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Helmut Friess

Publications and source records attributed to Helmut Friess.

At least 163 records · Page 9Linked to original sources
PubMed2002

Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer.

The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclin-dependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.

Adenocarcinoma↗
PubMed2002

Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents.

PURPOSE: Bax plays an important role in the regulation of apoptosis induced by chemotherapy and other stimuli. We therefore investigated the role of Bax in drug-induced apoptosis in human pancreatic cancer cells. METHOD: A tetracycline-inducible retroviral expression vector bearing the human bax-alpha gene was constructed. ASPC-1 cells were stably infected with this vector. The sensitivity of the transformed cell line to gemcitabine and 5-Fu was assessed. RESULTS: Western blots revealed that Bax expression was enhanced in these cells by the tetracycline analogue doxycycline. Enhanced expression of Bax itself did not inhibit the growth rate of infected cells and did not influence expression of Bcl-2 and Bcl-xL. However, it significantly increased the sensitivity of cells to the chemotherapeutic drugs gemcitabine and 5-Fu. These drugs also activated caspase-8 and caspase-3 by up to ninefold. Caspase activation and/or an imbalance in Bax and Bcl-2/Bcl-xL expression may be the reasons for the augmentation of cytotoxicity by these drugs. CONCLUSIONS: The findings suggest that enhanced Bax expression may have therapeutic application in enhancing the efficacy of chemotherapy in pancreatic cancers.

Anti-Bacterial Agents↗
PubMed2002

Connective tissue growth factor gene expression alters tumor progression in esophageal cancer.

The ability of cancer cells to initiate specific fibroblast reactions may subsequently determine tumor evolution. In the present study we examined the coordinated expression of transforming growth factor-beta-1 (TGF-beta1), its signaling receptors, and its downstream mediator-connective tissue growth factor (CTGF)--and their impact on tumor progression and fibrogenesis in esophageal carcinomas. Messenger ribonucleic acid (mRNA) expression of TGF-beta1, CTGF, TGF-beta receptor subtype I ALK5 (TbetaR-IALK5), and TGF-beta receptor type II (TbetaR-II) was studied by Northern blot analysis in esophageal cancer and the normal esophagus. By means of immunohistochemistry and Western blot analysis, the respective proteins were localized in the tissue samples and the protein content was quantitated. Northern blot analysis revealed 3-fold and 4-fold increases (p < 0.05) in TGF-beta1 and CTGF mRNA levels, respectively, in esophageal cancer in comparison with normal controls, whereas TbetaR-I mRNA levels were significantly decreased and TbetaR-II mRNA levels were unchanged in the cancer samples. Immunostaining revealed results similar to those seen on the RNA level. TGF-beta1 and CTGF immunoreactivity were increased, TbetaR-II was unchanged, and TbetaR-IALK5 immunoreactivity was decreased. CTGF immunoreactivity was mainly present in the stroma surrounding the cancer cells but was also present in the cancer cells. The degree of fibrosis was different in squamous and adenocarcinomas and was significantly related to CTGF mRNA expression levels. The presence of CTGF in squamous cell carcinomas was associated with longer survival, whereas in adenocarcinomas it influenced survival negatively. The findings indicate that TGF-beta signaling is disturbed in esophageal cancer. CTGF, a downstream effector of TGF-beta action, differentially influences the composition of tumor microenvironment and distinct cell-matrix interactions in the two histological types of esophageal carcinoma, resulting in differences in tumor progression and patient survival.

Adenocarcinoma↗
PubMed2002

DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer.

