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H Friess

Publications and source records attributed to H Friess.

At least 199 records · Page 11Linked to original sources
PubMed1998

Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma.

Src family tyrosine kinases participate in the regulation of cell adhesion, cell growth and differentiation. Here, we examine for the first time the potential role of Src for growth regulation of human pancreatic carcinoma cells. By immunohistochemical analysis, Src was overexpressed in 13/13 pancreatic carcinoma tissue but not in 6 normal pancreatic tissue specimen. In Western blots of total cellular extracts, Src protein expression was elevated in 14/17 carcinoma cell lines as compared to normal pancreas or cultured human pancreatic duct cells. Kinase activity was only detectable in cancer cells and did not correlate with the amount of kinase protein or with the expression of the regulatory kinase Csk, indicating that Src is not regulated through protein expression or through expression of Csk. The Src-specific tyrosine kinase inhibitor herbimycin A decreased cell growth in a dose-dependent manner. We suggest that Src family kinases participate in growth regulation of pancreatic cancer cells.

Aged↗
PubMed1998

Cloning of a new Kunitz-type protease inhibitor with a putative transmembrane domain overexpressed in pancreatic cancer.

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel putative transmembrane protein with two Kunitz-type serine protease inhibitor domains. The identified gene named kop (Kunitz domain containing protein overexpressed in pancreatic cancer) was assigned to chromosome 19 in the region 19q13.1. Kop was detected at high levels in pancreatic cancer cell lines and was overexpressed in pancreatic cancer tissues as compared to both, normal pancreas and chronic pancreatitis tissues. Being a member of the Kunitz-type serine protease inhibitor family, this new gene may participate in tumour cell invasion and metastasis and in the development of the marked desmoplastic reaction typical for human pancreatic cancer tissues. In this context, the fact that kop has a putative transmembrane domain may have functional implications of particular interest.

Adenocarcinoma↗
PubMed1998

DNA adducts in human pancreatic tissues and their potential role in carcinogenesis.

Pancreas cancer is the fourth and fifth leading cause of cancer death for men and women, respectively, in the United States. Although the etiology of this cancer is poorly understood, smoking and dietary fat have been implicated by epidemiological studies. To test the hypothesis that DNA damage derived from carcinogen exposure and diet is involved in pancreatic carcinogenesis, aromatic and lipid peroxidation-related DNA adducts in 13 normal tissues adjacent to tumor and 20 tumors from pancreatic cancer patients were analyzed by 32P-postlabeling. Normal pancreatic tissues from 5 nonpancreatic cancer patients and 19 healthy organ donors served as controls. To correlate the DNA adduct level with patients' characteristics, information on age, sex, body mass index, and smoking status of pancreatic cancer patients were collected from medical records. A significantly higher level of total DNA adducts was detected in pancreatic cancer patients as compared with controls. The mean level of adducts/10(8) nucleotides in adjacent normal pancreatic tissues from pancreatic cancer patients (A tissues) was 102 +/- 21 compared with 39 +/- 6 and 13 +/- 1 in pancreatic tumor tissues (T tissues) and normal pancreatic tissues from controls (C tissues), respectively. Among the adducts observed, one single aromatic adduct (spot 1) was present in 100, 90, and 0% of the A, T, and C tissues, respectively. Two novel clusters of adducts (spots 2 and 3) were observed in 11 of 13, 12 of 20, and 2 of 24 of A, T, and C tissues, respectively, and the presence of these adducts was positively correlated with smoking status. In addition, the previously defined smoking-related diagonal radioactive zone was detected in three A samples only, although 50% (10 of 20) of the patients with pancreatic cancers in this study were ever smokers. Putative lipid peroxidation-related adducts were detected in all samples examined and were significantly higher in A than in T and C samples. Multiple regression analyses showed that body mass index was positively correlated to the levels of spot 1 and the lipid peroxidation-related adducts in A tissues and the total aromatic adducts in tumors. Smoking was also positively correlated to the level of total adducts. These observations are consistent with previous epidemiological findings and support the hypothesis that DNA damage related to carcinogen exposure and lipid peroxidation is involved in human pancreatic carcinogenesis.

