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Biomedical subjects

M W Büchler

Publications and source records attributed to M W Büchler.

At least 19 recordsLinked to original sources
PubMed1999

Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer.

Macrophage Proinflammatory Human Chemokine-3alpha (Mip-3alpha/LARC/Exodus) belongs to a large family of chemotactic cytokines, which participate in directing inflammatory cell migration and in modulating angiogenesis. Mip-3alpha signals through a recently identified G-protein linked 7-transmembrane receptor, CCR6. In this study, we have characterized the expression of Mip-3alpha and CCR6 in 12 normal and 16 cancerous human pancreatic tissues and in 4 cultured pancreatic cancer cell lines, and assessed the effects of Mip-3alpha on growth and invasion of these cell lines. Pancreatic cancer tissues markedly overexpressed Mip-3alpha in comparison with normal pancreatic samples. By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors. In addition, Mip-3alpha was abundant in the macrophages infiltrating the tumor mass. Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines. Mip-3alpha stimulated the growth of one cell line, enhanced the migration of another cell line, and was without effect in the other 2 cell lines. Together, our findings suggest that Mip-3alpha has the potential to act via autocrine and paracrine mechanisms to contribute to the pathobiology of human pancreatic cancer.

Adolescent↗
PubMed1999

Human insulin receptor and insulin signaling proteins in hepatic disease.

Insulin regulates hepatocellular metabolism and growth following insulin receptor (IR) autophosphorylation and activation of the intracellular adapter protein, insulin receptor substrate 1 (IRS-1). IRS-1 activates SH2 domain proteins such as Grb2, which may be vital to hepatocyte growth. To determine if these substances are abnormally expressed under pathophysiologic conditions, IR, IRS-1, Grb2 protein, and IR mRNA were studied in normal human liver (n = 10), cirrhotic liver (n = 10), and hepatocellular carcinoma (HCC) (n = 10) that had been procured during operative procedures. IR mRNA was quantified by S1-nuclease assay using a 195-bp digoxigenin-labeled IR DNA probe and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Protein concentrations were determined by immunoblot analysis following SDS-PAGE of liver homogenate samples. Labeled DNA and antibody-complexed protein were detected by chemiluminescent means and quantified by densitometric analysis (mean densitometric units +/- standard error). Similar levels of IR mRNA were observed in normal tissue, cirrhosis, and HCC. IR protein concentration was significantly greater in HCC than in normal liver (1.82 +/- 0.2 vs 1. 25 +/- 0.17; P < 0.05). IRS-1 was significantly increased in cirrhosis compared to normal liver (1.61 +/- 0.31 vs 0.86 +/- 0.21; P < 0.05). No differences were observed in Grb2 in the three tissue types. Insulin receptor overexpression, previously seen in other tumor types, may confer an insulin-mediated growth advantage in HCC if added receptors reflect functional high affinity binding sites. Although an altered mass of IRS-1 protein was not observed in HCC, an IRS-1 increase in cirrhosis may favor hepatic regeneration.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma.

Epithelial cells of the normal human colonic mucosa secrete an astacin-type metalloprotease, meprin a (E. C. 3.4.24.18, N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase), into the intestinal lumen. We found that Caco-2 cells, a colon carcinoma cell line, expressed endogenous meprin alpha, which was secreted at both the basolateral and apical plasma membrane. The expression of meprin alpha in colorectal cancer was confirmed using Northern blot analysis. On tissue sections, a diversity of carcinoma cells with varying immunoreactivity for meprin alpha was observed. Western blots of a series of 11 paired samples of carcinomas and normal control colon tissue revealed that meprin alpha protein accumulated at significant levels in 6 carcinomas at Union International Contre le Cancer tumor stages I-IV. In contrast, the protease was never detected in normal control tissue samples. Meprin alpha zymogen was activated in the tumor tissue, as shown by a 3-fold increase in enzymatic activity. In conclusion, we describe a cancer-specific sorting of meprin alpha, leading to a redistribution with consecutively increased proteolytic activity in the tumor stroma. Because the protease is known to cleave extracellular matrix components in vitro, meprin a may contribute to tumor progression by facilitating migration, intravasation, and metastasis of carcinoma cells.