To test the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis in susceptible individuals, aromatic DNA adducts and 8-hydroxyguanosine (8-OH-dG) were measured by (32)P-postlabeling and HPLC-EC, respectively, in 31 pancreatic tumors and 13 normal tissues adjacent to the tumor from patients with pancreatic cancer. Normal pancreatic tissues from 24 organ donors, from six patients with non-pancreatic cancers, and from five patients with chronic pancreatitis served as controls. It was found that tissue samples from patients with pancreatic cancer had significantly higher levels of both aromatic DNA adducts and 8-OH-dG compared with control samples. The mean (+/-S.D.) levels of aromatic DNA adducts were 101.8+/-74.6, 26.9+/-26.6, and 11.2+/-6.6 per 10(9) nucleotides in adjacent tissues, tumors, and controls, respectively. The mean (+/-S.D.) levels of 8-OH-dG were 11.9+/-9.6, 10.8+/-10.6, and 6.7+/-4.6 per 10(5) nucleotides in adjacent tissues, tumors, and controls, respectively. Polymorphisms of the CYP1A1, CYP2E1, NAT1, NAT2, GSTM1, MnSOD, and hOGG1 genes were determined in these patients. The level of aromatic DNA adducts was significantly associated with polymorphism of the CYP1A1 gene. No significant correlation was found between the level of 8-OH-dG and the MnSOD, GSTM1, and hOGG1 polymorphisms. However, one novel polymorphism/mutation of the hOGG1 gene was found in a pancreatic tumor. Mutation at codon 12 of the K-ras gene was found in 25 (81%) of 31 pancreatic tumors, including three G-to-A transitions and 22 G-to-T transversions. Patients with the G-to-T mutation had a significantly higher level of aromatic DNA adducts than those with G-to-A or wild-type codon (P=0.02). On the other hand, the K-ras mutation profile was not related to the level of 8-OH-dG. Given the limitation of sample size, these preliminary data lend further support the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis.

Adult↗
PubMed2002

Influences of the lysosomal associated membrane proteins (Lamp-1, Lamp-2) and Mac-2 binding protein (Mac-2-BP) on the prognosis of pancreatic carcinoma.

BACKGROUND: Lamps and Mac-2-BP are ligands of galectin-3, and they were suggested to influence tumor proliferation and metastasis formation. The authors studied the expression of Lamp-1, Lamp-2, and Mac-2-BP in pancreatic carcinoma and evaluated their influence on patient prognosis. METHODS: Northern blot analysis, in situ hybridization, and immunohistochemistry were performed in 12 normal and 28 pancreatic carcinoma tissue samples and in pancreatic carcinoma cell lines. The molecular findings in the tumor samples were correlated with the prognosis and histopathologic tumor characteristics. In addition, in Lamp-1 transfected CAPAN-1 pancreatic carcinoma cells, cell proliferation was analyzed. RESULTS: Lamp-1, Lamp-2, and Mac-2-BP were overexpressed in 61% (1.6-fold increase, not significant), 71% (3.0-fold increase, P < 0.01), and 93% (5.6-fold increase, P < 0.01) of the pancreatic carcinoma samples. Lamp-1 and Lamp-2 immunoreactivity was present at the luminal side of the ductal carcinoma cells whereas Mac-2-BP immunoreactivity was diffusely spread over the whole cytoplasm and the nucleolus of ductal carcinoma cells. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited high Lamp-1 mRNA expression lived significantly longer (median, 17 months) after tumor resection than patients whose tumors exhibited low to moderate Lamp-1 mRNA levels (median, 8 months; P < 0.02). No relation between Lamp-2 and Mac-2-BP mRNA expression and any of the histopathologic parameters was found. Lamp-1 transfected CAPAN-1 cells showed decreased cell growth compared with the nontransfected cells. CONCLUSIONS: Lamp-1 might influence local tumor progression rather than the formation of tumor metastasis in pancreatic carcinoma, whereas Mac-2-BP and Lamp-2 seem to have little influence on these parameters in pancreatic carcinoma.

Aged↗
PubMed2002

Adhesion molecules in human pancreatic cancer.

BACKGROUND AND OBJECTIVES: Adhesion molecules are cell surface glycoproteins that are important in cell-to-cell and cell-to-extracellular matrix interactions. In the present study, we analyzed the adhesion molecules ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and ELAM-1 (endothelial leukocyte adhesion molecule-1) in human pancreatic cancer. METHODS: ICAM-1, VCAM-1, and ELAM-1 were analyzed in 20 pancreatic cancer specimens and 20 normal pancreatic tissues. mRNA expression encoding ICAM-, VCAM-1, and ELAM-1 was assessed with Northern blot analysis. The distribution and localization of ICAM-1, VCAM-1, and ELAM-1 was determined in the pancreatic specimens by immunohistochemistry. RESULTS: Northern blot analysis revealed a 5.4-fold increase of ICAM-1 (P<0.01) and a 3.7-fold increase in VCAM-1 (P<0.01) mRNA expression in cancer samples in comparison with normal controls. In contrast, ELAM-1 mRNA levels did not show significant differences between the cancer and the normal tissues. Immunohistochemical analysis of cancer tissues showed strong immunostaining for ICAM-1 and VCAM-1, and faint immunostaining for ELAM-1 in the pancreatic cancer cells. Fibrotic or noncancerous pancreatic tissue adjacent to the cancer mass was devoid of any immunoreactivity for ICAM-1, ELAM-1, and VCAM-1. In contrast, the normal pancreas exhibited no immunoreactivity of ICAM-1, ELAM-1, and VCAM-1. CONCLUSIONS: Enhanced expression of ICAM-1 and VCAM-1 in human pancreatic cancers suggests a role in tumor pathogenesis. The increase of these adhesion molecules might influence the detachment of cancer cells in the primary tumor, might contribute to cancer cell migration and the spread of cancer cells to distant organs, or both.

