Biomedical subjects

Y Yonemura

Publications and source records attributed to Y Yonemura.

At least 19 recordsLinked to original sources

PubMed2006

Neoadjuvant treatment of gastric cancer with peritoneal dissemination.

AIMS: To report our experience of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) for patients having a complete resection of the primary gastric cancer and peritoneal carcinomatosis (PC). PATIENTS AND METHODS: Patients with advanced peritoneal dissemination of primary gastric cancer had the placement of a peritoneal port system. For intraperitoneal chemotherapy, 40 mg of docetaxel and 150 mg of carboplatin were introduced in 1000 ml of saline on a weekly basis. Simultaneously, 100 mg/m2 of methotrexate and 600 mg/m2 of 5-fluorouracil were infused via a peripheral vein. A minimum of two cycles and up to six cycles of NIPS were used prior to cancer resection. At surgery a complete removal of the primary gastric cancer and the peritoneal implants by peritonectomy was attempted. RESULTS: Sixty-one patients were enrolled in the study. Thirty-nine had positive intraperitoneal cytology which reverted to negative cytology after treatment in 22. Thirty-eight showed a partial response. Thirty patients came to resection and 14 patients could be made disease-free. Median survival time of all patients was 14.4 months. Patients who received a complete resection had a median survival time of 20.4 months. Grade III/IV toxicities were not found after two courses of NIPS, but did develop in seven patients after more than three courses of NIPS. CONCLUSION: NIPS can downstage large volume peritoneal dissemination of gastric cancer. When combined with gastrectomy including peritonectomy a complete surgical resection was possible in one-quarter of the patients and resulted in a prolonged survival. This combined intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy of consideration for phase III clinical investigations.

Adult↗

PubMed2006

Quantitative prognostic indicators of peritoneal dissemination of gastric cancer.

There are three classifications that describe the quantitative prognostic indicators of peritoneal dissemination for gastric cancer. The Japanese classification (P1, P2, and P3, Lyon classification, (stage I, II, stage III, and stage IV), and the Peritoneal Cancer Index (PCI). Carcinomatosis with limited extent (P1/ P2) corresponds to the PCI less than 13 and the stage I and II from Lyon classification. Carcinomatosis with large extent (P3) corresponds to PCI of 13 or larger and stage III and IV from Lyon classification. PCI enables one to describe the precise distribution of peritoneal dissemination. All three classifications correlate with prognosis. With regard to the surgical cytoreduction of the primary tumor and the peritoneal dissemination, Sugarbaker proposed the classification of completeness of cytoreduction (CCR). Patients with no macroscopic residual tumor had significantly better prognosis than those with residual disease. CCR is a valuable prognostic indicator after cytoreductive surgery.

Humans↗

PubMed2006

Feasibility of left lobe living donor liver transplantation between adults: an 8-year, single-center experience of 107 cases.

Operative mortality for a right lobe (RL) donor in adult living donor liver transplantation (LDLT) is estimated to be as high as 0.5-1%. To minimize the risk to the donor, left lobe (LL)-LDLT might be an ideal option in adult LDLT. The aim of the study was to assess the feasibility of LL-LDLT between adults based on a single-center experience of 107 LL-LDLTs performed over 8 years. The mean graft weight of LL grafts was 452 g, which amounted to 40.5% of the estimated standard liver volume of the recipients. The overall 1-, 3- and 5-year patient survival rates in LL-LDLT were 81.4, 76.9 and 74.7%, respectively, which were comparable to those of RL-LDLT. Twenty-six grafts (24.3%) were lost for various reasons with three losses directly attributable to small-for-size graft syndrome. Post-operative liver function and hospital stay in LL donors were significantly better and shorter than that in RL donors, while the incidence of donor morbidity was comparable between LL and RL donors. In conclusion, LL-LDLT was found to be a feasible option in adult-to-adult LDLT. Further utilization of LL grafts should be undertaken to keep the chance of donor morbidity and mortality minimal.

Adult↗

PubMed2005

Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion.

