Expression of a fibroblast growth factor-binding protein during the development of adenocarcinoma of the pancreas and colon.

The activity of growth factors is crucial for tumor progression. We previously characterized a secreted fibroblast growth factor-binding protein (FGF-BP1) as a chaperone molecule, which enhances the biological functions of FGFs by releasing FGFs from the extracellular matrix. Here, we characterize the frequency and pattern of FGF-BP1 expression during the malignant progression of pancreas and colorectal carcinoma. For this, we generated monoclonal antibodies that detect FGF-BP1 protein in formalin-fixed, paraffin-embedded tissues and applied in situ hybridization to detect FGF-BP1 mRNA in adjacent tissue sections. FGF-BP1 protein and mRNA were found up-regulated (>70% positive) in parallel (r = 0.70, P < 0.0001) in colon adenoma (n = 9) as well as primary (n = 46) and metastatic (n = 71) colorectal cancers relative to normal colon epithelia (all P < 0.0001, versus normal). Similarly, pancreatitis (n = 17), pancreatic intraepithelial neoplasia (n = 80), and pancreatic adenocarcinoma (n = 67) showed a significant up-regulation of FGF-BP1 compared with normal pancreas (n = 42; all P < 0.0001, relative to normal). Furthermore, the biological activity of FGF-BP1 is neutralized by one of the antibodies, suggesting the potential for antibody-based therapeutic targeting. We propose that the up-regulation of the secreted FGF-BP1 protein during initiation of pancreas and colon neoplasia could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions.

Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors.

Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.

Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients.

Epidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega-3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5-lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double-blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/(l. sec)], ALAT [0.9 +/- 0.1 vs. 0.6 +/- 0.1 mmol/(l. sec)], bilirubin (16.1 +/- 5.3 vs. 6.9 +/- 0.6 mmol/l), LDH (7.7 +/- 0.4 vs. 6.7 +/- 0.4 mmol/(l. sec) and lipase (0.6 +/- 0.1 vs. 0.4 +/- 0.1 micromol/(l. sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL-6/IL-10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega-3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 +/- 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients.

Regulation of translation initiation by insulin and amino acids in skeletal muscle of neonatal pigs.

Previous studies have shown that intravenous infusion of insulin and/or amino acids reproduces the feeding-induced stimulation of muscle protein synthesis in neonates and that insulin and amino acids act independently to produce this effect. The goal of the present study was to delineate the regulatory roles of insulin and amino acids on muscle protein synthesis in neonates by examining translational control mechanisms, specifically the eukaryotic translation initiation factors (eIFs), which enable coupling of initiator methionyl-tRNAi and mRNA to the 40S ribosomal subunit. Insulin secretion was blocked by somatostatin in fasted 7-day-old pigs (n = 8-12/group), insulin was infused to achieve plasma levels of approximately 0, 2, 6, and 30 microU/ml, and amino acids were clamped at fasting or fed levels or, at the high insulin dose, below fasting. Both insulin and amino acids increased the phosphorylation of ribosomal protein S6 kinase (S6K1) and the eIF4E-binding protein (4E-BP1), decreased the binding of 4E-BP1 to eIF4E, increased eIF4E binding to eIF4G, and increased fractional protein synthesis rates but did not affect eIF2B activity. In the absence of insulin, amino acids had no effect on these translation initiation factors but increased the protein synthesis rates. Raising insulin from below fasting to fasting levels generally did not alter translation initiation factor activity but raised protein synthesis rates. The phosphorylation of S6K1 and 4E-BP1 and the amount of 4E-BP1 bound to eIF4E and eIF4E bound to eIF4G were correlated with insulin level, amino acid level, and protein synthesis rate. Thus insulin and amino acids regulate muscle protein synthesis in skeletal muscle of neonates by modulating the availability of eIF4E for 48S ribosomal complex assembly, although other processes also must be involved.

Pancreatic metallothionein-I may play a role in zinc homeostasis during maternal dietary zinc deficiency in mice.