Adenocarcinoma↗
PubMed2002

Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells.

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is overexpressed, and this overexpression is associated with increased perineural invasion. NGF has the potential to stimulate the growth of some pancreatic cancer cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase receptor A and mitogen-activated protein kinase activation; it is dependent on the expression levels of tyrosine kinase receptor A and p75 receptors. To determine whether cancer cell-derived NGF can participate in the regulation of pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were stably transfected with a full-length human beta-NGF expression vector. In vitro and in vivo growth characteristics were analyzed by proliferation assays and invasion assays and in a nude mouse tumor model. Stable transfection of NGF in PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in doubling times of up to 50%, and in an approximately twofold increase in anchorage-independent cell growth and cell invasion. Furthermore, stably transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These results suggest that NGF has the capacity to act in a paracrine and/or an autocrine manner in pancreatic cancer and that it enhances cancer cell growth and invasion in vivo, thereby contributing to the aggressiveness and poor prognosis of this disease.

Animals↗
PubMed2002

How to do a safe pancreatic anastomosis.

BACKGROUND/PURPOSE: Leakage of pancreaticojejunostomies has been associated with morbidity and mortality after pancreatic head resection. Different techniques have been described to perform a safe anastomosis to the left pancreatic remnant. METHODS: The pancreaticojejunostomy is preferably performed as an end-to-side anastomosis; drainage of the pancreatic duct by catheters or stents is not performed at our institution. RESULTS: Experience in more than 331 patients who underwent pancreaticojejunostomy indicates that a two-layer, single-stitch technique, with absorbable monofilament sutures and duct-to-mucosa adaptation, is a reliable method, with a pancreatic fistula rate of 2%. CONCLUSIONS: The results obtained with the described technique of pancreaticojejunostomy indicate that the pancreatic anastomosis is very safe when performed by experienced hands and does not necessarily contribute to morbidity and mortality after pancreatic head resection. The prevalence of pancreatic fistulae and intraabdominal abscesses may further decrease, and the prevalence of nonpancreatic complications may have a more important impact on the outcome in the future.

Anastomosis, Surgical↗
PubMed2002

Down-regulation of DOC-2 in colorectal cancer points to its role as a tumor suppressor in this malignancy.

PURPOSE: Colorectal cancer is the second most common cause of cancer death and the fourth most prevalent carcinoma in the Western world. Loss of tumor-suppressor gene function in colon cancer leads to ineffective negative growth regulation that is normally exerted by growth-suppressing factors. DOC-2/hDAB2 is a newly identified candidate tumor-suppressor gene in ovarian cancer and choriocarcinoma. In these tumors it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. In the present study we sought to determine the role of DOC-2 in colorectal cancer. METHODS: DOC-2 expression was analyzed by Northern blot analysis, hybridization, and immunohistochemistry in 27 primary and metastatic colorectal cancers and in 15 normal colon tissues in correlation with clinicopathologic data. RESULTS: Northern blot analysis demonstrated a decrease of DOC-2 messenger RNA levels in primary and metastatic colorectal cancers compared with normal controls. In normal colorectal tissues, DOC-2 immunoreactivity was strongly present on the surface columnar epithelial cells. In contrast, DOC-2 immunoreactivity was weak to moderate in the epithelium of colorectal cancers, and the intensity of the signals in colorectal cancer was greatly decreased compared with the normal colorectal tissues. In addition, DOC-2 immunoreactivity in lymph node and liver metastasis was weak to absent in the cancer cells and significantly decreased compared with their primary tumors. CONCLUSIONS: The expression of DOC-2 is down-regulated in primary tumors and metastases of colorectal cancer, which suggests that DOC-2 functions as a tumor suppressor in this malignancy.

Adaptor Proteins, Signal Transducing↗
PubMed2002

5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue.