BACKGROUND: There is no standard treatment for peritoneal dissemination from gastric cancer. A novel treatment consisting of peritonectomy and intraoperative chemohyperthermic peritoneal perfusion (CHPP) was compared with conventional surgery and CHPP. METHODS: Records of all patients who underwent CHPP after cytoreductive surgery between 1992 and 2002 were reviewed. RESULTS: Data for 107 patients with peritoneal dissemination were available. Complete cytoreduction was achieved in 47 (43.9 per cent) of the 107 patients: 18 of 65 who underwent conventional surgery and 29 of 42 who had peritonectomy. Twenty-three patients (21.5 per cent) suffered from complications. The overall operative mortality rate was 2.8 per cent. Seventeen patients (15.9 per cent) were disease free and 87 subsequent deaths were related to disease progression. The median survival for all patients was 11.5 months, with a 5-year survival rate of 6.7 per cent. Median survival after complete cytoreduction was 15.5 months and that after incomplete cytoreduction was 7.9 months, with 5-year survival rates of 13 and 2 per cent respectively. Completeness of cytoreduction and peritonectomy were independent prognostic factors. The 5-year survival rate after complete cytoreduction by peritonectomy with CHPP was 27 per cent. CONCLUSION: Complete cytoreduction after peritonectomy and CHPP may improve the survival of patients with peritoneal dissemination from gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value.

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. METHODS: Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. RESULTS: The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. CONCLUSIONS: A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.

Adult↗

PubMed2005

Influence of micrometastasis on N stage in gastric cancer and clinical application.

In order to evaluate the real extent of lymph node metastasis (LNM) in gastric cancer, an immunohistochemical (IHC) analysis was performed. We examined 11173 lymph nodes removed from 355 patients with all stages of gastric carcinoma. Tissue preparations were stained with cytokeratin 18, monoclonal antibody against cytokeratin. Micrometastases were found in 2.5% of the lymph nodes and in 31.3% of patients. The incidence of the patients with LNM increased to 9.1% in T(1m) (n = 99), 31.6% in T(1sm) (n = 95, 23.1% in sm1, 34.8% in sm2), 66.7% in T2 (n = 108, 48.8% in mp, 76.5% in ss), 88.1% in T3 (n = 42), and 90.9% in T4 (n = 11) lesions. Upstage was identified in 8.5% of patients: 6.7% in T1 (4.0% in m, 7.7% in sm1, 10.1% in sm2), 14.8% in T2 (20% in mp, 11.8% in ss), 2.4% in T3, and 0% in T4. Factors related to LNM were: tumor size and lymphatic invasion in mucosal lesions; only lymphatic invasion in submucosal lesions; size and depth of tumor, and lymphatic invasion in T2 lesions. In conclusion, the incidence of micrometastasis in regional lymph nodes was higher than we imagined in T1 lesions, more than D1 lymphadenectomy for sm1 and selected cases of mucosal cancer, and D2 lymphadenectomy for sm2 are necessary.

Adult↗

PubMed2004

Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study.

PURPOSE: The three principal studies dedicated to the natural history of peritoneal carcinomatosis (PC) from colorectal cancer consistently showed median survival ranging between 6 and 8 months. New approaches combining cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest improved survival. PATIENTS AND METHODS: A retrospective multicenter study was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy). PC from appendiceal origin was excluded. RESULTS: The study included 506 patients from 28 institutions operated between May 1987 and December 2002. Their median age was 51 years. The median follow-up was 53 months. The morbidity and mortality rates were 22.9% and 4%, respectively. The overall median survival was 19.2 months. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (P <.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, and poor histologic differentiation were negative independent prognostic indicators. CONCLUSION: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with PC from colorectal origin with acceptable morbidity and mortality. The complete cytoreductive surgery was the most important prognostic indicator.

Adolescent↗

PubMed2004

Is graft size a major risk factor in living-donor adult liver transplantation?

Graft size is known to be a major risk factor in living donor adult liver transplantation (LDALT). The aim of this study is to reassess whether graft size is a critical factor in LDALT or not. A series of 75 LDALTs excluding auxiliary transplantation and ABO blood-type incompatible transplantation were analyzed. The patients were divided into two groups, according to graft volume (GV) and standard liver volume (SLV): group 1 (small-size group) (GV/SLV: <40%), and group 2 (non-small-size group) (> or =40%). Perioperative clinical data were compared between the two groups, including graft survival and postoperative complications. These parameters were also compared under the conditions of cirrhotic recipients. No difference in graft survival was found between the two groups. No difference was found in incidence of postoperative complications, such as intractable ascites and persistent hyperbilirubinemia. Even in cirrhotic patients with Child-Pugh's class C, there was no difference in graft survival between the two groups. Risk factors related to graft loss were a preoperative urgent status due to chronic liver disease, pre-operative hyperbilirubinemia of over 10 mg/dl, and ABO blood type of not identical but compatible combination between donor and recipient. Graft size is not always considered to be a major risk factor in LDALT, although the number of patients was small in this study. Therefore, a left-lobe graft, even a "small-for-size" graft for adult recipients, remains a feasible option in LDALT.

Adolescent↗

PubMed2004

Prognostic value of age and sex in early gastric cancer.

