Biomedical subjects

K Mizumoto

Publications and source records attributed to K Mizumoto.

At least 19 recordsLinked to original sources

PubMed2006

Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice.

Intraductal papillary mucinous neoplasms (IPMNs) are common cystic tumours of the pancreas. Sonic hedgehog (SHH) is involved in gastric epithelial differentiation and pancreatic carcinogenesis. However, a comprehensive analysis of SHH expression in IPMN has not yet been performed. In the present study, one-step quantitative real-time reverse transcription-polymerase chain reaction with gene-specific priming was used to examine mRNA levels in various types of clinical samples. SHH expression in IPMN was measured and the possible association of gastric epithelial differentiation with development of IPMN was evaluated. In bulk tissue analyses (IPMNs, 11 pancreatic cancer, and 20 normal pancreatic tissues), IPMN expressed significantly higher levels of SHH than did normal pancreas (IPMN versus normal pancreas, p = 0.0025; pancreatic cancer versus normal pancreas, p = 0.0132), but SHH expression did not differ between IPMN and pancreatic cancer (p = 0.3409). In microdissection analyses (infiltrating ductal carcinoma cells from 20 sections, IPMN cells from 20 sections, pancreatitis-affected epithelial cells from 11 sections, and normal epithelial cells from 12 sections), IPMN cells expressed significantly higher levels of SHH than did cancer cells, normal cells, or pancreatitis-affected ductal cells (all comparisons, p < 0.008). Pancreatic juice analyses (20 samples from pancreatic cancers, 31 samples from IPMNs, and 27 samples from chronic pancreatitis) revealed that SHH expression differed significantly between IPMN juice and pancreatitis juice (p < 0.0001), and between cancer juice and pancreatitis juice (p = 0.0125). Receiver operating characteristic curve analyses revealed that SHH measurement in pancreatic juice was useful for discriminating IPMN from chronic pancreatitis (area under the curve = 0.915; 95% confidence interval: 0.796-0.976). The data suggest that overexpression of SHH is an early event in the development of IPMN and that SHH measurement in pancreatic juice may provide some advantages for the treatment or follow-up of a subset of patients with IPMN or chronic pancreatitis.

Biomarkers, Tumor↗

PubMed2006

Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival.

NK4 or adenovirus vector expressing NK4 (Ad-NK4) can act bifunctionally as a hepatocyte growth factor antagonist and angiogenesis inhibitor and has potential value in cancer therapy. The aim of this study was to evaluate the therapeutic efficacy of Ad-NK4 in combination with gemcitabine (GEM) against pancreatic cancer. In vitro study showed a strong antiproliferative effect of GEM and a potent anti-invasive effect of Ad-NK4 against pancreatic cancer cells. In in vivo experiments, SUIT-2 human pancreatic cancer cells were implanted into the pancreas of nude mice. Mice were treated with Ad-NK4 by injection into the peritumoral region of the pancreas on day 5 after implantation followed by weekly i.p. injections of GEM. On day 28 after implantation, pancreatic tumor volume was significantly smaller than that in mice treated with Ad-LacZ, Ad-NK4 alone, or GEM alone. Furthermore, combination therapy completely suppressed peritoneal dissemination and liver metastases, leading to significantly increased survival. Histologic and immunohistochemical assays of primary tumors indicated that combination therapy prohibited both cell proliferation and angiogenesis, resulting in high levels of apoptosis. These results suggest that peritumoral injection of Ad-NK4 plus GEM is a potent combination therapy for pancreatic cancer.

Adenoviridae↗

PubMed2006

Propofol inhibits phorbol 12, 13-dibutyrate-induced, protein kinase C-mediated contraction of rat aortic smooth muscle.