Adult↗
PubMed1998

KAI1, a new metastasis suppressor gene, is reduced in metastatic hepatocellular carcinoma.

Down-regulation of KAI1 expression has been shown to be associated with formation of metastases or disease progression in prostate and pancreatic cancer. In the present study we analyzed the expression pattern of KAI1 in metastatic and nonmetastatic hepatocellular carcinomas (HCCs) in comparison with normal livers to evaluate whether alteration of KAI1 also facilitates the metastatic ability in this malignancy. Thirty-nine primary HCCs and 10 normal liver tissue samples were studied for KAI1 messenger RNA (mRNA) expression with use of Northern blot analysis and in situ hybridization. By Northern blot analysis, moderate to strong KAI1 mRNA expression was present in normal liver samples. In contrast, KAI1 mRNA expression in tissue samples of primary HCCs was markedly decreased compared with normal controls. The normal/tumor ratio of KAI1 mRNA expression was 2.6:1 (P <.01). Primary HCCs that gave rise to metastasis showed significantly lower KAI1 mRNA levels than nonmetastasized HCCs (P <. 05). As seen by in situ hybridization, moderate to strong cytoplasmic KAI1 mRNA staining was present in almost all normal hepatocytes. Bile ducts, blood vessels, and connective tissue showed no or only faint KAI1 mRNA expression in the normal liver samples. In nonmetastatic HCCs, the cancer cells exhibited in situ hybridization signals that were similar to the normal controls. In contrast, most of the primary HCC cells in samples with metastases showed only faint or moderate KAI1 mRNA expression predominantly in the perinuclear regions. When KAI1 mRNA expression of primary hepatocellular cancer cells was compared with metastasized cancer cells in lymph nodes, with intrahepatic satellite metastasis, or with peritoneal metastasis in the same patients, significantly lower (P <.01) KAI1 mRNA levels were present in the metastasized HCC cells. Reduced KAI1 mRNA in HCC cells seems to influence their metastatic ability and thereby enhances the malignant potential of HCC.

Aged↗
PubMed1998

Celiac axis infusion chemotherapy in advanced nonresectable pancreatic cancer.

CONCLUSION: Based on these data we suggest that regional intra-arterial chemotherapy for advanced pancreatic cancer seems not to be superior to common treatment modalities, such as combined radiochemotherapy. BACKGROUND: The prognosis for advanced pancreatic cancer is very poor. No standard treatment is available. Recently, better survival and quality of life was reported from regional cancer treatment via celiac axis infusion. In an attempt to confirm these results we conducted a phase II study of intra-arterial chemotherapy for nonresectable pancreatic cancer. METHODS: From May 1994 to February 1995, 12 consecutive patients with biopsy-proven advanced ductal carcinoma of the exocrine pancreas were given intra-arterial infusions consisting of Mitoxantrone, 5-FU + folinic acid, and Cisplatin via a transfemorally placed catheter in the celiac axis. Six patients were classified as UICC stage III and six as stage IV with the liver as the sole site of distant metastasis. Nine patients had primary and three had recurrent pancreatic carcinoma after a Whipple procedure. Nonresectability of primary tumors was assessed in all patients by laparotomy or laparoscopy. RESULTS: A total of 31 cycles of chemotherapy (mean 2.6 cycles/patient) was administered. Catheter placement was technically feasible in all cycles. A groin hematoma was the only catheter complication. The follow-up by CT scans at 2-mo intervals revealed partial remission in 1 patient (8%), temporary stable disease in 4 patients (33%), and disease progression in 7 patients (58%). The same response was obtained after analyzing the CA 19-9 course. Median survival in stage III patients was 8.5 mo (3-12 mo) and in stage IV patients 5 mo (2-11 mo). Toxicity according to WHO criteria consisted of grade III (4 events), grade II (10 events), and grade I (17 events), mainly resulting from leucopenia and diarrhea/vomiting. Nine of 11 patients experienced temporary relief of pain immediately after regional treatment.

