James D. Evans

Protein Kinase C Isoenzyme Patterns Characteristically Modulated in Early Prostate Cancer

Expression of protein kinase C (PKC) isoenzymes -alpha, -beta, -delta, -epsilon, -gamma, -iota, -lambda, -mu, -theta, and -zeta, and of their common receptor for activated C-kinase (RACK)-1, was determined immunohistochemically using specific antibodies in formalin-fixed and paraffin-embedded specimens of early prostatic adenocarcinomas (n = 23) obtained at radical prostatectomy. Expression of each isoenzyme by malignant tissues was compared with nonneoplastic prostate tissues removed at radical cystectomy (n = 10). The most significant findings were decreased PKC-beta expression in early neoplasia when compared to benign epithelium (P < 0.0001), together with a reciprocal increase in expression of PKC-epsilon (P < 0.0001). Detectable levels of PKC-alpha and PKC-zeta were also significantly increased in the cancers (P = 0.045 and P = 0.015 respectively) but did not correlate with either PKC-beta or PKC-epsilon for individual cases. Alterations in the levels of the four PKC isoenzymes occurred specifically and consistently during the genesis and progression of human prostate cancer. PKC-delta, -gamma, and -theta were not expressed in the epithelium of either the benign prostates or the cancers. Levels of expression for PKC-A, -iota, -mu, and RACK-1 were not significantly different between the benign and malignant groups. Although changes in PKC isoenzyme expression may assist in explaining an altered balance between proliferation and apoptosis, it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on particular pathways regulating cellular homeostasis. The findings of this study raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis, including expression of the p170 drug-resistance glycoprotein, intracellular Ca2+ concentrations, and enhanced cellular mobility resulting in the metastatic dissemination of human prostate cancer cells. Attenuation of PKC-beta expression is currently being assessed as a reliable objective adjunct to morphological appearance for the diagnosis of early progressive neoplasia in human prostatic tissues.

Detailed Tissue Expression of bcl-2, bax, bak and bcl-x in the Normal Human Pancreas and in Chronic Pancreatitis, Ampullary and Pancreatic Ductal Adenocarcinomas

Background: The aim of this study was to evaluate expression of the bcl-2 family of apoptosis regulating proteins in normal and diseased human pancreatic tissues. Method: Expression of bcl-2, bax, bcl-x, bak and p53 was determined in formalin-fixed paraffin wax-embedded archival specimens of normal pancreatic tissue (n = 7), chronic pancreatitis (n = 7), pancreatic ductal adenocarcinoma (n = 23) and ampullary cancer (n = 7) by immunohistochemistry using specific antibodies. Results: In normal pancreas and chronic pancreatitis tissues, bcl-2, bax and bcl-x were predominantly expressed in ductal epithelial cells while p53 was not detected. In pancreatic ductal adenocarcinoma and ampullary cancer, bcl-2 was not detected compared with expression seen in normal acini (p < 0.01), minor (p < 0.001) and major ducts (p < 0.01). bax expression was reduced with respect to minor ducts (p < 0.01) but no different from normal acini or major ducts. bak and bcl-x were more strongly expressed in malignant epithelia compared with acini and major ducts but reduced when compared with minor ducts (p < 0.01). Overexpression of p53 was identified in 11 (48%) of 23 pancreatic adenocarcinomas and 4 (57%) of 7 ampullary cancers. Differential survival of individual patients was predicted by the relative level of bcl-x expression but not bax or bak, such that strong expression of bcl-x was associated with a median post-operative survival of 171 days when compared with 912 days for diminished expression (p < 0.001) of bcl-x. Conclusion: Pancreatic and ampullary cancer are associated with absent bcl-2 expression. bax, bak and bcl-x expression was reduced compared with normal minor ducts whilst bak and bcl-x expression was increased when compared with major ducts. bcl-x expression correlates with survival following resection and may represent a potential prognosis marker.

Expression Patterns of Protein Kinase C Isoenzymes Are Characteristically Modulated in Chronic Pancreatitis and Pancreatic Cancer