BACKGROUND: Propofol induces dose-dependent vasodilation and hypotension in the clinical situation, and protein kinase C (PKC)-mediated Ca2+ sensitization plays an important role in vascular smooth muscle contraction. This study is designed to examine the effects of propofol on the active phorbol ester (phorbol 12, 13-dibutyrate; PDBu)-induced, PKC-mediated contraction of rat aortic smooth muscle. METHODS: The PDBu-induced contraction of endothelium-denuded rat aortic rings was measured in the presence or absence of PKC inhibitor, bisindolylmaleimide I, or propofol, using isometric force transducers. The PDBu-induced PKC phosphorylation of endothelium-denuded rat aortic strips was detected in the presence or absence of bisindolylmaleimide I or propofol, using Western blotting. RESULTS: PDBu, but not the inactive phorbol ester, 4-alpha-phorbol 12-myristate-13-acetate, dose-dependently induced both a slowly developing sustained contraction and PKC phosphorylation of rat aortic smooth muscle, reaching the peak level at the concentration of 10(-6) M. The PDBu (10(-6) M)-induced contraction was dose-dependently inhibited by bisindolylmaleimide I with reductions of 6.8 +/- 1.8% (P > 0.05), 39.8 +/- 8.7% (P < 0.01) and 96.7 +/- 1.4% (P < 0.01) in response to concentrations of 5 x 10(-7) M, 10(-6)x M and 5 x 10(-6) M, respectively, and by propofol with decreases of 5.2 +/- 1. 6% (P > 0.05), 9.4 +/- 1.7% (P < 0.05), 65.3 +/- 9.2% (P < 0.01) and 96.2 +/- 1.6% (P < 0.01) in response to concentrations of 5 x 10(-7) M, 10(-6) M, 5 x 10(-6) M and 10(-5) M, respectively. Both bisindolylmaleimide I and propofol also inhibited the PDBu-induced increase in the density of the phosphorylated PKC bands in a dose-dependent manner, with decreases of 6.3 +/- 2.8% (P > 0.05), 42.9 +/- 3.2% (P < 0.01) and 96.6 +/- 3.4% (P < 0.01) in response to 5 x 10(-7) M, 10(-6) M or 5 x 10(-6) M bisindolylmaleimide I, respectively, and with decreases of 4.2 +/- 2.5% (P > 0.05), 13.5 +/- 1.7% (P < 0.05), 69.5 +/- 3.5% (P < 0.01) and 95.3 +/- 4.3% (P < 0.01) in response to 5 x 10(-7) M, 10(-6) M, 5 x 10(-6) M and 10(-5) M propofol, respectively. CONCLUSION: Propofol dose-dependently inhibits PDBu-induced, PKC-mediated contraction of rat aortic smooth muscle.

Anesthetics, Intravenous↗

PubMed2005

Comparison of the effects of isoflurane and sevoflurane on protein tyrosine phosphorylation-mediated vascular contraction.

BACKGROUND: Isoflurane induces greater effects on vasodilation and decreasing blood pressure than sevoflurane. Tyrosine kinase-catalyzed protein tyrosine phosphorylation plays an important role in regulating vascular smooth muscle contraction. The aim of the present study was to compare the effects of isoflurane and sevoflurane on tyrosine phosphorylation-mediated vascular constriction, by assessing the degree of sodium orthovanadate (Na(3)VO(4), tyrosine phosphatase inhibitor)-induced contraction and protein tyrosine phosphorylation of rat aortic smooth muscle. METHODS: Na(3)VO(4)-induced contraction and protein tyrosine phosphorylation of rat aortic smooth muscle were measured in the presence of genistein, a tyrosine kinase inhibitor, and different concentrations of isoflurane and sevoflurane, using isometric force measurement and Western blot, respectively. RESULTS: Na(3)VO(4) (10(-4) M) induced sustained contraction and tyrosine phosphorylation of substrates that were both markedly attenuated in the presence of genistein (5 x 10(-5) M). Isoflurane and sevoflurane dose-dependently (1, 2, 3 MAC) attenuated the Na(3)VO(4)-induced contraction (P < 0.05-0.005, n = 8), with a greater degree of inhibition by isoflurane than sevoflurane at 2 MAC (P < 0.01) and 3 MAC (P < 0.05). Both anesthetics also attenuated the total band density of the Na(3)VO(4)-induced, tyrosine-phosphorylated substrates in a concentration-dependent manner (P < 0.05-0.005, n = 4), with much greater attenuation by isoflurane than sevoflurane at 1 and 2 MAC (P < 0.05), respectively. CONCLUSION: The results of the present study demonstrate that isoflurane exhibits a greater degree of inhibition on the Na(3)VO(4)-stimulated contraction and protein tyrosine phosphorylation of rat aortic smooth muscle compared with sevoflurane. These findings suggest that isoflurane depresses the protein tyrosine phosphorylation-mediated contraction of vascular smooth muscle to a greater degree than sevoflurane.