Adult↗
PubMed1998

Characterization of keratinocyte growth factor and receptor expression in human pancreatic cancer.

Keratinocyte growth factor (KGF) is an angiogenic and mitogenic polypeptide that has been implicated in cancer growth and tissue development and repair. Its actions are dependent on its binding to a specific cell-surface KGF receptor (KGFR), which is encoded by the fibroblast growth factor (FGF) receptor type II (FGFR-2) gene. In the present study, we compared the immunohistochemical localization of KGF and KGFR/FGFR-2 in the normal and cancerous pancreas using specific antibodies that recognize KGF and KGFR/FGFR-2 and examined the expression of KGF, KGFR, and FGFR-2 in human pancreatic cancer by in situ hybridization with the corresponding riboprobes. In the normal pancreas, KGF immunoreactivity was present principally in the islet cells, whereas KGFR/FGFR-2 immunoreactivity was present both in the islet and ductal cells. In the pancreatic cancers, moderate KGF and moderate to strong KGFR/FGFR-2 immunoreactivity was present in many of the cancer cells. Furthermore, the ductal and acinar cells adjacent to the cancer cells exhibited moderate to strong KGF and KGFR/FGFR-2 immunoreactivity. By in situ hybridization, KGF, KGFR, and FGFR-2 were overexpressed and co-localized in the cancer cells within the pancreatic tumor mass but were even more abundant in the acinar and ductal cells adjacent to the cancer cells. These findings indicate that KGF, KGFR, and FGFR-2 are overexpressed in both the cancer cells and the adjacent pancreatic parenchyma and raise the possibility that KGF may act in an autocrine and paracrine manner to enhance pancreatic cancer cell growth in vivo.

Fibroblast Growth Factor 10↗
PubMed1998

Keratinocyte growth factor promotes healing of left-sided colon anastomoses.

BACKGROUND: Inadequate healing and consequent leakage from bowel anastomoses are a significant cause of postoperative morbidity and mortality. Systemic application of keratinocyte growth factor (KGF) has been shown to promote mucosal healing in models of colitis in rats and mice. The aim of the present study was to evaluate the effect of systemic KGF administration on healing of colonic anastomoses in rats. METHODS: Rats underwent laparotomy, division of the left colon, and sigmoido-sigmoidostomy. KGF (5 mg/kg) or vehicle were administered intraperitoneally in two groups (n = 30 per group) 12 hours prior to surgery, and then once daily until sacrifice (6 animals per group; 2, 4, 7, 12, and 21 days after surgery). Bursting pressure measurements, histologic evaluation, morphometric analysis, mucin and collagen staining, and hydroxyproline measurements of the anastomotic site were performed. RESULTS: Administration of KGF significantly increased anastomotic bursting pressure on postoperative days 2, 4, and 7 by 34%, 49%, and 19%, respectively. Histology, mucin staining, and measurements of the colonic crypt depth showed markedly less extended inflammation with an increased acidic mucin content and a significantly thickened mucosal layer in the KGF treated group when compared with vehicle-treated animals. CONCLUSIONS: KGF promotes healing of colonic anastomoses in rats during a 1-week postoperative period following large bowel surgery. KGF may be acting to accelerate host reparative processes as well as to enhance protection of the anastomotic wound bed by increased colonic epithelium proliferation, increased mucus production, and reduction of the inflammatory activity at the anastomotic site.

Anastomosis, Surgical↗
PubMed1998

Adaptation of the human pancreas to inhibition of luminal proteolytic activity.