We immunohistochemically identified protein kinase C (PKC) isoenzymes and the receptor for activated C-kinase (RACK-1) in normal, chronically inflamed, and malignant pancreas specimens. Expression patterns were specific and consistent for each microanatomic structure. In chronic pancreatitis, the expression patterns by epithelial cells were indistinguishable from those in normal pancreas. In the stroma, there was a gain of PKC-delta (P < .05) and loss of PKC-mu (P < .0001). Expression in pancreatic duct carcinomas, compared with control normal minor ductular epithelial cells, revealed relative loss of PKC-epsilon (P < .0001), PKC-iota (P = .005), and PKC-theta (P < .0001) but no gain in any isoenzyme. Compared with control normal major duct epithelial cells, the principal differences were a relative loss in PKC-gamma (P < .05) and a relative gain in PKC-beta (P < .05), PKC-iota (P < .05), and PKC-zeta (P < .005). The stroma adjacent to ductal carcinomas was characterized by prominent expression of PKC-mu and a gain in PKC-delta (P < .0001) and PKC-zeta (P > .005). Ampullary carcinomas revealed a relative gain of PKC-iota (P < .05) and RACK-1 (P < .05). In the adjacent stroma was enhanced expression of PKC-delta (P < .005) and PKC-gamma (P < .001) and loss of PKC-mu (P < .05). Specific changes in isoenzyme expression in stroma of chronic pancreatitis and in epithelial cells and stroma of ductal and ampullary pancreatic adenocarcinomas reflect specific modulation of intracellular signaling pathways that control critical homeostatic mechanisms.

Role of Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer

BACKGROUND/AIMS The matrix metalloproteinases are a family of proteolytic enzymes which normally have an important physiological role in tissue remodelling and wound healing, but more recently have been implicated in the proteolytic events which occur during tumour invasion. METHODS The expanding family of matrix metalloproteinases and the specific tissue inhibitors of the matrix metalloproteinases are reviewed including their classification, structure, function, regulation of activity, and tissue expression with particular reference to pancreatic cancer. The effect of synthetic matrix metalloproteinases inhibitors in preclinical studies is reviewed together with the results of ongoing clinical trials in pancreatic cancer. RESULTS Pancreatic cancer is associated with the overexpression of several matrix metalloproteinases with a reduced expression of their specific inhibitors. Orally bioavailable matrix metalloproteinase inhibitors have successfully completed phase I/II clinical trials with promising results. Multicentre randomised controlled phase IIb/III clinical trials aren currently under way in pancreatic cancer. CONCLUSIONS Matrix metalloproteinase inhibition may represent a novel approach to the management of pancreatic cancer not only in advanced disease, but in the adjuvant treatment setting following tumour resection either alone or in combination with existing chemotherapeutic agents.

Tuberculosis of the Pancreas Presenting as Metastatic Pancreatic Carcinoma

Pancreatic tuberculosis (TB) is extremely rare and is frequently misdiagnosed. A case of pancreatic TB is presented together with a review of all previously published cases. A 54-year-old Indian man presented with a history consistent with pancreatic cancer. Radiology revealed an ‘unresectable’ pancreatic mass associated with bony lesions in the ribs and vertebral column. Endoscopic retrograde pancreatography was normal however which prompted a tissue biopsy revealing a diagnosis of TB which was successfully treated by chemotherapy. TB of the pancreas should be considered especially in those patients of non-White ethnic origin who are relatively young with a short history of pancreatic disease in the absence of obstructive jaundice. A normal endoscopic retrograde cholangiopancreatography should raise serious doubts as to accepting a diagnosis of more common pancreatic diseases which are frequently mimicked

Questionnaire for Trial Submission

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Fatal Intestinal Perforation Secondary to Fragmentation of a Celestin Tube

Background/Aims: Oesophageal intubation remains one of the principal methods of palliation for an obstructing oesophageal carcinoma. We present a case which illustrates a rare but fatal complication of this procedure. Methods: A 60-year-old female with oesophageal cancer presented with total dysphagia 9 months following insertion of a Celestin tube for palliation. Oesophagoscopy revealed a bolus obstruction which was successfully cleared. Two days later she developed generalised peritonitis and subsequently died. Results: A post-mortem examination demonstrated fragmentation and displacement of the distal part of the Celestin tube resulting in perforation of the small bowel. Conclusion: Celestin tube disintegration is a risk associated with long-term use, and routine replacement is indicated in patients with a prolonged survival to avoid this complication.

Metalloproteinases and Stromal Biology in Cancer

The normal extracellular matrix (ECM) comprises the basement membrane and interstitial stroma and functions as a supportive framework for parenchymal cells and a physical barrier which regulates the entry of cells into the tissue (35). The integrity of the ECM is carefully controlled but may be disrupted during tissue remodelling or various pathological situations including healing, inflammation and neoplastic disease (54,91,127). In several cancers including carcinoma of the breast and rectum, loss of basement membrane integrity is associated with an increased risk of metastases and a poorer prognosis (13,31). Pancreatic cancer is characterised by a strong desmoplastic reaction with proliferation of interstitial connective tissue (50) in particular type I collagen and fibronectin (63). In addition, however, loss of type IV collagen, the principal constituent of the basement membrane, is frequently observed indicating that proteolytic degradation may be an important feature of the invasive phenotype of pancreatic cancer (51,117).