Anesthetics, Inhalation↗

PubMed2004

Laparoscopic pancreatic surgery: current indications and surgical results.

BACKGROUND: Although minimally invasive surgery has achieved worldwide acceptance in various fields, laparoscopic surgery for pancreatic diseases has been reported only rarely. The purpose of this study was to evaluate the outcomes and feasibility of laparoscopic pancreatic surgery. METHODS: Fifteen patients, comprising eight men and seven women with an average age of 54 years, underwent laparoscopic pancreatic surgery. Distal pancreatectomy was indicated for solid tumors ( n = 4), cystic lesions ( n = 3), and chronic pancreatitis ( n = 2). Cystogastrostomy was performed for pseudocysts ( n = 4) and enucleation for insulinomas ( n = 2). The lesions varied in size from 1 to 9 cm (2.9 +/- 2.4 cm) and were located in the pancreatic head ( n = 2), body ( n = 3), or tail ( n = 10). For distal pancreatectomy, the splenic artery was divided and the parenchyma was transected with a linear stapler. Laparoscopic ultrasonography was used to determine the distance between the tumor and the main pancreatic duct for enucleation as well as to localize the lesion for distal pancreatectomy. Cystogastrostomy, 4.5 cm in length, was also performed with the linear stapler through the window of the lesser omentum. RESULTS: Mean operation time was 249 +/- 70 min (293 +/- 58 min in distal pancreatectomy, 185 +/- 14 min in enucleation, 204 +/- 50 min in cystogastrostomy), and mean blood loss was 138 +/- 184 g (213 +/- 227 g, 75 +/- 35 g, 38 +/- 48 g, respectively). Two distal pancreatectomies (13%) were converted to open surgery due to severe peripancreatic inflammation. There was no related mortality, but there were two cases (15%) of pancreatic fistula, one in a distal pancreatectomy case and the other in an enucleation case, and both were treated conservatively. CONCLUSIONS: Laparoscopic pancreatic surgery is safe and feasible for patients with benign tumors and cystic lesions.

Adult↗

PubMed2003

Gallbladder duplication successfully removed laparoscopically using endoscopic nasobiliary tube.

Laparoscopic cholecystectomy is sometimes difficult due to complicated biliary anatomy including gallbladder duplication, a rare anomaly of the biliary tract. We report a case of duplicated gallbladder successfully removed under laparoscopy using endoscopic nasobiliary (ENB) tube cholangiography. A 61-year-old Japanese woman presented us with right upper abdominal pain. Ultrasonography revealed two cystic structures lying in the gallbladder fossa, and the upper one contained multiple stones. Endoscopic retrograde cholangiography showed two gallbladders, each of which has a cystic duct draining into the common bile duct separately. Laparoscopic cholecystectomy was planned under the preoperative diagnosis of double gallbladder with gallstones in the accessory gallbladder. The ENB tube was inserted just before the operation. Laparoscopic removal of the double gallbladder was successfully done using the ENB tube to identify the biliary tree anatomy and to close the stump of the cystic duct. In this communication, we would like to stress the usefulness of the ENB tube at the time of laparoscopic biliary surgery in patients with biliary anomalies including gallbladder duplication.

Bile Ducts↗

PubMed2002

Laparoscopic wedge resection of gastric submucosal tumors.