BACKGROUND & AIMS: Feedback regulation of pancreatic enzyme secretion is well established in animals, and their pancreases are able to adapt to intraduodenal inhibition of pancreatic enzymes by proteinase inhibitors such as Camostate (FOY-305; Schwarz GmbH, Monheim, Germany). In this study, we addressed whether similar adaptive changes occur in the human pancreas after 4 weeks of 2 g/day Camostate application. METHODS: Before, at the end of, and 2 weeks after 4-week Camostate treatment (four times 500 mg daily), pancreatic changes were analyzed with the use of a secretin-cerulein test, a test-meal stimulation, cholecystokinin plasma measurement, and standardized ultrasonographic investigations of the pancreas. RESULTS: Duodenal trypsin output after secretion stimulation was significantly increased (+44%; P < 0.01) and duodenal bicarbonate output decreased 22% (P < 0.05) after 4 weeks of Camostate application. The size of the pancreatic head (vertical) increased 8% (P < 0.05) at week 4 and decreased to pretreatment values 2 weeks after treatment (week 6). The other three diameters measured (head oblique, body, and tail) showed a similar pattern. Stimulated cholecystokinin plasma levels 15 minutes after application of a standard test meal increased 62% (P < 0.05). CONCLUSIONS: The human pancreas adapts to oral application of the proteinase inhibitor Camostate. These findings support the theory that feedback control of the exocrine pancreas operates in humans.

Adaptation, Physiological↗
PubMed1998

Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2.

ErbB3 is a transmembrane signaling molecule that shares close structural homology with epidermal growth factor receptor (EGFR), erbB2, and erbB4. They have all been implicated in cell transformation and tumor pathogenesis, but very little is known about the role of erbB3 in normal colon and colorectal cancer. Therefore, in the current study, we determined whether erbB3 is found in normal human colon and whether its expression is altered in colorectal cancer. Because of some evidence that erbB3 might interact with erbB2 and EGFR, respectively, by heterodimerization, we also included erbB2 and EGFR analysis with special regard to coexpression. The study was performed on 35 patients operated on for colorectal carcinoma. The normal human colon showed weak erbB3 and erbB2 immunostaining, predominantly in surface epithelial cells. EGFR immunoreactivity in normal colon varied from weak to strong. In contrast, in 31 of 35 (89%) and in 29 of 35 (83%) colonic cancers, moderate to strong immunoreactivity for erbB3 and erbB2, respectively, was present in most epithelial cancer cells. A concomitant erbB3 and erbB2 immunostaining advantage could be found in 77% of cancerous tissues in comparison with the normal colon. No difference in EGFR immunostaining was evident between normal colon and cancer. Northern blot analysis showed an increase in erbB3 and erbB2 mRNA levels in 64% of cancers in comparison with normal colon samples. By densitometry, 2.3-fold and a 1.5-fold significant increases in erbB3 and erbB2 mRNA levels, respectively, were calculated in the cancerous tissues. Eighty-five percent of cancers with erbB3 mRNA overexpression showed an increase in erbB2 mRNA. Southern blot analysis did not indicate any gene amplification or rearrangement responsible for erbB2 or erbB3 overexpression. EGFR, however, was decreased in cancer on mRNA level. These findings indicate that erbB2 and erbB3, but not EGFR, may contribute to tumor growth and disease progression in colon cancer. The correlation between increased erbB2 and erbB3 expression in both Northern blots and immunohistochemical analysis suggests a co-overexpression of erbB2 and erbB3 and might support the hypothesis that these two growth factor receptors act together by heterodimer formation.

Adenocarcinoma↗
PubMed1998

The role of diagnostic laparoscopy in pancreatic and periampullary malignancies.