Herein, the function of pancreatic metallothionein (MT)-I during zinc deficiency in pregnancy was examined using transgenic mice, which constitutively express the mouse MT-I gene driven by the rat elastase I promoter. Pancreatic MT protein levels and zinc levels were elevated significantly in the transgenic mice compared with those in control mice. Pregnant transgenic and control mice were fed zinc-deficient (1 micro g/g beginning at d 8) or zinc-adequate (50 micro g/g) diets during pregnancy, and the effects on the morphology of embryos were determined at d 14 of pregnancy (d 1 = vaginal plug). As other indicators of zinc deficiency, maternal pancreatic MT levels, as well as the expression of zinc-regulated genes in the embryonic visceral yolk sac were examined. Under these experimental conditions of moderate dietary zinc deficiency, 21.3% of the embryos in control mice exhibited morphological defects, whereas only 5.8% of the embryos in the elastase-MT-I transgenic females had developed abnormally by d 14. Surprisingly, dietary zinc deficiency caused a >95% decrease in pancreatic MT protein concentration in these transgenic mice. This suggests the post-transcriptional control of MT protein levels during zinc deficiency because the rat elastase I promoter is not metal-regulated. The decrease in pancreatic MT protein levels was paralleled by a dramatic decrease in the relative abundance of MT-I mRNA and a dramatic increase in the relative abundance of the zinc/iron regulated transporter-related zinc transporter-4 (ZIP4) mRNA in the embryonic visceral yolk sac. Thus, the constitutive overexpression of pancreatic MT-I in these mice attenuated, but did not prevent the effects of maternal or embryonic zinc deficiency under these conditions. Overall, these findings are consistent with the hypothesis that mouse pancreatic MT-I may participate in providing a labile pool of maternal zinc for the developing embryo during periods of zinc deficiency.

Pancreatic enzyme replacement therapy.

Malabsorption due to severe pancreatic exocrine insufficiency is one of the most important late features of chronic pancreatitis. Generally, steatorrhea is more severe and occurs several years prior to malabsorption of other nutrients because synthesis and secretion of lipase are impaired more rapidly, its intraluminal survival is shorter, and the lack of pancreatic lipase activity is not compensated for by nonpancreatic mechanisms. Patients suffer not only from nutritional deficiencies but also from increased nutrient delivery to distal intestinal sites, causing symptoms by profound alteration of upper gastrointestinal secretory and motor functions. Adequate nutrient absorption requires delivery of sufficient enzymatic activity into the duodenal lumen simultaneously with meal nutrients. The following recommendations are based on modern therapeutic concepts: 25,000 to 40,000 units of lipase per meal using pH-sensitive pancreatin microspheres, with dosage increases, compliance checks, and differential diagnosis in case of treatment failure. Still, in most patients, lipid digestion cannot be completely normalized by current standard therapy, and future developments are needed to optimize treatment.

Growth factors in pancreatic health and disease.

In this article the role of different growth factors and their receptors in the pathogenesis of chronic pancreatitis and pancreatic cancer is discussed. The expression of members of the epidermal growth factor family, the fibroblast growth factor family, the transforming growth factor-beta family, the platelet-derived growth factor family, the nerve growth factor family, the insulin-like growth factor family and their signaling receptors is presented, and a correlation of the molecular data with clinical and pathological changes is performed. A number of these growth factors and their receptors are markedly overexpressed in chronic pancreatitis and pancreatic cancer. In chronic pancreatitis, overexpression of growth factors and their receptors contributes to tissue remodeling and fibrogenesis. In contrast to chronic pancreatitis, pancreatic cancer is associated with a variety of genetic alterations, including mutations in tumor suppressor genes and cell cycle regulators. In the presence of these genetic disturbances, enhanced expression of growth factors and their receptors contributes to cell proliferation and enhances the aggressiveness of pancreatic cancer cells. In summary, growth factors and their receptors are often altered in chronic pancreatitis and pancreatic cancer and contribute to various pathogenetic aspects in these disorders.

Diet stimulation as a synergistic factor of aggravation in a pancreatic bile duct ligation-induced rat pancreatitis model.

We evaluated the association between aggravation of pancreatitis and multiple factors enhancing pancreatic exocrine secretion using a rat model of pancreatic bile duct ligation (PBDL)-induced pancreatitis. Under fasting and non-fasting conditions, a PBDL group, a second group treated by hepatic bile duct ligation (BDL) and a third group treated by pancreatic duct ligation (PDL) were compared in terms of serum amylase (S-amylase) activity. The S-amylase activity in the PBDL group was higher than in the sham group. In the PDL group, the increase in S-amylase activity was lower than in the PBDL group. In the BDL group, no increase in S-amylase activity was observed. Diversion of pancreatic and/or bile juice in these groups resulted in no increase of S-amylase activity. Truncal vagotomy or injection of an anticholinergic drug or a cholecystokinin (CCK)1-receptor antagonist inhibited pancreatic exocrine secretion and S-amylase activity in the non-fasting PBDL group but not in the fasting PBDL group. These results suggest that retention of pancreatic juice in the pancreatic duct is necessary for the increase of S-amylase activity, and that dietary stimulation and impaired duodenal inflow of bile and pancreatic juice commonly enhance pancreatic exocrine secretion, acting synergistically as aggravating factors in pancreatitis. CCK and the vagus nerve system appears to be involved in enhancing pancreatic exocrine secretion with diet stimulation as an aggravating factor.