BACKGROUND/AIMS: The purpose of this study was to evaluate the clinical utility of laparoscopic surgery for gastric submucosal tumor. METHODS: The records of 11 patients who underwent laparoscopic wedge resection (LR group) for gastric submucosal tumors were reviewed and compared with those of 8 patients who underwent open surgery (OS group). RESULTS: Mean operation time was 145 +/- 43 min in the LR group and 127 +/- 33 min in the OS group (p = 0.301). Mean blood loss was 97 +/- 107 and 107 +/- 47 g, respectively (p = 0.387). Patients in the LR group began walking 1.4 +/- 0.7 days after surgery, which was significantly earlier than those in the OS group (2.7 +/- 1.3 days, p = 0.021). The first flatus (1.5 +/- 0.5 vs. 3.1 +/- 0.6 days, respectively, p = 0.0004) and resumption of oral food intake (3.0 +/- 1.7 vs. 4.3 +/- 0.9 days, respectively, p = 0.020) were also earlier in the LR group. White blood cell count on the first postoperative day was lower (7,000 +/- 2,100 vs. 11,900 +/- 3,580/mm(3), respectively, p = 0.004) in the LR group than in the OS group, and the duration of fever (>38.0 degrees C; 0.1 +/- 0.3 vs. 0.9 +/- 0.8 days, respectively, p = 0.014) and the period of postoperative hospitalization (13.2 +/- 3.7 vs. 20.8 +/- 6.1 days, respectively, p = 0.014) were significantly shorter in the LR group than in the OS group. No complications occurred in either group. CONCLUSION: Laparoscopic surgery was superior to open surgery in terms of postoperative recovery time with comparable operation time and blood loss. Laparoscopic wedge resection is a promising surgical alternative for the treatment of gastric submucosal tumors.

Aged↗

PubMed2002

Simulated microgravity culture system for a 3-D carcinoma tissue model.

An in vitro organotypic culture model is needed to understand the complexities of carcinoma tissue consisting of carcinoma cells, stromal cells, and extracellular matrices. We developed a new in vitro model of carcinoma tissue using a rotary cell culture system with four disposable vessels (RCCS-4D) that provides a simulated microgravity condition. Solid collagen gels containing human pancreatic carcinoma NOR-P1 cells and fibroblasts or minced human pancreatic carcinoma tissue were cultured under a simulated microgravity condition or a static Ig condition for seven days. NOR-P1 cultures subjected to the simulated microgravity condition showed greater numbers of mitotic, cycling (Ki-67-positive), nuclear factor-kappa B-activating cells, and a lower number of apoptotic cells than were shown by cultures subjected to the static Ig condition. In addition, human pancreatic carcinoma specimens cultured under the simulated microgravity condition maintained the heterogeneous composition and cellular activity (determined by the cycling cell ratio and mitotic index) of the original carcinoma tissue better than static culture conditions. This new 3-D rotary cell culture system with four disposal vessels may be useful for in vitro studies of complex pancreatic carcinoma tissue.

Adenocarcinoma↗

PubMed2001

Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model.

Hepatocyte growth factor (HGF) is involved in malignant behavior of cancers as a mediator in tumor-stromal interactions through enhancing tumor invasion and metastasis. We found recently that NK4, a four-kringle fragment of HGF, functions as both an HGF-antagonist and an angiogenesis inhibitor. We have now determined whether blockade of the HGF-c-Met/HGF receptor pathway and tumor angiogenesis by administration of recombinant NK4 would inhibit growth, invasion, and metastasis of human pancreatic carcinoma implanted into the pancreas of nude mice. When treatment with NK4 or anti-HGF neutralizing antibody was initiated from the third day after orthotopic injection of SUIT-2 human pancreatic cancer cells, both NK4 and anti-HGF antibody suppressed the conversion of orthotopic pancreatic tumors from carcinoma in situ to aberrantly invading cancers during days 3-14. On the other hand, when the treatment was begun on day 10, a time when cancer cells were already invading surrounding tissues, NK4 but not anti-HGF antibody inhibited tumor growth, peritoneal dissemination, and ascites accumulation at 4 weeks after the inoculation. Antitumor effects of NK4 correlated with decreased microvessel density in pancreatic tumors thereby indicating that the antiangiogenic activity of NK4 may have mainly contributed to its antitumor effects. Moreover, although NK4-treatment was initiated from the end stage (day 24 after tumor inoculation), NK4 prolonged survival time of mice, and the suppression of peritoneal dissemination, ascites accumulation, and invasion of metastasized cancer cells into the peritoneal wall were remarkable. We propose that simultaneous targeting of both tumor angiogenesis and the HGF-mediated invasion-metastasis may prove to be a new approach to treating patients with pancreatic cancer.

