Hans Guski

Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma

Purpose: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3′-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. Experimental Design: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. Results: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P < 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. Conclusions: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.

Cytoplasmic overexpression of ALCAM is prognostic of disease progression in breast cancer

Background: Activated leucocyte cell adhesion molecule (ALCAM, CD166) is a cell surface member of the immunoglobulin superfamily. ALCAM expression has prognostic relevance in prostate and colon cancer. Objective: To evaluate ALCAM protein expression in breast cancer by immunohistochemistry and to correlate expression levels with clinicopathological data. Methods: 162 primary breast carcinomas with a mean clinical follow up time of 53 months were immunostained using a monoclonal ALCAM antibody. The staining was evaluated as an immunoreactive score (IRS) and grouped into low v high for both membranous and cytoplasmic staining. Results: Intraductal and invasive carcinomas showed a higher ALCAM expression (median IRS 4 and 6 respectively) than normal breast tissue (IRS 2). In univariate survival analyses a significant association of high cytoplasmic ALCAM expression with shortened patient disease-free survival (mean (SD) five year non-progression rate, 69.4 (4.6)% v 49.4 (11.1)%, p = 0.0142) was found. In multivariate analyses of disease-free survival times, high cytoplasmic ALCAM expression (relative risk (RR) = 2.086, p = 0.026) and nodal status (RR = 2.246, p = 0.035) were significantly associated with earlier disease progression, whereas tumour grading (RR = 1.6, p = 0.052) was of borderline significance. Conclusions: The data suggest that strong cytoplasmic ALCAM expression in primary breast cancer, as detected by immunohistochemistry, might be a new marker for a more aggressive breast cancer biology.

Effects of Celebrex and Zyflo on BOP-Induced Pancreatic Cancer in Syrian Hamsters

Background/Aims: Selective inhibition of eicosanoid synthesis decreases inflammation, however, it is still unknown whether oxidative stress and carcinogenesis might be influenced in ductal pancreatic ductal cancer as well. Methods: 120 male hamsters were randomized into 8 groups (n = 15). While control group 1–4 received 0.5 ml normal saline s.c. weekly for 16 weeks, groups 5–8 were injected 10 mg BOP/kg body weight to induce pancreatic cancer. After establishment of pancreatic cancer, groups 1 and 5 received no therapy, groups 2 and 6 were fed 7 mg Celebrex daily, groups 3 and 7 were given 28 mg Zyflo and groups 4 and 8 received Celebrex and Zyflo orally daily in weeks 17–32. In week 33, all animals were sacrificed, macroscopic size of pancreatic carcinomas was measured, incidence of pancreatic cancer was analyzed histopathologically and activities of antioxidative enzymes and concentration of products of lipid peroxidation in tumor-free and pancreatic intratumoral tissue were determined. Results: Incidence and size of macroscopic pancreatic carcinomas were decreased by single therapy with Zyflo as well as combined therapy (Zyflo + Celebrex). Activities of antioxidative enzymes were increased and the concentration of products of lipid peroxidation was decreased in tumor-free pancreas. On the other hand, lipid peroxidation was increased in pancreatic tumors. Conclusion: Zyflo alone or in combination with Celebrex reduce tumor growth in pancreatic cancer and thus might be a new therapeutic option in advanced pancreatic cancer.

Morphometric characterization of left ventricular myocardial cells of male rats during postnatal development

Abstract Morphometric investigations of the left ventricular myocardial cells of male Wistar rats aged 0, 1, 2, 3, 4, 5, 6, 7, 14, 21 days and 1, 2, 3, 4, 5, 6 months were carried out. The volume density of the sarcoplasm decreased from 0.33 (at birth) to 0.018 (6th month). The volume density of the myofibrils diminished during the first 7 days of life, whereas after the 6th month (0.57) it was nearly the same again as at birth (0.52). The volume density of the mitochondria increased from 0.16 at birth to 0.33 in the 6th month. The surface density of the outer mitochondrial membrane increased at different rates. The number of mitochondria per unit area grew from 0.51 (at birth) to 0.88 (6th month). The distance between the mitochondria decreased from 4.33 μm (at birth) to 1.67 μm (6th month). The mitochondrial/myofibrillar ratio doubled in the course of the period covered by the study (0.32 at birth; 0.64 in the 6th month). The postnatal development of heart muscle cells can be characterized by data obtained on the heart at birth, at the ages of 3, 4, 5, 7, and 14 days and in the 1st, 3rd and 6th month.

Influence of octreotide and tamoxifen on tumor growth and liver metastasis in N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancer in Syrian hamsters.

In prospective clinical trials single octreotide therapy or combined therapy with tamoxifen has improved the quality of life and survival time in patients with pancreatic cancer. In this study we analyzed the influence of octreotide and tamoxifen on tumor growth and liver metastases in chemically induced pancreatic adenocarcinoma in Syrian hamsters. Octreotide alone and the combined therapy (octreotide/tamoxifen) decreased the incidence of macroscopic pancreatic carcinomas as well as the number and size of liver metastases. The combined therapy showed no superior effect to octreotide alone. Furthermore, there was no difference between the tamoxifen and the control group.

Effects of octreotide in acute hemorrhagic necrotizing pancreatitis in rats

Background and Aim:  Octreotide is considered to reduce exocrine pancreatic secretion in acute hemorrhagic necrotizing pancreatitis decreasing pancreatic autodigestion. The aim of this study was to determine whether octreotide also has antioxidative effects in acute pancreatitis. Additionally time and dose of application were of interest.

