Protection by vascular endothelial growth factor against sinusoidal endothelial damage and apoptosis induced by cold preservation.

Background: It is well known that sinusoidal endothelial cell (SEC) damage during cold preservation of liver tissue is closely involved in early graft failure. The objective of this study was to investigate the involvement of apoptosis in the SEC damage induced by cold preservation and to demonstrate the protective effect of vascular endothelial growth factor (VEGF) on SEC injury, including apoptotic changes.

Methods: Isolated SECs and liver tissue of Wistar rats were cold-preserved in University of Wisconsin (UW) solution, and the protective effect of VEGF was then investigated.

Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis.

Background: It has been suggested that tissue factor (TF) plays an important role in tumor metastasis. Its expression in sarcoma cells was reported to up-regulate the vascular endothelial growth factor (VEGF) gene and thereby enhance tumor angiogenesis, which is essential to tumor metastasis. Although many malignant tumors have been reported to express this protein constitutively, recent clinical studies have focused mainly on the correlations among TF expression, tumor progression, and histologic grade.

Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma.

Objective: To determine molecular mechanisms involved in angiogenesis of hepatocellular carcinoma (HCC).

Summary Background Data: Tumor angiogenesis is believed to derive from the balance between angiogenic stimulators and inhibitors. It has been suggested that the switch to the angiogenic phenotype requires both upregulation of the first and downregulation of the second.

Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas.

Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin).

Production of specific antibody and T helper 1-dominant cytokine elicited by dendritic cells genetically modified with an adenovirus vector.

In this study we examined how dendritic cells (DCs) transduced with an adenovirus vector encoding a model tumor antigen (beta-galactosidase; beta-gal) would influence the humoral immune response to this antigen. Mice immunized with LacZ transduced DCs by an adenovirus vector could produce more anti-beta-gal antibody, especially of IgG2a subclass, than mice immunized with DCs alone, although the amount of serum IgG antibody did not increase. Compared with mice immunized with DCs alone, splenocytes of mice immunized with LacZ transduced DCs could produce more interferon-gamma (IFN-gamma) against the beta-gal derived, H-2Ld-restricted nonapeptide (TPHPARIGL) in a dose-dependent manner.

Pretreatment with soluble thrombomodulin prevents intrasinusoidal coagulation and liver dysfunction following extensive hepatectomy in cirrhotic rats.

The major cause of posthepatectomy liver dysfunction is supposed to be microcirculatory disturbance caused by imbalance of intrasinusoidal coagulation equilibrium. Thrombomodulin (TM) is a potent anticoagulant expressed on the endothelial cell surface that regulates the coagulation system by binding thrombin and accelerating the thrombin-catalyzed activation of protein C. Therefore, we examined the effect of soluble TM purified from human urine (UTM) on intrasinusoidal coagulation in cirrhotic rats.

Implication of vascular endothelial growth factor in the development and metastasis of human cancers.

Vascular endothelial growth factor (VEGF) is a most potent angiogenic molecule. In this article, we demonstrated that VEGF is participated in the tumor angiogenesis of hepatocellular carcinoma, esophageal cancer, and pancreatic cancer. Furthermore, we revealed that VEGF is one of the molecules which are responsible for metastasis and prognosis in esophageal cancer and colon cancer.

Morphologic alteration of hepatocytes and sinusoidal endothelial cells in rat fatty liver during cold preservation and the protective effect of hepatocyte growth factor.

Background: Fatty liver grafts are considered to be one of the main factors of primary nonfunctioning graft in transplantation. We investigated here, the hepatic damage during cold preservation in a rat fatty liver model by ultrastructural observation, and examined the effect of human recombinant hepatocyte growth factor (hrHGF) on amelioration of the cold-preserved graft condition.

Methods: Wistar rats were fed a choline-deficient diet (CDD) for 7 days.

Vascular endothelial growth factor-induced tumor angiogenesis and tumorigenicity in relation to metastasis in a HT1080 human fibrosarcoma cell model.

