vessel involvement) was seen in eight patients, and 17 patients had secondary vascular involvement. Resection and vascular repair were done in 22 patients (no vascular repair in three patients due to ligation of the external iliac vein in one patient, and debulking procedures in two). All patients with arterial involvement (type I and II) had arterial reconstruction consisting of aortic replacement (Dacron, n = 3; and expanded polytetrafluoroethylene [ePTFE], n = 2), iliac repair (Dacron, n = 3), and truncal reimplantation (n = 1). The inferior vena cava (6 ePTFE tube grafts, 3 ePTFE patches, 2 venoplasties), iliac vein (1 ePTFE bypass, 1 Dacron bypass, 1 venous patch), and superior mesenteric vein (1 anastomosis, 1 Dacron bypass) were restored in 80% of the patients (n = 16) with either arterial and venous or only venous involvement (type I and type III setting). Morbidity was 36% (hemorrhage, others), and mortality was 4%. At a median follow-up of 19.3 months (interquartile range, 12.8 to 49.9 months) the arterial patency rate was 88.9%, and the venous patency rate was 93.8% (primary and secondary). Thrombosis developed in one arterial and venous (type I) iliac reconstruction due to a perforated sigmoid diverticulitis 12 months after surgery. The local control rate was 82.4%. The 2-year and 5-year survival rates were 90% and 66.7% after complete resection with tumor-free resection margins (n = 10 patients, median survival not reached at latest follow-up). The median survival was 21 months in patients with complete resection but positive resection margins (n = 7) and 8 months in patients with incomplete tumor clearance (n = 8, persistent local disease or metastasis). CONCLUSIONS: Patency rates and an acceptable surgical risk underline the value of en bloc resection of retroperitoneal STS together with involvement of blood vessels. The oncologic outcome is positive, especially after complete resection with tumor-free resection margins. A classification of vascular involvement can be used to plan resection and vascular replacement as well as to compare results among reports in a standardized fashion.

Adolescent↗
PubMed2006

Expression of cytokeratin-20 in pancreatic cancer: an indicator of poor outcome after R0 resection.

BACKGROUND: After complete removal of the neoplasm (R0 resection), approximately 80% of pancreatic cancer patients will die of the disease within 5 years. The expression panel of cytokeratins (CK) is linked closely with cell differentiation. The aim of the study was to investigate the expression of CK-20 in pancreatic cancer tissue and to correlate CK-20 expression with survival in R0-resected pancreatic cancer patients. METHODS: Tissue samples of 63 patients with pancreatic cancer were subjected to CK-20 reverse-transcription polymerase chain reaction. Thirty-four of 63 patients underwent R0 resection and were followed-up for survival statistics. From these 34 patients, 26 (76%) neoplasms were CK-20 positive and 8 (24%) samples were CK-20 negative. The mean follow-up period for the entire group was 17 months (range, 4-36 mo), the follow-up period in censored patients was 23 months (range, 10-36 mo). RESULTS: In the R0-resected group, 3 of 8 (38%) patients with CK-20-negative neoplasms, and 16 of 26 (62%) patients with CK-20-positive neoplasms (P = .15) died of recurrent disease. The median survival time of patients with CK-20-positive neoplasms was 13 months (range, 4-36), the median survival in R0-resected patients with CK-20-negative neoplasm was 26 months (range, 13-35; P = .06). The survival difference observed in patients with CK-20-negative neoplasms could not be attributed to intergroup variations in tumor stage or tumor grade. CONCLUSIONS: A majority of primary ductal pancreatic adenocarcinomas express CK-20. This seems to be associated with poorer survival in R0-resected patients. Our data suggest that ductal pancreatic adenocarcinomas negative for CK-20 constitute a subgroup of patients showing a more favorable disease outcome. The expression of CK-20 in resected pancreatic cancer may be of interest as a prognostic parameter.

Carcinoma, Pancreatic Ductal↗
PubMed2006

Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice.

BACKGROUND & AIMS: Basic research aimed at a better understanding of pancreatic carcinogenesis and improving the treatment of this disease is crucial because the majority of pancreatic cancers are highly aggressive and therapeutically nonaccessible. Cyclooxygenase (COX)-2, which is a key enzyme of prostaglandin (PG) biosynthesis, is overexpressed in around 75% of human carcinomas including those of the pancreas. METHODS: The pathologic changes of transgenic mouse pancreas with keratin 5-promoter-driven expression and activity of COX-2 were characterized. RESULTS: Aberrant expression of COX-2 in a few ductal cells and COX-2-mediated PG synthesis in the transgenic mice resulted in keratin 19- and mucin-positive intraductal papillary mucinous neoplasm- and pancreatic intraepithelial neoplasia-like structures, characterized by an increased proliferation index and serous cystadenomas. Moreover, Ras activation was enhanced and the HER-2/Neu receptor was overexpressed. Loss of acini, fibrosis, and inflammation were pronounced. Feeding a COX-2-selective inhibitor to the transgenic mice suppressed the accumulation of PG and the phenotype. The changes resemble the human disease in which COX-2 was overexpressed consistently. CONCLUSIONS: We present strong evidence for a causal relationship between aberrant COX-2 overexpression and COX-2-mediated PG synthesis and the development of serous cystadenoma, intraductal papillary mucinous, and pancreatic intraepithelial neoplasms. This model offers the unique possibility of identifying molecular pathways leading to the formation and malignant progression of the various types of preinvasive lesions of pancreatic adenocarcinomas that show different dismal outcomes.

Animals↗
PubMed2006

Hedgehog signaling in the normal and diseased pancreas.

The hedgehog (Hh) family of genes, sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh) encode signaling molecules that regulate multiple functions during organ development and in adult tissues. Altered hedgehog signaling has been implicated in disturbed organ development as well as in different degenerative and neoplastic human diseases. Hedgehog signaling plays an important role in determination the fate of the mesoderm of the gut tube, as well as in early pancreatic development, and islet cell function. Recently, it has been shown that deregulation of hedgehog signaling molecules contributes to the pathogenesis and progression of pancreatic cancer and of chronic pancreatitis. Inhibition of hedgehog signaling using hedgehog antagonists reduces pancreatic cancer cell growth in vitro and in vivo, thus holding promise of novel agents in the treatment of this devastating disease. In this review, we discuss the role of hedgehog signaling during pancreatic development, its role in the pathogenesis of both chronic pancreatitis and pancreatic cancer, and lastly, the implications of this newly available information with regards to treatment of pancreatic cancer.

Animals↗