Blotting, Western↗
PubMed1999

ErbB-4 mRNA expression is decreased in non-metastatic pancreatic cancer.

The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor (EGFR); erbB-4 is stimulated by the heregulins and betacellulin, which enables this receptor to form heterodimers with erbB-2, a prerequisite for erbB-2 activation. Because the expression of erbB-4 mRNA is generally low in the pancreas, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the erbB-4 levels in human normal and cancerous pancreatic tissue. Our results show that the mRNA expression of this receptor is 6-fold decreased in the non-metastatic stages of pancreatic cancer when compared to tumors with lymph node or distant metastases or to the normal pancreas. In addition, immunohistochemistry demonstrated that in the normal pancreas, the erbB-4 antigen was predominantly present in the cell membrane and cytoplasm of the ductal and acinar cells and at a much lower level, in islet cells. In pancreatic cancer, 61 of 75 samples exhibited weak to moderate immunoreactivity for erbB-4 in the tumor cells. Moreover, in the peri-tumorous region with chronic pancreatitis-like morphological changes, there was weak-to-moderate erbB-4 immunostaining in small ductules and degenerating acinar cells. Uni- and multivariate survival analyses using as variables age, sex, stage of cancer, histo-pathological grading, and erbB-4 immunoreactivity, revealed a significant effect for stage of cancer (p < 0.01) whereby the risk of dying was 2.3 times higher in patients with metastases than in patients without. However, the level of erbB-4 immunoreactivity in pancreatic cancer cells had no influence on patient survival.

Adult↗
PubMed1999

Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer.

Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells.

Adolescent↗
PubMed1999

Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma.

BACKGROUND: Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that have been suggested to influence tumor growth. They mediate their functions via specific cell surface receptors (type I ALK5 and type II TGF-beta receptors). The aim of this study was to analyze the roles of the three TGF-betas and their signaling receptors in human hepatocellular carcinoma (HCC). METHODS: HCC tissue samples were obtained from 18 patients undergoing partial liver resection. Normal liver tissues from 7 females and 3 males served as controls. The tissues for histological analysis were fixed in Bouin's solution and paraffin embedded. For RNA analysis, freshly obtained tissue samples were snap frozen in liquid nitrogen and stored at -80 degrees C until used. Northern blot analysis was used in normal liver and HCC to examine the expression of TGF-beta1, -beta2, -beta3 and their receptors: type I ALK5 (TbetaR-I ALK5), type II (TbetaR-II), and type III (TbetaR-III). Immunohistochemistry was performed to localize the corresponding proteins. RESULTS: All three TGF-betas demonstrated a marked mRNA overexpression in HCC in comparison with normal controls, whereas the levels of all three TGF-beta receptors showed no significant changes. Intense TGF-beta1, TGF-beta2, and TGF-beta3 immunostaining was found in hepatocellular carcinoma cells and in the perineoplastic stroma with immunohistochemistry, whereas no or mild immunostaining was present in the normal liver. For TbetaR-I ALK5 and TbetaR-II, the immunostaining in both HCC and normal liver was mild to moderate, with a slightly higher intensity in the normal tissues. CONCLUSION: The upregulation of TGF-betas in HCC suggests an important role for these isoforms in hepatic carcinogenesis and tumor progression. Moreover, the localization of the immunoreactivity in both malignant hepatocytes and stromal cells suggests that TGF-betas act via autocrine and paracrine pathways in this neoplasm.

Activin Receptors, Type I↗
PubMed1999

Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo.

BACKGROUND & AIMS: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. METHODS: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). RESULTS: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P < 0.01), 2-fold (P < 0.01), and 8-fold (P < 0.01) increase of BMP-2, BMP receptor (R)-IA, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN-1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. CONCLUSIONS: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

Adolescent↗
PubMed1999

SR140333, a substance P receptor antagonist, influences morphological and motor changes in rat experimental colitis.