Animals↗

PubMed2001

Effect of serum depletion on centrosome overduplication and death of human pancreatic cancer cells after exposure to radiation.

The tumor microenvironment is one of the key factors affecting the cellular response to radiation; however, the influence of serum concentration on tumor radiosensitivity remains poorly understood. We recently discovered that gamma-irradiation of tumor cells causes centrosome overduplication, which may lead to lethal nuclear fragmentation through the establishment of multipolar mitotic spindles. In the present study, we investigated the effect of serum depletion on radiation-induced cell death in relation to the centrosome dynamics in human pancreatic cancer cells. Exposure of Capan-1 cells to gamma-irradiation resulted in a time-dependent increase in cells containing multiple centrosomes in association with the appearance of mitotic cell death. Treatment of irradiated cells with serum depletion drastically accelerated centrosome overduplication and the formation of multipolar spindles, resulting in increased nuclear fragmentation and cell death. Cell cycle analysis of irradiated cultures revealed that the reduced serum level increased the population of cells arrested in the G2/M phase, which might be responsible for the abnormal centrosome accumulation. These findings suggest that serum concentration can influence radiation-induced cell killing through modulating cell cycle progression and possibly centrosome overduplication.

Cell Death↗

PubMed2001

Enolase, a cellular glycolytic enzyme, is required for efficient transcription of Sendai virus genome.

Cellular proteins (host factors) may play key roles in transcription of Sendai virus (SeV) genome. We have previously shown that the host factor activity, which stimulates in vitro mRNA synthesis of SeV, from bovine brain comprises at least three complementary factors, and two of them were identified as tubulin and phosphoglycerate kinase (PGK). Here the third host factor activity was further resolved into two complementary factors, and one of them was purified to an almost single polypeptide chain with an apparent M(r) of 52,000 (p52) and was identified as a glycolytic enzyme, enolase. Recombinant human alpha-enolase, as did p52, acted synergistically with other three host factors to stimulate SeV mRNA synthesis. West-Western blot analysis demonstrated that tubulin specifically binds enolase as well as PGK, suggesting that these two glycolytic enzymes regulate SeV transcription through their interactions with tubulin.

Alcaligenes↗

PubMed2001

Differential roles of viral RNA and cRNA in functional modulation of the influenza virus RNA polymerase.

The RNA-dependent RNA polymerase of influenza virus is composed of three viral P proteins (PB1, PB2, and PA) and involved in both transcription and replication of the RNA genome. For the molecular anatomy of this multifunctional enzyme, we have established a simultaneous expression of three P proteins in cultured insect cells using recombinant baculoviruses. For purification of P protein complexes, the PA protein was expressed as a fusion with a histidine tag added at its N terminus. By using affinity chromatography, a complex consisting of the three P proteins was isolated from nuclear extracts of virus-infected cells. The affinity-purified 3P complex showed the activities of capped RNA binding, capped RNA cleavage, viral model RNA binding, model RNA-directed RNA synthesis, and polyadenylation of newly synthesized RNA. We conclude that a functional form of the viral RNA polymerase with the catalytic specificity of transcriptase is formed in recombinant baculovirus-infected insect cells. Using the viral RNA-free 3P complex, we found that the capped RNA cleavage takes place in the presence of vRNA but not of cRNA, indicating that the vRNA functions as a regulatory factor for the specificity control of viral RNA polymerase as well as a template for transcription. The structural elements of RNA directing the expression of RNA polymerase functions were analyzed using variant forms of the model RNA templates.

Baculoviridae↗

PubMed2001

Laparoscopically assisted resection of choledochal cyst and Roux-en-Y reconstruction.