BACKGROUND: The role of diagnostic laparoscopy before laparotomy in patients with pancreatic or periampullary malignancies remains controversial. We analyzed the value of using diagnostic laparoscopy to avoid laparotomy in these patients. STUDY DESIGN: Between November 1993 and December 1996, 254 patients with pancreatic or periampullary malignancies were treated. In 74 patients, multiple distant metastases precluded further surgical treatment. In all, 180 patients underwent laparotomy for pancreatic cancer (119 patients) or periampullary cancer (61 patients). Preoperatively, all patients underwent computed tomography for staging and to assess resectability of the tumor. Based on the results of the imaging procedure, the patients were scheduled for either tumor resection or a palliative operation. RESULTS: Twenty-one of 180 patients (12%) with pancreatic or periampullary malignancies were scheduled preoperatively for nonresectional operations because of distant metastasis or retroperitoneal tumor infiltration. In none of these patients was the operative strategy changed. In 159 of 180 patients (88%), a pancreatic resection was planned preoperatively; 119 patients underwent pancreatic resection. In the remaining 40 patients preoperatively scheduled for tumor resection, removal of the tumor was not possible. In 24, this resulted from tumor infiltration into the retropancreatic vessels, and in 16 it resulted from liver or peritoneal metastasis detected for the first time intraoperatively. These 16 patients (10%) could have benefited from diagnostic laparoscopy. Similar results were found in the subgroup of 119 patients with pancreatic cancer, of whom 102 were planned for tumor resection and 17 for palliative operation. Of the 102 patients planned preoperatively for tumor resection, 71 patients (70%) underwent pancreatic resection. In the remaining 31 patients scheduled for tumor resection, removal of the tumor was not possible: in 17 because of tumor infiltration into the retropancreatic vessels and in 14 because of liver or peritoneal metastasis detected for the first time intraoperatively. These 14 patients (14%) also would have benefited from laparoscopy. CONCLUSIONS: Preoperative computed tomography is a reliable technique to detect tumor metastasis in patients with pancreatic or periampullary cancer. Unlike other investigators, we found that only 10% of patients with periampullary or pancreatic cancer and 14% of patients with pancreatic cancer might profit from laparoscopy. Because of this low number, laparoscopy cannot generally be recommended for patients with pancreatic or periampullary cancer before laparotomy.

Adult↗
PubMed1998

Overexpression of platelet-derived growth factor (PDGF) B chain and type beta PDGF receptor in human chronic pancreatitis.

Platelet-derived growth factors (PDGF) are mitogenic polypeptides that are involved in cellular proliferation and tissue repair. The expression of PDGFs and type beta PDGF receptor was examined in the normal human pancreas and in chronic pancreatitis, a fibrotic disease associated with fibroblastic proliferation, atrophy, and acinar cell dedifferentiation. In the normal human pancreas, PDGF A chain mRNA levels were relatively abundant, whereas PDGF B chain mRNA levels were not detected, and type beta PDGF receptor mRNA transcripts were present at low levels. In the normal pancreas, PDGF immunoreactivity was present in islet cells, whereas type beta PDGF receptor immunoreactivity was present in acinar cells. In chronic pancreatitis, PDGF A chain mRNA transcripts were also abundant, and 11 of 19 samples exhibited the PDGF B chain mRNA transcript. In addition, there was a significant increase in the mRNA levels of type beta PDGF receptor in the pancreatitis samples by comparison with the normal pancreas (P < 0.001). In chronic pancreatitis tissues, PDGF and type beta PDGF receptor immunoreactivity were present in acinar, ductal, islet, and endothelial cells, fibroblasts, and leukocytes. The concomitant overexpression of PDGFs and of the type beta PDGF receptor points to the existence of autocrine and paracrine PDGF-dependent loops in human chronic pancreatitis.

Blotting, Northern↗
PubMed1998

Apoptosis inhibiting factor Bcl-xL might be the crucial member of the Bcl-2 gene family in colorectal cancer.

Since the role of the Bcl-2 gene family has been only poorly investigated in colorectal cancer, we have examined the expression of the apoptosis blockers Bcl-xL and Bcl-2, as well as the proapoptotic factors Bax and Bak. Northern blot analysis and immunohistochemistry were performed on normal and cancerous colonic tissue from 12 patients. In colorectal cancer, Bcl-xL immunoreaction was stronger than in normal controls, and 83% of the cancers had increased Bcl-xL mRNA expression. The median densitometric Bcl-xL values were 3.4-fold higher in carcinomas (P<0.005). In contrast to the normal colon, colorectal carcinomas often lack any Bcl-2 immunostaining, and Bcl-2 mRNA was not detectable by Northern blots either. Bax was not obviously altered in colorectal cancer, either at the protein level or at the mRNA level compared to the normal control colon. Bak mRNA expression exhibited a wide variation in carcinomas, but was somewhat decreased in comparison to the controls. Of these members of the Bcl-2 gene family, Bcl-xL seems to play a major role in colorectal tumorigenesis and disease progression. An agonistic effect might have caused the tendency for reduced Bak expression. The Bcl-2/Bax regulation system of cell homeostasis seems to be of lesser importance.