BACKGROUND: The need for lymph node dissection in early gastric cancer (EGC) is controversial. The present study investigated the possibility of planning treatment for EGC according to age and sex rather than node status. METHODS: Overall survival rate and cause of death were analysed according to age (5-year increments) and sex in 4231 patients with EGC. Cox proportional hazard regression analyses were used to identify the most valuable predictor. RESULTS: In patients with EGC 5- and 10-year cancer-specific survival rates were 98.4 and 96.3 per cent respectively, whereas corresponding overall survival rates were 90.2 and 80.9 per cent. The critical age for determining prognosis was 70 years for men (chi2 = 131.34, P < 0.001) and 75 years for women (chi2 = 64.35, P < 0.001). For both sexes, the 10-year overall survival rate was less than 30 per cent in patients over 80 years old. Multivariate Cox stepwise regression analysis identified age as the most powerful prognostic indicator in EGC. The rate of death from causes unrelated to the tumour increased significantly with age, whereas that from recurrence was not affected by age. CONCLUSION: Age is a better prognostic indicator than node status in both men and women with EGC. Age and sex should be taken into account as well as conventional clinicopathological variables related to lymph node metastases when determining appropriate therapy for EGC.

Adolescent↗

PubMed2001

Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer.

Vascular endothelial growth factor C (VEGF-C) is the only factor known to cause lymphangiogenesis. We studied the correlation between VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression of 85 primary gastric cancers by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, and the results were correlated with the number of lymphatic vessels, stained with anti-VEGFR-3 antibody. RT-PCR and immunohistology demonstrated that VEGF-C was mainly produced from cancer cells, but not from stromal elements. Morphologically, VEGFR-3 expression was detected in the endothelial cells of the stromal lymphatic vessels. There was a statistically positive correlation between the incidence of VEGF-C and VEGFR-3 mRNA expression in the primary tumours (P=0.0002). The number of VEGFR-3-positive lymphatic vessels in VEGF-C mRNA positive tumours was significantly larger than that in VEGF-C-negative tumours. The number of VEGFR-3-positive vessels in the tumour stroma was closely related to the grade of lymphatic invasion of gastric cancer. These results strongly indicate that VEGF-C may induce the proliferation of lymphatic vessels in the stroma of primary gastric cancer via activation of VEGFR-3, expressed on the endothelial cells of lymphatic vessels. In these circumstances, cancer cells can easily invade the lymphatic vessel, because of the increase of the contact points of cancer cells with the lymphatic vessels.

Blotting, Western↗

PubMed2001

Diagnostic value of preoperative RT-PCR-based screening method to detect carcinoembryonic antigen-expressing free cancer cells in the peritoneal cavity from patients with gastric cancer.

BACKGROUND: At present the most reliable method for the diagnosis of peritoneal micrometastasis of gastric cancer is peritoneal wash cytology, but the sensitivity of this method is low. The aim of the present study was to verify whether carcinoembryonic antigen (CEA) reverse transcriptase-polymerase chain reaction (RT-PCR) assay can enhance the sensitivity and specificity of conventional cytology, and to determine how this technique can improve the accuracy of peritoneal recurrence. METHODS: The present study included 230 patients with gastric cancer. Preoperative peritoneal wash was done by a paracentesis, followed by conventional cytology, CEA measurement, and CEA RT-PCR of recovered fluid. RESULTS: The CEA RT-PCR assay yielded 40 (17%) positives, which included none of the 26 patients with benign disease. The incidence of positive cytology and CEA level in wash fluid was 19% and 15%, respectively. Logistic stepwise regression analysis revealed that lymph node status, depth of invasion, venous invasion, and the results of peritoneal cytological examination, and CEA RT-PCR assay were independently related to peritoneal recurrence. The CEA level in the wash fluid was not related to peritoneal recurrence. Peritoneal cytological examination was the most significant predictive factor for peritoneal recurrence with a sensitivity of 46%, specificity of 94% and accuracy of 73%, while the corresponding values of the CEA RT-PCR assay were 31%, 95%, and 73%. Combining cytological examination with CEA RT-PCR assay resulted in a sensitivity rate for peritoneal recurrence of 57%, an 11% improvement over that of cytology alone. CONCLUSION: The data indicate that the use of a combination of CEA RT-PCR and cytological assay is more likely to identify patients who will develop peritoneal recurrence. This may be useful for the classification of patients for the most suitable therapeutic trials.

Adult↗

PubMed2001

Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma.