UNLABELLED: Laparoscopic surgery for a congenital choledochal cyst was accomplished in five of eight adult patients for whom it was attempted (63%). Creation of a Roux-en-Y jejunal limb by midline minilaparotomy and hepaticojejunostomy using a laparoscopic sewing instrument facilitated the procedure. BACKGROUND: Congenital choledochal cyst is a good indication for laparoscopic surgery. However, only two case reports are available at this writing. METHODS: Eight adult patients, ages 19 to 61 years (mean, 32.6 years), underwent laparoscopically assisted resection of the choledochal cyst and Roux-en-Y hepaticojejunostomy. RESULTS: The whole procedure was accomplished in five patients (63%). The duration of the procedure ranged from 525 to 680 min (average, 616 min). Open conversion in three patients was necessitated by severance of a small common hepatic duct because of disorientation caused by previous laparoscopic cholecystectomy, electrocautery injury to the common channel distal to the anomalous pancreaticobiliary junction, or heavy adhesion around the cyst secondary to recent severe cholangitis. Creation of a Roux-en-Y jejunal limb by midline minilaparotomy and hepaticojejunostomy using a laparoscopic sewing instrument facilitated the procedure. CONCLUSIONS: Laparoscopically assisted resection of the choledochal cyst and hepaticojejunostomy are technically feasible and deserve further clinical trials.

Adult↗

PubMed2001

Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells.

Chromosomal instability, characterized by abnormal numbers or structures of chromosomes, is a common feature of human cancers, but the mechanisms behind these changes are still unclear. Since centrosomes play a pivotal role in balanced chromosomal segregation during mitosis, we attempted to investigate the association between centrosome abnormalities and chromosomal instability in a large number of human pancreatic cancer cell lines. Immunofluorescence microscopy revealed centrosomes that were highly atypical with respect to their size, shape, and number in most cell lines. These abnormal centrosomes contributed to the assembly of multipolar spindles, resulting in defective mitosis and chromosome mis-segregation. Interestingly, a high frequency of centrosome defects inversely correlated with the growth rate of cells in culture. Fluorescence in situ hybridization revealed a dramatic variation of chromosome numbers in cell lines with the defective centrosome phenotype. Furthermore, a significant positive correlation existed between the level of centrosome defects and the level of chromosomal imbalances. These results indicate that centrosome abnormalities can lead to spindle disorganization and chromosome segregation errors, which may drive the accumulation of chromosomal alterations. Thus, defects in centrosome function may be an underlying cause of genetic instability in human pancreatic cancers.

Centrosome↗

PubMed2001

Actinohivin, a novel anti-HIV protein from an actinomycete that inhibits syncytium formation: isolation, characterization, and biological activities.

Blocking human immunodeficiency virus (HIV) entry into target cells is an important goal of HIV and acquired immune deficiency syndrome (AIDS) therapies. We have searched for anti-HIV substances from microorganisms using a syncytium formation assay system constructed with HeLa/CD4/Lac-Z and HeLa/T-env/Tat cells. We discovered a novel anti-HIV protein that inhibits syncytium formation, designated as actinohivin, from a cultured broth of a soil isolate, actinomycete strain K97-0003. ESI mass spectrometry of actinohivin isolated from the culture filtrate showed an ion with molecular mass of 12,520.3 Da. The amino acid sequence was determined by N-terminal Edman degradation of the intact protein and peptide fragments formed by endoproteinase digestions. Actinohivin consists of a 114-amino-acid chain that exhibits internal sequence triplication. Actinohivin inhibited both T-cell and macrophage tropic syncytium formation, with IC(50) values of 60 and 700 nM, respectively, and the cytopathic effect of HIV-1(IIIB) in MT-4 cells, with IC(50) value of 230 nM.

Actinomycetales↗

PubMed2001

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells.