Aged↗
PubMed1998

Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+ cells and CD8+CD103+ cells by multi-epitope imaging.

Pancreatic cancer is characterized by an increasing incidence and an extremely poor prognosis. It is resistant to most of the conventional treatment modalities. Histomorphologically, it presents with a strong desmoplastic reaction around cancer cells, and lymphocytes are typically localized as aggregates in the fibrotic interstitial tissue. Using the method of multi-epitope imaging with fluorochrome-tagged specific MoAbs which allows the simultaneous localization and characterization of T cells in tissues, we studied phenotypes and distribution of tumour-infiltrating lymphocytes (TIL) in pancreatic cancer. CD3+ T cells comprised up to 90% of the tumour-infiltrating cells which were either CD4+ or CD8+, most of them being memory cells (CD45RO+). In decreasing order of frequency, T lymphocytes carried the markers for CD45RO, CD18, CD103 and TCR gammadelta. Very few natural killer cells (CD56+) were observed. Twenty percent of CD8+ were labelled with CD103. These CD8+CD103+ T cells, analogous to the gut intraepithelial lymphocytes (IEL), were found in the fibrous interstitial tissue. Furthermore, an inverse correlation was found between the expression of CD18, the beta2-integrin, which mediates adhesion of activated lymphocytes, and CD45RO in the CD8+ subset of TIL (P = 0.046). In conclusion, phenotyping of T lymphocytes in pancreatic cancer raises the possibility that pancreatic cancer cells develop several strategies to escape the T cell-induced cytolysis by (i) the aggregation of cytotoxic CD8+CD103+ T cells in the fibrous tissue distant from the tumour cells, and (ii) the presence of CD18-bearing cells which lack the expression of the activation marker CD45RO.

Adolescent↗
PubMed1998

Enhanced expression of TGF-betas and their receptors in human acute pancreatitis.

OBJECTIVES: To determine which mechanisms are involved in pancreatic remodeling, repair, and fibrosis after acute necrotizing pancreatitis (NP) in humans. SUMMARY BACKGROUND DATA: Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that have been implicated in the regulation and formation of extracellular matrix and fibrosis. They exert their functions by binding to specific receptors. In this study, we analyze the expression of TGF-beta1, TGF-beta2, and TGF-beta3 and their receptors type I (Tbeta-RI [ALK5]), type II (Tbeta-RII), and type III (Tbeta-RIII) in NP. PATIENTS: Pancreatic tissue samples were obtained from 6 female and 8 male patients with a median age of 65 years (range, 37 to 77 years) undergoing surgery for NP. The median Ranson score of the patients was 6 (range, 2 to 9). The operation was performed a median 5.5 days (range, 4 to 17 days) after the onset of acute pancreatitis. Pancreatic tissue obtained from 12 previously healthy organ donors (6 male, 6 female; median age of 43 years) served as controls. METHODS: The expression of TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), Tbeta-RII, Tbeta-RIII, and collagen type I mRNA was analyzed by Northern blot analysis. In addition, immunohistochemical analysis using polyclonal antibodies was performed to detect TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), and Tbeta-RII. RESULTS: Northern blot analysis showed an increase in TGF-betas and their receptors in NP tissue samples compared with samples from normal controls. The increase was 3.5-fold for TGF-beta1 (p < 0.05), 2.7-fold for TGF-beta2 (p < 0.05), 3.5-fold for TGF-beta3 (p < 0.05), 10-fold for Tbeta-RI (ALK5) (p < 0.05), 5.7-fold for Tbeta-RII (p < 0.05), and 1.4-fold for Tbeta-RIII (not significant). Collagen type I mRNA was also markedly increased in NP samples and correlated with the level of TGF-betas. Immunohistochemical analysis demonstrated intense TGF-beta1, TGF-beta2, TGF-beta3, Tbeta-RI (ALK5), and Tbeta-RII immunoreactivity in the remaining acinar and ductal cells in most NP samples; in the normal control pancreas, there was weak to moderate immunoreactivity for these factors only in some acinar cells and a few ductal cells. CONCLUSION: The marked increase in expression of TGF-betas and their signaling receptors Tbeta-RI (ALK5) and Tbeta-RII suggests a role for TGF-betas in the repair process after the onset of NP in humans and raises the possibility that TGF-betas might be involved in tissue remodeling and the fibrotic reaction that occurs in the pancreas after necrosis.

