Features Of Pancreatic Cancer Research Articles

Proliferating Cell Nuclear Antigen, Survivin, and CD34 Expressions in Pancreatic Cancer and Their Correlation With Hypoxia-Inducible Factor 1α

Hypoxia-inducible factor 1alpha (HIF-1alpha) has been universally detected in many types of cells and plays a key role in modulation of tumor-related genes. The purpose of this study was to explore the relationship between HIF-1alpha messenger RNA (mRNA) expression and biologic characteristics in pancreatic cancer, such as tumor angiogenesis, tumor cell proliferation, differentiation, apoptosis, and metastasis. Reverse transcriptase-polymerase chain reaction was used to detect HIF-1alpha mRNA expression. The expressions of survivin, proliferating cell nuclear antigen (PCNA), and CD34 proteins were measured immunohistochemically. The correlation between the expression levels of HIF-1alpha mRNA and survivin, PCNA, and CD34 were analyzed. There was very significant difference in the expression of HIF-1alpha between the pancreatic cancer tissue and adjacent normal tissue (P < 0.01), but no significant difference was found among tumor histopathologic grades (P > 0.05). There was significant difference in the expression of HIF-1alpha mRNA between Japanese Pancreatic Society stages I to II and stages III to IV (P < 0.05). The expression of HIF-1alpha mRNA was closely correlated with the expression of survivin, PCNA, and CD34 proteins. The expression level of HIF-1alpha mRNA is surmised to have a significant correlation with tumor angiogenesis, cell proliferation, apoptosis, and metastasis. Inhibition of HIF-1alpha may be an important and approachable therapeutic target for pancreatic cancer.

Thrombospondin-1 expression as a prognostic predictor of pancreatic ductal carcinoma

Pancreatic cancer is a malignant tumor with an extremely poor prognosis. Thrombospondin-1 (TSP-1) was suggested to be a potential regulator of tumor growth and metastasis. We examined TSP-1 expression in 77 cases of invasive ductal adenocarcinoma of the pancreas, and analyzed the correlation between the TSP-1 expression pattern and clinicopathological features in pancreatic cancer. TSP-1 immunoreactivity was detected in the cancer stroma. The diffusely positive and focally positive patterns of TSP-1 were found in 33 (42.9%) and 40 (51.9%) of 77 cases, respectively. The TSP-1 diffuse expression was significantly correlated with lymph node metastasis (p<0.01), neural invasion (p<0.05) and TNM stage (p<0.01). The prognostic significance of clinicopathological parameters were analyzed by univariate and multivariate analysis using the log-rank test and the Cox proportional hazards model. Based on the univariate analysis, histological differentiation (p<0.01), lymphatic invasion (p<0.01), venous invasion (p<0.05), neural invasion (p<0.01), TNM stage (p<0.01) and TSP-1 expression (p<0.01) were significant parameters. These observations suggested that TSP-1 plays important roles in cancer cell growth and metastasis of human pancreatic cancer, and that stromal TSP-1 immunoreactivity is a good prognostic predictor of patients with pancreatic cancer.

The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines

Pancreatic cancer cells are usually resistant to apoptosis mediated by intrinsic or extrinsic factors. BAG-3 (Bis, CAIR), which was identified as a BAG-1-related protein, is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2. In this study we analyzed BAG-3 expression in human pancreatic cancer tissues and cell lines. BAG-3 mRNA was expressed at moderate to high levels in all pancreatic cancer samples, but at low levels in normal pancreas tissues. In situ hybridization and immunohistochemistry analysis revealed that BAG-3 was present in the cancer cells within the pancreatic tumor mass. When BAG-3 mRNA was analyzed in other gastrointestinal cancers (hepatocellular carcinoma; esophageal, stomach and colon cancer), no difference was found from their corresponding normal controls. In pancreatic cancer cells, BAG-3 mRNA expression levels were strongly induced after heat stress, but not in response to members of the tumor necrosis factor (TNF)-α family (TNF-α, TRAIL, FasL). These findings indicate that in pancreatic cancer, in contrast to other gastrointestinal malignancies, increased levels of BAG-3 might function to block apoptosis. This characteristic of pancreatic cancer might contribute to its more aggressive growth behavior and poor responsiveness to treatment in vivo.

The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model.

Diabetes associated with pancreatic cancer is characterized by profound peripheral insulin resistance. The intracellular mechanism of insulin resistance was investigated in skeletal muscles from N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. Effects of high-fat diet and exercise also were studied. BOP (20 mg/kg body weight) was administrated weekly for 2 weeks. Hyperinsulinemia was found in BOP-treated hamsters at 20 weeks after BOP treatment, suggesting the peripheral insulin resistance is an early feature in pancreatic cancer. Hamsters were killed at 42 weeks, and soleus muscles were taken for the analysis. Skeletal muscle insulin-receptor binding and insulin receptor tyrosine kinase activities were similar between the control and BOP-treated hamsters. However, maximal muscle glycogen synthase activity was significantly reduced in BOP-treated hamsters compared with the control group. Muscle glycogen phosphorylase activity was increased in the BOP-treated group fed with high-fat diet as well as in BOP-treated groups with exercise. These findings indicate that insulin resistance in the hamster pancreatic cancer model is caused by a postreceptor defect, which led to significant decrease of muscle glycogen synthase activity. Whereas a high-fat diet causes more severe insulin resistance in BOP-treated hamsters, high-fat diet and exercising had no significant effects on skeletal muscle insulin-receptor function and glycogen synthase activity. Furthermore, both high-fat diet and exercise enhanced glycogen phosphorylase activity in BOP-treated hamsters.

Ultrastructural study of the mechanism of perineural extension in pancreatic cancer

Nerve invasion is one of the biological features of pancreatic cancer, and its mechanism remains to be determined. In this paper, we report on 37 pancreatic cancer specimens observed by immunohistochemical and electron microscopical techniques. The results showed that pancreatic cancer directly invaded and destroyed the perineurium. At the early stage of disease, the peripheral nerve and synaptic membrane were easily destroyed by cancer cells, and invasion and metastasis continuously advanced along the perineural space and central side of nerves. These results suggest that the soft tissue and nerve plexus on the dorsal region of the pancreas may contribute to the recurrence of pancreatic cancer after duodenopancreatectomy.

Patterns of neural and plexus invasion of human pancreatic cancer and experimental cancer

Specimens from four patients who underwent resection of cancer of the pancreatic head were examined histologically by serial sections to study the patterns of extrapancreatic nerve plexus invasion of cancer. To understand the mode of neural invasion and its specificity for pancreatic cancer, we also examined retropancreatically transplanted virus-induced rabbit papilloma (VX2) cells in six rabbits. Histological evaluation of the specimens from patients revealed neural invasion near the primary lesion, where cancer cells broke the perineurium and showed communication of cancer cells between the inside and outside of the perineurium. Tumor cells found distant from the primary cancer were confined to the perineurium, grew in a continuous pattern, and followed the branches of nerves. When the rabbit's VX2 cells were implanted into the retropancreatic region of recipient rabbits we also observed neural invasion. This study shows that neural invasion is a common, but not a specific, feature of pancreatic cancer, and it suggests that en bloc excision of the retropancreatic tissue, including fat tissue and the extrapancreatic nerve plexus, should be the basic procedure of radical surgery in the treatment of pancreatic cancer.