Because of the highly aggressive behaviour, i.e. invasive, disseminative and metastatic properties, the outcome for patients with pancreatic cancer is morbid. A better understanding and interference with the malignant behaviour of pancreatic cancer may provide new directions for treatment. We report here the induction of highly motile and invasive properties in human pancreatic cancer cells by hepatocyte growth factor (HGF) and blockage of these properties by NK4, a newly identified antagonist for HGF. In all of eight human pancreatic cancer cell lines we used (AsPC-1, BxPC-3, H-48N, KP-1N, KP-2, KP-3, MIA PaCa-2 and SUIT-2 cells), the c-Met/HGF receptor was expressed at varying levels. Although weak mitogenic activity of HGF was seen only in SUIT-2 and KP-3 cells, HGF strongly stimulated migration and invasion of these pancreatic cancer cells, except for BxPC-3 and MIA PaCa-2 cells. In contrast, migration and invasion potently induced by HGF in KP-1N, KP-3 and SUIT-2 cells were inhibited by NK4. The invasion of SUIT-2 cells was also potently stimulated with the influence of cocultured pancreatic fibroblasts and by ascitic fluid obtained after pancreatic cancer resection, however, invasiveness of the cancer cells in such conditions was practically abolished by NK4. Consistently, the ascitic fluid in patients who had undergone pancreatic cancer surgery contained high levels of HGF. These findings mean that HGF is probably involved in invasion, dissemination, and metastasis of pancreatic cancer, particularly through tumour-stromal interaction and after resection of the pancreatic cancer. NK4, an effective antagonist of HGF, may prove to have the potential for anti-invasion/metastasis.

Antineoplastic Agents↗

PubMed2001

Telomerase activity of cultured human pancreatic carcinoma cell lines correlates with their potential for migration and invasion.

BACKGROUND: Despite the recent clinical finding that high telomerase activity is an unfavorable prognostic marker for various human malignant tumors, there has been no experimental evidence supporting the link between telomerase and tumor aggressiveness. In the current investigation, the authors examined the relation between telomerase activity and potential for biologic aggressiveness in human pancreatic carcinoma cells. METHODS: Telomerase activity was measured in a poorly metastatic cell line HPC-3 and its highly metastatic variant HPC-3H4, as well as in many pancreatic carcinoma cell lines. Aggressive behavior of cancer cells was assessed by in vitro migration and invasion assay. RESULTS: Compared with parental HPC-3, HPC-3H4 displayed higher telomerase activity, which was associated with a scattered phenotype and enhanced migration activity. Furthermore, the authors found that relative telomerase levels correlated well with both motility (P = 0.0041) and invasion (P = 0.0114) in 13 pancreatic carcinoma cell lines. There was, however, no significant association between telomerase activity and cell proliferation. When telomerase activity of KP-1N cells was inhibited by transfection with antisense oligonucleotides, their motility and invasion rates were significantly decreased. CONCLUSIONS: The authors concluded that the magnitude of telomerase activation may reflect the potential for aggressive behavior within cancer cells. These findings support the clinical utility of telomerase activity as a prognostic indicator. Their results also suggest a therapeutic potential for telomerase inhibitors to prevent tumor invasion and possibly metastasis.

Biomarkers, Tumor↗

PubMed2001

Instability of chromosome 8 as an indicator of aggressive tumor phenotype in pancreatic cancer.

BACKGROUND AND OBJECTIVES: Chromosomal instability is a common feature of pancreatic carcinoma, but its biological significance remains unclear. In this study, we investigated the association between chromosomal instability and biological aggressiveness in human pancreatic cancer cells. METHODS: Fluorescence in situ hybridization was performed to examine changes in chromosomal numbers in a total of 13 pancreatic cancer cell lines. We also assessed the potential for tumor aggressiveness within cancer cells by in vitro migration and invasion assay and by subcutaneous implantation into nude mice. RESULTS: Chromosomal instability, characterized by numerical variations in copy numbers of chromosome 8, was observed in most cell lines, and the magnitude of instability was correlated well with both motility (P < 0.001) and invasion rate (P < 0.001) of these cells. Furthermore, a significant positive correlation existed between chromosome instability and tumor growth in vivo (P < 0.01). CONCLUSIONS: These results suggest that the increased level of chromosomal instability may play a critical role in the development of aggressive tumor phenotype during pancreatic cancer progression. J. Surg. Oncol. 2001;76:181-187.

Animals↗