The etiology of inflammation, edema, and smooth muscle contraction characteristic of inflammatory bowel disease is not clearly understood. There is evidence that several neuropeptides, including substance P (SP), may play a role. In this study we evaluated the ability of a SP-antagonist (SR140333) to modify the course of experimental colitis induced in the rat by trinitrobenzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applied by intrarectal enema. Twelve TNB-treated rats received SR140333, 0.1 mg/kg intraperitoneally, 30 min before the administration of TNB and every 48 hr until death. Twelve rats receiving only intrarectal 0.9% saline served as controls. Rats of each group were killed after 14 days. At day 14, the control group showed no signs of inflammation whereas the TNB-treated rats without SR140333 treatment exhibited a well-established colitis. The TNB-treated group had a higher level of inflammation, as seen histologically and by the significantly greater weight of colon strips, compared to the controls (0.30 +/- 0.09 g vs 0.13 +/- 0.03 g, P < 0.001) and to the SR140333-treated rats (0.30 +/- 0.09 g vs 0.14 +/- 0.05 g, P < 0.001). In addition, smooth muscle contractility was significantly reduced in the inflamed colons of TNB-treated rats when compared with the controls (carbachol: 42.7 +/- 20.3 vs 254.2 +/- 69.78 mg/mm2; SP: 18.5 +/- 10.02 vs 89.45 +/- 23.17 mg/mm2; KCl: 11.4 +/- 2.2 vs 98.32 +/- 33.57 mg/mm2, P < 0.01). However, SR140333-treated rats showed a recovery from inflammation and motor alterations caused by TNB (carbachol: 150.9 +/- 46.1 mg/mm2, P < 0.01; SP: 32.5 +/- 9.4 mg/mm2, P < 0.05; KCl: 125.7 +/- 36.1 mg/mm2, P < 0.01). In conclusion, treatment with SP antagonist SR140333 reduces the severity of colitis and has beneficial effects on the concomitant alterations of contractility. Thus, the blockade of substance P may represent a possibility in the treatment of intestinal inflammation.

Animals↗
PubMed1999

Keratinocyte growth factor ameliorates dextran sodium sulfate colitis in mice.

Keratinocyte growth factor (KGF) is emerging as an important mediator of mucosal defense and repair in the colon. The aim of the present study was to evaluate and further characterize the effects of exogenous KGF administration utilizing the dextran sodium sulfate (DSS) model of colitis in mice. Colitis was induced via oral administration of DSS (5 g/100 ml) to Balb/c mice for eight days. Intraperitoneal administration of KGF (5 mg/kg, once daily) or vehicle (VEH) was initiated 1 hr prior to the induction of the colitis (N = 10, each group). Mucosal injury of the entire colon was histologically assessed and graded. An approximately fourfold reduction in the crypt damage score was noted in the KGF group when compared to controls (VEH) (2.8 +/- 1.03 and 11.4 +/- 0.78, respectively). The significant reduction of mucosal injury in KGF treated mice confirms that KGF is a key mediator maintaining the integrity of the colonic mucosa.

Animals↗
PubMed1999

Transforming growth factor-betas and their signaling receptors are coexpressed in Crohn's disease.