The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However, the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including, PANC-1, AsPC-1, and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally, 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite, leukotriene B(4). The current study demonstrated marked expression of 5-LOX and the leukotriene B(4) receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease.

Arachidonate 5-Lipoxygenase↗
PubMed2002

Glypican-3 expression is markedly decreased in human gastric cancer but not in esophageal cancer.

BACKGROUND: Deregulation of the expression of glypican-3, a heparan sulfate proteoglycan, has been demonstrated in several human cancers. METHODS: In the present study, glypican-3 mRNA expression was analyzed by Northern blotting and in situ hybridization in 20 normal and 41 cancerous esophageal specimens as well as in 15 normal and 32 cancerous gastric tissues. RESULTS: Glypican-3 mRNA was expressed in both normal and esophageal cancer tissues without a significant difference between normal and cancerous tissues, and without a correlation with histological type, tumor stage, tumor grade, or patient survival. Moderate to strong glypican-3 mRNA signals were found in the cytoplasm of squamous epithelial cells of the normal esophagus. In both squamous and adenocarcinomas of the esophagus glypican-3 mRNA signals were also moderately to strongly present in the cytoplasm of the cancer cells. In gastric tissues, glypican-3 mRNA was present in 53% of normal gastric tissue samples, but was below the detection level in all examined gastric cancer samples. Glypican-3 mRNA signals were moderately to strongly present in the cytoplasm of gastric mucosal epithelial cells, but were only very faintly present in some cancer cells. CONCLUSIONS: Glypican-3 may be involved in the growth control of normal esophageal and gastric epithelial cells. Furthermore, our results suggest that glypican-3 may play a tumor suppressor role in gastric but not in esophageal cancer.

Adult↗
PubMed2002

Pancreatic polypeptide in pancreatitis.

Pancreatitis is a disease with increasing incidence which can be divided into an acute and a chronic form. In both acute and chronic pancreatitis, changes in plasma concentration of pancreatic polypeptide (PP) and its regulation have been reported. In daily clinical work a serologic test for the precise diagnosis and staging of acute and chronic pancreatitis is still desirable. Therefore, many studies have investigated plasma concentrations of PP in acute and chronic pancreatitis as a diagnostic marker and as a therapeutic option to treat pancreatogenic diabetes mellitus. Although the study results are presently inconclusive and potentially contradictory, the findings are nevertheless encouraging, and indicate that PP might have a role in diagnosis, grading and estimation of the prognosis of pancreatitis. Further data and prospective controlled studies are needed to judge whether PP is of clinical value for diagnosing, staging and predicting long-term outcome in acute and chronic pancreatitis.

Acute Disease↗
PubMed2002

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors.

Pancreatic ductal adenocarcinomas (PDACs) overexpress various cell-surface tyrosine kinase receptors, including the type I high-affinity fibroblast growth factor receptor (FGFR-1). The purpose of this study was to determine whether FGFR-targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibroblast growth factor (FGF)-2 linked to a Fab' fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase (AdTK) gene. An adenoviral vector containing the firefly luciferase reporter gene (AdLuc) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high-affinity FGFRs, transduction with AdLuc was enhanced 7- to 10-fold with the FGF2-Fab' conjugate, whereas in L6 cells transfected to express FGFR-1, it was enhanced 39- to 52-fold. The pancreatic cancer cell lines expressed variable levels of the four high-affinity FGF receptors, and exhibited 2- to 34-fold increases in gene transduction in the presence of the FGF2-Fab' conjugate. In the absence of FGF2-Fab' there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2-Fab', enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC-1 and PANC-1 cells were resistant to ganciclovir even in the presence of FGF2-Fab'. Ganciclovir-mediated inhibition was dependent on the conjugate in CAPAN-1 and COLO-357 cells, but was independent of the conjugate in T3M4 and MIA-PaCa-2 cells. Real-time quantitative PCR of laser-captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2-Fab' in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various high-affinity FGFRs. In view of the overexpression of high-affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2-Fab' may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.

Adenocarcinoma↗
PubMed2002

Adult-type hepatocellular carcinoma in the center of a fibrolamellar hepatocellular carcinoma.