S100A4 has been implicated in invasion and metastasis of cancer, but prognostic significance of its expression in esophageal squamous cell carcinoma remains unclear. In this study, we examined the expression of S100A4 by Western blot analysis and immunohistochemistry in surgically resected esophageal squamous cell carcinoma. The relationship between S100A4 tissue status and clinicopathological findings was analyzed to assess the prognostic significance of S100A4 in esophageal squamous cell carcinoma. The S100A4 protein level was significantly higher in tumor tissue than in corresponding normal esophageal mucosa (p<0.05) in 22 cases of esophageal carcinoma by Western blot analysis. S100A4 expression was detected in 25% of 52 cases of esophageal squamous cell carcinoma by immunohistochemistry and correlated with the depth of invasion (p<0.05). Patients with S100A4-positive carcinoma had significantly poorer prognosis than those with S100A4-negative carcinoma, which was also true in the cases with deep invasion of the primary cancer (T3, T4) (p<0.01 and p<0.05, respectively). Moreover, S100A4 tissue status remained the only independent prognostic parameter in the multivariate analysis. Our results suggest that S100A4 may play a key role in the progression of esophageal carcinoma and that immunohistochemical detection of S100A4 in the primary tumor may be useful for the prediction of a poor prognosis.

Adult↗

PubMed2001

Significance of integrin alpha2/beta1 in peritoneal dissemination of a human gastric cancer xenograft model.

In the present study, the role of integrin alpha2/beta1 in peritoneal dissemination of gastric cancer was investigated using an in vivo xenograft model for the highly metastatic MKN-45-P gastric cancer cells. Metastatic ability of MKN-45-P cells was significantly associated with the simultaneous expression of integrin alpha2 and alpha3 subunits. In an in vitro adhesion assay, neutralizing antibody for integrin alpha2 or beta1 subunit inhibited the adhesion of MKN-45-P cells to collagen type I and type IV. Moreover, the injection of anti-beta1 monoclonal antibody reduced the number of cancer cells on the peritoneum in nude mice that had been inoculated with MKN-45-P cells. These results suggest that integrin alpha2/beta1 represents a candidate target molecule available for the prevention of gastric cancer peritoneal dissemination.

Adenocarcinoma↗

PubMed2001

Prediction of peritoneal micrometastasis by peritoneal lavaged cytology and reverse transcriptase-polymerase chain reaction for matrix metalloproteinase-7 mRNA.

PURPOSE: Peritoneal dissemination is the most common cause of death associated with gastric cancer. In this study, we report the significance of molecular diagnosis of peritoneal dissemination by means of matrix metalloproteinase-7 (MMP-7) reverse transcriptase-PCR (RT-PCR) assay using preoperative peritoneal wash fluid. EXPERIMENTAL DESIGN: Preoperative peritoneal lavage by paracentesis was performed on 152 patients with gastric cancer. The peritoneal lavaged fluid was subjected to RT-PCR analysis with primers specific for MMP-7 and conventional cytological Papanicolaou examination. RESULTS: The MMP-7 RT-PCR assay was able to detect cancer cells at densities even lower than 10 cells/sample. There was no signal of MMP-7 mRNA from mesothelial cells, fibroblasts, peripheral blood, and lavaged fluid from patients with benign disease. Cytological examination and MMP-7 RT-PCR assay results were positive for 27 (18%) and 28 (18%) samples, respectively. The sensitivity for the prediction of peritoneal dissemination by cytology and MMP-7 RT-PCR assay were 46% and 33%, but the combination analysis using both parameters improved the sensitivity rate with 62%. Logistic regression analysis revealed that the cytological examination and MMP-7 RT-PCR assay are independent predictors of peritoneal dissemination. CONCLUSION: The combination of cytological examination and RT-PCR assay of preoperative peritoneal lavaged fluid is a highly efficient and reliable method for the selection of patients for adjuvant i.p. chemotherapy.

Adult↗

PubMed2001

Inhibition of peritoneal dissemination in human gastric cancer by MMP-7-specific antisense oligonucleotide.