OBJECTIVE: To evaluate mechanisms that contribute to tissue repair and tissue remodeling in Crohn's disease (CD). SUMMARY BACKGROUND DATA: Transforming growth factor-betas (TGF-betas) are involved in different chronic inflammatory disorders. They function by binding to two receptors, type I (TbetaR-I) subtype ALK5 and type II (TbetaR-II), which are concomitantly required for signal transduction. METHODS: Tissues were obtained from 18 patients with CD (10 female patients, 8 male patients, median age 38.7 years [range 16 to 58 years]) undergoing surgery because of CD-related complications. Tissue samples of 18 healthy organ donors (10 female subjects, 8 male subjects, median age 50.3 years [range 15 to 65 years]) served as controls. The expression and localization of TGF-beta1, TGF-beta2, TGF-beta3, TbetaR-IALK5, TbetaR-II, and TbetaR-III were studied by Northern blot analysis, in situ hybridization, and immunohistochemistry. RESULTS: On Northern blot analysis, 94% of the CD samples exhibited enhanced TGF-beta1, TGF-beta3, and TbetaR-II mRNA expression compared with controls. TGF-beta2 was increased in 72%, TbetaR-IALK5 in 72%, and TbetaR-III in 82% of the patients with CD. On in situ hybridization and immunohistochemical analysis, TGF-beta1, TbetaR-IALK5, and TbetaR-II were seen to be colocalized in the lamina propria cells and in the lymphocytes closest to the luminal surface, but also in the remaining epithelial cells, and in fibroblasts of CD tissue samples. CONCLUSIONS: The concomitant overexpression of TGF-betas and their signaling receptors in CD points to a potential role of these regulatory molecules in the pathophysiology of CD. Activation of TGF-beta-mediated pathways might promote the repair of mucosal injury by enhancing the process of reepithelization, but might also contribute to extracellular matrix generation and subsequently to intramural fibrosis and intestinal obstruction.

Adolescent↗
PubMed1999

Alteration of fibroblast growth factor and receptor expression after acute pancreatitis in humans.

After an episode of acute pancreatitis (AP) in humans, the pancreas exhibits varying degrees of fibrosis, acinar cell regeneration, and the formation of tubular complexes. The mechanisms underlying these changes are unknown. By using Northern blot analysis and immunohistochemistry, we assessed the expression and distribution of fibroblast growth factors (FGFs) and their receptor in human pancreatic tissues obtained from patients with AP. By comparison with the normal pancreas, acidic FGF (aFGF) and FGF-receptor 1 (FGFR-1, flg), mRNA levels were significantly decreased in human pancreatic tissues, which were obtained approximately 8 days after onset of AP. In the normal pancreas, acidic FGF, basic FGF, and FGFR-1 immunoreactivity was present at low to moderate levels in a heterogeneous pattern in the cytoplasm of acinar and ductal cells. Two patterns of immunoreactivity were observed in the AP group. In regions that have undergone necrosis, there was complete loss of aFGF, bFGF, and FGFR-1 immunostaining. In contrast, in the regenerating areas, aFGF and bFGF were readily evident in exocrine-type cells, in association with a marked increase in FGFR-1 immunoreactivity. These findings indicate that FGF/receptor expression is altered after AP, and raise the possibility that FGFs may be involved in the process of pancreatic exocrine regeneration during recovery from AP.

Acute Disease↗
PubMed1999

Impacted papilla minor stone in pancreas divisum causing severe acute pancreatitis: a case for early ERCP in acute pancreatitis of unknown origin.

This is the first description of severe acute pancreatitis in pancreas divisum caused by a solitary stone impacted in the minor papilla. Recovery was rapid after diagnostic endoscopic retrograde cholangiopancreaticography (ERCP) and endoscopic stone removal. Since other etiological factors accounting for the acute pancreatitis were carefully excluded, it seems that obstruction of the minor papilla by a solitary pancreatic concrement was the most likely cause of acute pancreatitis. This case report demonstrates the diagnostic importance of early ERCP in cases of etiologically unexplained acute pancreatitis.

Acute Disease↗
PubMed1999

Changes in gastric intramucosal pH following mesenteric traction in patients undergoing pancreas surgery.