Although vascular endothelial growth factor (VEGF) is well known to be a potent mitogen for vascular endothelial cells, the role of VEGF in a developmental process of tumor angiogenesis and metastatic potential remains poorly understood. The present study was designed to investigate VEGF-induced vascular formation from a spatiotemporal viewpoint and to analyze VEGF-enhanced metastatic potential using stable clones of HT1080 human fibrosarcoma cells transfected with VEGF cDNA (S) or with vector alone (V). Microangiography revealed massive angiogenesis in the S cell-derived tumors and demonstrated that the angiogenesis occurred not in the tumor itself, but rather around the S cell tumor early after inoculation into the thigh muscles of mice.

Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors.

The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-1. As aberrant activation of signal transducing molecules such as Ras and Raf-1 has been linked with cancer, we examined whether constitutive activation of the 41-/43-kDa MAP kinases is associated with the neoplastic phenotype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.

Hepatocyte growth factor prevents lipopolysaccharide-induced hepatic sinusoidal endothelial cell injury and intrasinusoidal fibrin deposition in rats.

Background: Acute endotoxemia is known to cause activation of Kupffer cells as well as serious injury in parenchymal and nonparenchymal cells in the liver. We have recently shown that a continuous recombinant hepatocyte growth factor (rHGF) supply prevents lipopolysaccharide (LPS)-induced liver injury in rats. As an attempt to elucidate the mechanism, here we investigate the cytoprotective effect of rHGF on sinusoidal endothelial cells (SECs) in LPS-induced liver injury in rats.

Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer.

Vascular endothelial growth factor (VEGF) may affect the phenotype of cancer cells, such as growth velocity and metastatic potential, due to its probable multifunctional property including a mitogenic activity for vascular endothelial cells. The present study was designed to investigate the association of VEGF mRNA expression with progression and metastasis of human colorectal cancer. The level of VEGF mRNA expression was quantified by Northern blot hybridization in tumorous and non-tumorous tissues obtained from 60 primary colorectal cancer patients.

Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: correlation with angiostatin generation and its clinical significance.

Macrophage metalloelastase, a member of the human matrix metalloproteinase family, is believed to play an important role in angiostatin generation, which, in experimental studies, has an antiangiogenic function and is a key molecule in tumor dormancy. However, no clinical studies have been reported regarding the correlation between human macrophage metalloelastase (HME) gene expression and angiostatin production. Therefore, the present study was designed to evaluate the HME messenger RNA (mRNA) expression and angiostatin generation in hepatocellular carcinoma (HCC).

Inhibition of tumor growth and microvascular angiogenesis by the potent angiogenesis inhibitor, TNP-470, in rats.

The antiangiogenic effects of TNP-470 on the neovascularization of tumors were studied by examining ultrastructural alterations in the vasculature and interstitial fluid pressure (IFP) of tumors. Wistar rats were first inoculated subcutaneously (s.c.

[Implication of VEGF and MMPs in hepatic metastasis of human colon cancer].

This article describes the significance of mRNA expression of VEGF, MMP-2, MMP-9, and MT1-MMP in human colorectal cancer metastases, particularly hepatic metastases. The levels of gene expression were quantified by Northern blot hybridization in tumor and nontumor tissues obtained from 66 primary cases. Significantly higher levels of expression of VEGF mRNA were observed in patients with synchronous hepatic metastases (n = 15) and/or lymph node metastases than in those without.

Results of surgical treatment for recurrent hepatocellular carcinoma; comparison of outcome among patients with multicentric carcinogenesis, intrahepatic metastasis, and extrahepatic recurrence.

No consensus has been reached on the indications for and effectiveness of surgery for secondary intrahepatic hepatocellular carcinoma (HCC) and extrahepatic metastasis after macroscopically complete removal of primary HCC. Secondary intrahepatic HCCs, usually regarded as recurrence are classified into those arising as a result of multicentric carcinogenesis or intrahepatic metastases derived from the primary HCC. The present study was designed to evaluate the utility of surgical treatment in relation to the pathogenesis of the secondary HCC: classified as multicentric carcinogenesis (MC), intrahepatic metastasis (IM), and extrahepatic metastasis.

Expression of membrane-type matrix metalloproteinase-1 in human pancreatic adenocarcinomas.