Effects of the antioxidative vitamins A, C and E on liver metastasis and intrametastatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

Background/Aims: Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (α-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster. Methods: One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1–4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5–8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given α-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue. Results: Retinol and α-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins. Conclusion: Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Comparison of different telepathology solutions for primary frozen section diagnostic

In a retrospective study on a set of 125 cases we compared the following three telepathology solutions for primary frozen section diagnosis: ATM‐TP (connection via ATM), TPS 1.0 (connection via LAN) and TELEMIC (connection via Internet), which represent different concepts of telepathological procedures. A set of 125 routine frozen sections (breast) was selected from the Charité cases of the year 1999. Four experienced pathologists diagnosed retrospectively all of these cases. Using the ATM‐TP and TPS systems and 53 of them with the TELEMIC system. Using the ATM‐TP we recorded no false positive (0%), 4 false negative (3.2%) and 4 deferred (3.2%) cases. Using the TPS we recorded no false positive (0%), 4 false negative (3.2%) and 4 deferred (3.2%) cases. Using the TELEMIC we recorded in 53 cases no false positive (0%), no false negative (0%) and 16 deferred (30.2%) cases. The average time of 2.2 minutes per case using ATM‐TP is also short enough for routine frozen section diagnostic. This is also true for the TPS system with 7.2 minutes per case.

Validation of a new experimental model of colon cancer

BackgroundMost of the published animal studies that have evaluated tumor growth and port site metastases in laparoscopy have utilized a cell suspension model and thus cannot be compared to the clinical situation. Although solid tumor models have been developed, there has been no experimental model that establishes an orthotopic tumor in the rectum, reflecting the clinical situation of a solid colonic cancer.MethodsTumor cells (colon adenocarcinoma DHD/K1/TRb) were administered intraperitoneally in rats, which were used as solid tumor donors. A 20-mg piece of solid tumor from the donor was placed in a submucosal blister created in the rectum wall of the study rats. The approach to the submucosal blister was made through the mucosa after contralateral enterotomy. In order to validate the model, this intervention was performed in 10 cases (group A). After 10 days of intervention, the rats were submitted to resection of the rectum and histological examination of the specimen. In another 10 rats (group B), manipulation of the tumor was performed after 10 days to cause tumor cell spillage. The likelihood of tumor dissemination was investigated in this group 20 days after this intervention.ResultsGroup A developed solid tumors in seven of 10 cases (70%). All of the tumors were localized between the muscular and the mucosal layer, with preservation of the serosa and without affecting the enterotomy. In all of the rats in group B, macroscopic tumor was observed in the upper rectum (100%) 10 days after its induction. Twenty days after tumor manipulation, nine rats had local tumor dissemination; two of them also had general tumor dissemination in the abdominal cavity.ConclusionsWe established a novel solid colonic tumor model in rats for the investigation of intraoperative tumor cell spillage during resection of the colon and the development of port site metastases.

Influence of Different Dietary Fat Intake on Liver Metastasis and Hepatic Lipid Peroxidation in BOP-Induced Pancreatic Cancer in Syrian Hamsters

Objectives: Effects of polyunsaturated fatty acids (PUFA) on carcinogenesis are discussed controversially. Thus, tumor growth seems to be influenced by type and composition of fat dietary; however, the pathomechanism is still unknown. Therefore, we investigated the impact of different PUFAs on liver metastasis and hepatic lipid peroxidation in a solid model of ductal pancreatic cancer in Syrian hamsters. Methods: 90 male hamsters were randomized into 6 groups (n = 15). Accordingly groups 2, 4 and 6 received 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly by subcutaneous injection for 12 weeks in order to induce ductal pancreatic cancer, while groups 1, 3 and 5 were treated with 0.5 ml 0.9% sodium chloride. All hamsters received a standard fat diet (SFD) rich in n–6 PUFA for 16 weeks (2.9% fat). Afterwards, groups 1 and 2 had free access to SFD, while groups 3 and 4 were given a diet enriched with n–3, n–6 and n–9 PUFA (SMOF) and groups 5 and 6 were fed a diet high in n–3 PUFA (FISH-OIL). After 32 weeks all hamsters were sacrificed in order to determine incidence of pancreatic carcinoma and liver metastasis. Furthermore hepatic activities of glutathionperoxidase (GSH-Px) and superoxiddismutase (SOD) as well as levels of lipidperoxidation were analyzed intra- and extrametastatically. Results: The incidence of liver metastasis was decreased in the FISH-OIL tumor group compared to the SFD and SMOF groups. However, GSH-Px activity was not influenced by different diets. Extrametastatic hepatic SOD activity did not differ between all groups, while intrametastatic hepatic SOD activity in the SFD-BOP group was increased. In the FISH-OIL-BOP and the SMOF-BOP group intrametastatic SOD activity was lower than in non-metastatic hepatic tissue. Furthermore levels of hepatic lipid peroxidation were decreased in the tumor groups treated with fish oil and SMOF compared to the SFD group. Comparing intra- and extrametastatic TBARS concentration there was no difference in the SFD-BOP and the SMOF-BOP groups, while in the FISH-OIL-BOP group intrametastatic TBARS concentration was increased. Conclusion: Conclusively, fish oil reduced the incidence of liver metastasis in experimental ductal pancreatic cancer. Maybe this effect is caused by an increase of intrametastatic hepatic lipid peroxidation.