Adolescent↗
PubMed1998

Phospholipase A2 isoforms are altered in chronic pancreatitis.

OBJECTIVE: To determine if phospholipase A2 (PLA2) type II and type IV mRNA expression and protein are altered in chronic pancreatitis. SUMMARY BACKGROUND DATA: PLA2s have an important regulatory function in several signaling pathways, especially in inflammation. In this study, we examined the expression of three PLA2 isoforms (type I, type II, and type IV) in chronic pancreatitis. METHODS: The distribution of PLA2 was studied in 15 pancreas samples obtained from patients with chronic pancreatitis using immunohistochemical, Northern blot, and in situ hybridization techniques. Normal pancreas obtained from healthy organ donors served as control. RESULTS: Northern blot analysis revealed enhanced mRNA levels of PLA2 type II (5.7-fold) and type IV (5.1-fold) in chronic pancreatitis (p < 0.01) versus normal pancreas. In normal pancreas, intense PLA2 type I immunostaining was present in acinar cells, whereas PLA2 type II immunostaining was visible only in some acinar cells. In chronic pancreatitis, PLA2 type II immunostaining was present more frequently and with higher intensity in acinar cells. Furthermore, PLA2 type II immunoreactivity was more abundant in metaplastic ductal cells in the chronic pancreatitis samples. By in situ hybridization, areas with ductal metaplasia in chronic pancreatitis exhibited intense PLA2 type IV mRNA signals. All chronic pancreatitis tissues with concomitantly increased mRNA expression for PLA2 type II and type IV exhibited a higher degree of degeneration, ductal metaplasia, and fibrosis. CONCLUSIONS: Upregulation of PLA2 types II and IV in areas with more histologic damage suggests that these PLA2 isoforms might contribute to the morphologic changes that occur in chronic pancreatitis.

Adult↗
PubMed1998

Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer.