BACKGROUND/AIM: During major abdominal surgery, mesenteric traction (MT) may result in hemodynamic instability mainly due to endogenous prostacyclin release. Gastric intramucosal pH (pHi) and PiCO2 are indicators of splanchnic tissue perfusion with a predictive value for the postoperative outcome. We investigated the influence of MT on gastric pHi and on postoperative outcome in patients undergoing pancreas surgery. METHODS: Forty-six consecutive patients scheduled for pancreas surgery were investigated. We registered hemodynamics and pHi by gastric tonometry and documented postoperative outcome (complications, hospital stay). Baseline data (T0) were recorded after skin incision. Further assessments followed 30, 60 and 120 min after intentional MT (T1-3) and at the end of surgery (T4). RESULTS: Thirty-three patients demonstrated a decrease in mean arterial pressure (MAP) following MT, whereas 13 patients showed entirely stable hemodynamics. The significant reduction in MAP in patients with an MT response was not associated with changes in pHi as compared to patients with no response (stable MAP) (T0 7.34 +/- 0.08 vs. 7.35 +/- 0.06; T1 7.34 +/- 0.05 vs. 7.32 +/- 0.07; T2 7.32 +/- 0. 05 vs. 7.31 +/- 0.08; T3 7.32 +/- 0.05 vs. 7.32 +/- 0.07; T4 7.26 +/- 0.1 vs. 7.27 +/- 0.08; mean +/- SD, MT response vs. no response). Neither MT response nor gastric intramucosal acidosis as evidenced by a pHi <7.32 at the end of surgery predicted postoperative complications or longer hospital stay. CONCLUSION: No deterioration of gastric pHi was found, which could reflect acceptable splanchnic perfusion and oxygenation despite systemic blood pressure reactions in patients experiencing an MT response.

Adult↗
PubMed1999

The role of octreotide in the prevention of complications following pancreatic resection.

Postoperative complications following major pancreatic surgery are mainly due to the difficulties of performing a safe and proper anastomosis between the stomach or small bowel and the pancreas. Continuous pancreatic juice secretion and the often soft structure of the pancreatic parenchyma are major risk factors. The present paper summarizes the results of six previously published, placebo-controlled, double-blind trials and one open randomized trial analyzing the efficacy of octreotide in preventing postoperative complications in patients who undergo major pancreatic surgery. Patients were given either octreotide (3x100-150 microg subcutaneously/day) or a placebo perioperatively for 5-7 days starting at least 1 h before operation. The patients were monitored postoperatively for typical postoperative complications such as: leakage of the anastomosis, pancreatic fistula, abscess, fluid collection, shock, sepsis, pulmonary insufficiency, renal insufficiency, bleeding, postoperative pancreatitis, and death. Six of the seven studies showed significantly fewer postoperative complications in the octreotide group in comparison with the placebo group (p<0.05). The effectiveness of octreotide was most apparent in the prevention of secretion-related complications such as fistula, fluid collection and leakage of the anastomosis. These studies demonstrated that inhibition of perioperative pancreatic secretion is a viable treatment concept in patients undergoing major pancreatic surgery. The perioperative and prophylactic application of octreotide in patients who undergo major pancreatic resection reduces the postoperative complication rate significantly.

Humans↗
PubMed1999

The role of octreotide and somatostatin in acute and chronic pancreatitis.

Acute pancreatitis may follow a mild or a severe course. Whereas mild or edematous pancreatitis is a self-limiting disease with a low complication rate and low death rate, morbidity and mortality in severe or necrotizing pancreatitis are still unacceptably high. The major problem is the lack of a specific drug, especially in the early phase of the disease, to interfere with the systemic inflammatory response syndrome and to limit or prevent complications of the disease. Although the initiating pathophysiological process is not known, the destruction of the gland ('autodigestion') by digestive enzymes may be responsible for disease progression. Inhibition of pancreatic activity, which reduces exocrine secretion and further prevents the release and activation of enzymes, was therefore suggested as a specific treatment concept. The results of clinical investigations using somatostatin or its analogue are controversial, since all these trials had low statistical power. In a recent multicenter randomized controlled study with a large number of patients (n = 302) (and an adequate level of disease severity), no benefit of octreotide on progression or outcome was found. Chronic pancreatitis is characterized by an irreversible destruction of the exocrine and endocrine pancreatic parenchyma leading to maldigestion and diabetes. Pain, which may be caused by increased ductal pressure, is one of the most dominant symptoms in chronic pancreatitis. However, no beneficial effects on pain with pancreatic exocrine secretion-inhibiting drugs have been demonstrated. Treatment of other complications of the disease (pseudocyst formation, fistula and pancreatic ascites), with somatostatin or octreotide has given conflicting results. However, in a prophylactic clinical setting (e.g. elective pancreatic surgery) the inhibition of exocrine pancreatic secretion reduces complications.

Acute Disease↗