A large hepatic tumor was detected in the noncirrhotic liver of a 27-year-old female patient. The tumor was radiologically characterized by a peripheral mass encircling a central ovoid tumor, and was resected by an extended right hemihepatectomy. Histologic examination revealed that the peripheral and major component of the tumor represented a fibrolamellar hepatocellular carcinoma, whereas the central, well-demarcated tumor was a less well-differentiated adult-type hepatocellular carcinoma completely encircled by the former. Cells of the peripheral tumor mass abundantly expressed cytokeratin-7, typically present in the fibrolamellar variant, whereas no cytokeratin-7 immunoreactivity was found in the central tumor. To our knowledge, this is the first reported case of a not admixed but clearly separated evolution of these 2 histologic patterns within the same tumor, and suggests that the 2 types of hepatocellular carcinoma may share a common pathogenic pathway.

Adult↗
PubMed2002

Connective tissue growth factor is involved in pancreatic repair and tissue remodeling in human and rat acute necrotizing pancreatitis.

OBJECTIVE: To analyze the involvement of connective tissue growth factor (CTGF) in the transforming growth factor-beta (TGF-beta) pathway during acute necrotizing pancreatitis (ANP) in humans and rats. SUMMARY BACKGROUND DATA: Connective tissue growth factor is involved in several fibrotic diseases and has a critical role in fibrogenesis and tissue remodeling after injury. METHODS: Normal human pancreas tissue samples were obtained through an organ donor program from five individuals without a history of pancreatic disease. Human ANP tissues were obtained from eight persons undergoing surgery for this disease. In rats, ANP was induced by intraductal infusion of taurocholate. The expression of CTGF was studied by Northern blot analysis, in situ hybridization, and immunohistochemistry in both human and rat pancreatic tissue samples. RESULTS: Northern blot analysis revealed enhanced CTGF mRNA expression in human ANP tissue samples compared with normal controls. In addition, a concomitant increase in TGF-beta1 was present. By in situ hybridization, CTGF mRNA was localized in the remaining acinar and ductal cells and in fibroblasts. In regions of intense damage adjacent to areas of necrosis, CTGF mRNA signals were most intense. Inflammatory cells were devoid of any CTGF mRNA signals. By immunohistochemistry, CTGF protein was localized at high levels in the same cell types as CTGF mRNA. In ANP in rats, concomitantly enhanced mRNA levels of CTGF, TGF-beta1, and collagen type 1 were present, with a biphasic peak pattern on days 2 to 3 and day 7 after induction of ANP. CONCLUSIONS: These data indicate that CTGF participates in tissue remodeling in ANP. The expression of CTGF predominantly in the remaining acinar and ductal cells indicates that extracellular matrix synthesis after necrosis is at least partly regulated by the remaining pancreatic parenchyma and only to a minor extent by inflammatory cells. Blockage of CTGF, a downstream mediator of TGF-beta in fibrogenesis, might be useful as a target to influence and reduce fibrogenesis in this disorder.

Adult↗
PubMed2002

Human macrophage metalloelastase worsens the prognosis of pancreatic cancer.

OBJECTIVE: To evaluate the role of human macrophage metalloelastase (HME) in pancreatic cancer. SUMMARY BACKGROUND DATA: HME, a member of the human matrix metalloproteinase family, possesses elastolytic activity and is critical for the degradation of extracellular matrix proteins. Inasmuch as tumor invasion and metastasis formation require lysis of extracellular matrix, HME plays a critical role in both processes. METHODS: HME expression was analyzed by Northern blot analysis, reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry in 39 pancreatic cancer tissues and 13 normal controls. The molecular data were related to clinicopathologic parameters and patient survival. RESULTS: In human pancreatic cancer, overexpression of HME mRNA was present in 25 of 39 pancreatic cancer tissues (64%) and in five pancreatic cancer cell lines. In contrast, low levels of HME mRNA expression were present in 13 normal pancreatic tissues samples. By Western blot analysis, high levels of HME were found in pancreatic cancer tissues and in the pancreatic cancer cell lines compared with the normal controls. Fifty-six percent of the cancer samples exhibited HME immunoreactivity in the cancer cells, and 63% in the stromal cells. Analysis of the survival data revealed that patients whose tumors exhibited HME mRNA overexpression lived significantly shorter compared with patients whose tumors did not overexpress HME. No relationship between HME expression and tumor stage, tumor grading, or presence of lymph node metastases was found. CONCLUSIONS: These findings indicate that HME participates in pancreatic cancer progression and that its presence worsens the prognosis. These data suggest a benefit of its inhibition in the treatment of pancreatic cancer.

Adult↗