The expression of a new type of matrix metalloproteinase, membrane-type matrix metalloproteinase-1 (MT-MMP-1), was examined in 24 cases of primary pancreatic adenocarcinomas and 9 cases of secondary liver tumors derived from pancreatic adenocarcinomas, using a non-radioactive in situ hybridization and immunohistochemical methods. Out of 24 cases of primary pancreatic adenocarcinomas, 18 showed positive expression of MT-MMP-1 transcripts in cancer cells and 20 of 24 showed positive expression in the tumor stromal cells. The immunoreactivity of the gene products for MT-MMP-1 was demonstrated to be almost the same, as shown by in situ hybridization in these 24 cases.

Expression of the Na+/Ca2+ exchanger emerges in hepatic stellate cells after activation in association with liver fibrosis.

Activation of hepatic stellate (Ito) cells is a final common pathway of liver fibrosis. The findings presented in this paper indicate that expression of Na+/Ca2+ exchanger (NCX) emerges in rat hepatic stellate cells after activation in vitro during primary culture or in vivo in response to intoxication with CCl4. NCX mRNA became detectable by Northern blot analysis in cultured stellate cells on day 3, as was alpha-smooth muscle actin, an indicator not only of smooth muscle differentiation but also of stellate cell activation.

Membrane-type matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas.

Background/aims: The matrix metalloproteinase (MMP) family play important roles in the invasion of cancer cells by degrading the extracellular matrices. The current study was designed to determine the expression pattern of membrane-type matrix metalloproteinase-1 (MT1-MMP) in hepatocellular carcinomas and its participation in invasion potential.

Methods: MT1-MMP mRNA expression was examined in 25 human hepatocellular carcinoma specimens using Northern blot, and the correlation to clinicopathological features was evaluated.

Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma.

Background: Activation of matrix metalloproteinase-2 (MMP-2) has been implicated in the progression, invasion, and metastasis of various cancers, but little information is available with regard to its role in pancreatic carcinoma with poor prognosis.

Methods: Gelatin zymography was used for the detection of latent and activated forms of MMP-2 and MMP-9 in 13 normal pancreatic tissue specimens, 14 chronic pancreatitis tissue specimens, and 33 pancreatic carcinoma tissue specimens. The gelatinase activity was quantified by densitometer, and the 66-kilodalton (kDa)/(66-kDa + 72-kDa) ratio was calculated as the MMP-2 activation ratio.

Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method.

To identify the intercellular signal-transducing proteins and receptors produced by cancer cells, we attempted to clone cDNAs encoding secreted and type I membrane proteins using a signal sequence trap (SST) method with some modifications. By screening an SST library derived from pancreatic cancer cells, we identified two secretory proteins (neutrophil gelatinase-associated lipocalin (NGAL) and lung surfactant protein D) and three membrane proteins (carcinoembryonic antigen, BiP/GRP78 and Hsa4 mitochondrion cytochrome oxidase subunit II). NGAL mRNA was expressed in eight of the pancreatic cancer cell lines and eight pancreatic cancer tissues.

Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas.

It has been reported that the rho genes, which consist of a ras-related small GTPase protein family, regulate cytoskeletal structures and have the potential to transform cultured cells. To investigate the biological relevance of the rho genes in pancreatic carcinogenesis, we examined expressions of the rhoA, B and C genes by polymerase chain reaction after reverse transcription (RT-PCR) in 33 cases of ductal adenocarcinoma of the pancreas. In addition, mutations of the K-ras, rhoA, B and C genes were studied in the same series of tumour tissues to correlate with rho gene expressions.

Results of pancreatectomy with radiation therapy for pancreatic cancer.

Background/aims: Surgical resection provides the only chance for long-term survival for adenocarcinoma of the pancreas. However, a major problem of surgery appears to be post-resection recurrence. The purpose of the current study was to evaluate the efficacy of intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) in combination with resective surgery.

Amelioration of sinusoidal endothelial cell damage by Kupffer cell blockade during cold preservation of rat liver.

Recent studies have shown that Kupffer cell function is enhanced in the cold-preserved liver, and blockade of Kupffer cells attenuates the injury induced by cold preservation with subsequent reperfusion. This study was designed to investigate the contribution of Kupffer cell blockade with gadolinium chloride (GdCl3) to the rescue of sinusoidal endothelial cell (SEC) damage by comparing the time-related morphological and ultrastructural changes. GdCl3 injection reduced the number of Kupffer cells reactive with monoclonal antibodies ED2 and Ki-M2R directed against macrophage.