OBJECTIVE: To analyze the expression of the antiapoptotic gene bcl-xL in human pancreatic cancer and to correlate the results with clinical patient parameters. SUMMARY BACKGROUND DATA: Bcl-xL belongs to the bcl-2-related gene family and acts as a broad antiapoptotic factor to extend both normal and tumor cell survival. Recent findings indicate that tumor cell death induced by chemotherapy and radiotherapy is mediated by the activation of apoptosis. The fact that pancreatic cancer has an extremely malignant potential and that it is resistant to most anticancer treatment modalities suggests that mechanisms are activated that increase the viability of pancreatic cancer cells. METHODS: Seventy-four pancreatic cancer tissue samples were obtained from 32 female and 42 male patients undergoing surgery for exocrine pancreatic cancer. Normal human pancreatic tissue samples were available from 11 organ donors and 4 patients without pancreatic disease. The levels of bcl-xL mRNA expression were analyzed by Northern blot analysis. The exact site of bcl-xL mRNA transcription was determined by nonradioactive in situ hybridization. In addition, immunohistochemistry using specific polyclonal antibodies was used to localize the protein. RESULTS: Northern blot analysis indicated that, in comparison with the normal pancreas, bcl-xL mRNA was markedly overexpressed in 54% of the pancreatic cancer samples. Densitometric analysis revealed that pancreatic adenocarcinomas exhibited a mean 3.4-fold increase (p < 0.01) in bcl-xL mRNA levels in comparison with normal controls. With in situ hybridization, bcl-xL mRNA was found to be highly expressed in the cancer cells of tumor samples that exhibited increased mRNA expression by Northern blot analysis. Immunohistochemical analysis revealed bcl-x immunostaining in 88% of the cancer samples. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited no, faint, or weak bcl-xL expression lived significantly longer after tumor resection (median 12 months) than patients whose tumors exhibited moderate bcl-xL mRNA expression (median 5 months) (p < 0.05). However, 5 patients whose tumors exhibited intense bcl-xL mRNA expression tended to live longer (median 14 months). CONCLUSION: Enhanced expression of the antiapoptotic gene bcl-xL in pancreatic cancer and its association with shorter patient survival suggests that this factor may enhance the viability of pancreatic cancer cells in vivo. Inhibition of apoptotic pathways might be one of the reasons why pancreatic cancer shows only limited sensitivity to anticancer treatment.

Adult↗
PubMed1998

Transforming growth factor betas and their receptors in human liver cirrhosis.

BACKGROUND: Transforming growth factor betas (TGF-betas) are a group of homologous polypeptides that exert pleiotropic effects on various cell types and stimulate the formation of extracellular matrix and fibrosis. To evaluate whether TGF-beta isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) and their receptors (types I-III) are also of importance in the pathophysiology of liver cirrhosis, we analysed their concomitant expression and localization in human liver cirrhosis. PATIENTS: Cirrhotic liver tissue samples were obtained from 17 patients (four women, 13 men) with a median age of 41 years (range 22-67). Normal liver tissues from ten patients (seven women, three men) with a median age of 55 years (range 45-75) served as controls. METHODS: The tissues were fixed in Bouin's solution and paraffin-embedded for histological analysis. For RNA analysis, freshly obtained tissue samples were snap-frozen in liquid nitrogen and stored at -80 degrees C until analysed. Northern blot analysis was used to examine the expression of TGF-beta1, beta2 and beta3 and their receptors, type I (TbetaR-I), type II (TbetaR-II) and type III (TbetaR-III). Immunohistochemistry was performed to determine the localization of the corresponding proteins in the normal and the cirrhotic liver. RESULTS: Northern blot analysis revealed enhanced expression (P < 0.05) of TGF-beta1 (twofold increase), TGF-beta2 (threefold increase) and TGF-beta3 (8.5-fold increase) and of TbetaR-II (threefold increase) mRNA in liver cirrhosis in comparison with normal controls. In contrast, TbetaR-I (ALK-5) and TbetaR-III mRNA expression showed no significant changes. No TGF-beta isoform immunoreactivity was present in hepatocytes in either normal livers or in liver cirrhosis. However, in liver cirrhosis, intense TGF-beta1 immunoreactivity was present in bile duct and ductular epithelial cells (including ductular proliferations) and in inflammatory cells. In a few sinusoidal lining cells, faint TGF-beta1 and moderate TGF-beta2 immunoreactivity was present. TGF-beta3 immunostaining was present in bile duct and ductular epithelial cells, in inflammatory cells and in fibroblast-like spindle cells in liver cirrhosis. For TbetaR-I and TbetaR-II, the immunoreactivity was localized in hepatocytes and biliary cells in normal and cirrhotic liver tissues, with higher intensity for TbetaR-II in the cirrhotic liver. CONCLUSION: Enhanced expression of all three TGF-bea isoforms and of TbetaR-II in liver cirrhosis suggests their involvement in this fibrotic disorder. The higher immunoreactivity of the three TGF-beta isoforms in the bile duct epithelial cells in cirrhotic tissues suggests a possible role of these cells in the pathogenesis of liver cirrhosis.

Adult↗