MMP-7 is a matrix-degrading enzyme that is mainly produced from cancer cells, and has a great role in the invasion and metastasis of cancer. We have established a highly metastatic cell line (MKN-45-P) on the peritoneum of nude mice from MKN-45 by repeated intraperitoneal inoculation of intraperitoneal free cancer cells. By the precise screening of metastasis-related genes using reverse transcriptase-polymerase chain reaction (RT-PCR), MKN-45-P characteristically expressed more MMP-7 than the original cell line of MKN-45. In this study, we studied the effects of antisense oligonucleotides complementary to exon 3 of MMP-7 mRNA on the expression of MMP-7 and metastatic potential of MKN-45-P by using in vitro and in vivo experiments. RT-PCR and western blot analysis demonstrated that 10 microM antisense oligonucleotides suppressed MMP-7 expression at both the mRNA level (84%) and protein level (56%). Antisense oligonucleotides, specific for MMP-7 suppressed invasion by MKN-45-P cells without influencing proliferation. On the other hand, scrambling sequence control oligonucleotides did not show any inhibitory effects. In addition, survival of MKN-45-P bearing mice, which had been treated for 48 hrs with antisense oligonucleotides before intraperitoneal injection, was significantly better than that of control mice. In contrast, control oligonucleotides did not influence the survival of mice with the peritoneal dissemination model. These results strongly suggest that MMP-7 may have a great role in the formation of peritoneal dissemination in gastric cancer, and the molecular control of MMP-7 using antisense oligonucleotides may be a hopeful treatment modality for peritoneal dissemination.

Animals↗

PubMed2000

Alteration of beta-catenin expression in esophageal squamous-cell carcinoma.

beta-catenin regulates cadherin-mediated cell-cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E-cadherin, alpha-catenin and beta-catenin in 22 cases of esophageal squamous-cell carcinoma by Western-blot analysis. Expression of E-cadherin, alpha-catenin and beta-catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E-cadherin, 6 cases (27.3%) for alpha-catenin and 9 cases (40.9%) for beta-catenin. Expression of beta-catenin was not always correlated with that of E-cadherin. Over-expression of beta-catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over-expression of beta-catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of beta-catenin was observed in one case that had higher beta-catenin level in tumor tissue (1.4-fold higher than normal mucosa). The genomic DNA sequences of the beta-catenin and the APC gene were analyzed. No mutation of the beta-catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over-expression or nuclear localization of the beta-catenin protein. These results indicate that alterations of the cadherin-catenin complex may play an important role in a sub-set of esophageal carcinogenesis. Furthermore, it is suggested that beta-catenin over-expression is not caused by genetic alteration of either the beta-catenin or the APC gene.

Blotting, Western↗

PubMed2000

Does hyperthermia induce peritoneal damage in continuous hyperthermic peritoneal perfusion?

To investigate the mechanisms of the peritoneal damage induced by continuous hyperthermic peritoneal perfusion (CHPP), protein and fluid loss during and after CHPP and continuous normothermic peritoneal perfusion (CNPP) was studied. Sixteen patients with advanced gastric cancer underwent peritoneal perfusion therapy with saline solution containing 150 to 300 mg cisplatin and 30 to 60 mg mitomycin C for 60 minutes. The temperature in Douglas' pouch was maintained at 42.0 degrees C in the CHPP group (n = 9) and 37.0 degrees C in the CNPP group (n = 7) during perfusion. No statistical differences were found in patients' characteristics between the groups except the maximum temperature in Douglas' pouch during perfusion (41.6 degrees +/- 0.4 degrees C and 37.6 degrees +/- 0.4 degrees C in CHPP and CNPP groups, respectively, p < 0.05). The amount of protein lost into the perfusate was 0.35 +/- 0.22 g/kg body weight in the CHPP group and 0.37 +/- 0.19 g/kg in the CNPP group, showing no significant difference. On the day of surgery, there was no significant difference in the amount of protein and fluid lost through the abdominal drains between the CHPP group (27.9 +/- 24.6 mg/kg/hr and 0.94 +/- 0.63 ml/kg/hr, respectively) and the CNPP group (25.9 +/- 8.6 mg/kg/hr and 1.03 +/- 0.31 ml/kg/hr, respectively). We could not find any significant differences in postoperative protein and fluid loss between the groups on the following 3 days either. We conclude that the peritoneal damage by CHPP is not caused by the hyperthermia but by the peritoneal perfusion with saline solution containing anticancer drugs.

Chemotherapy, Cancer, Regional Perfusion↗

PubMed2000

Membrane-type 1 matrix metalloproteinase enhances lymph node metastasis of gastric cancer.

The mechanisms of the lymph node metastasis remain unclear. We demonstrate the role of MT1-MMP on the lymph node metastasis using in vivo experimental model of lymph node metastasis by orthotopic implantation of MT1-MMP transfected gastric cancer cell line in the stomach of nude rats. TMK-1 cell line without expression of MT1-MMP was transfected with the pcDNA3 plasmid containing a 3.4-kb MT1-MMP cDNA fragment by calcium phosphate method, and the transfected cell line was designated as TMK-MT. Western blot and RT-PCR analyses showed the specific bands corresponding to MT1-MMP in the TMK-MT cells. By gelatin zymography, the activated form (62-kDa) of MMP-2 was identified in the medium of TMK-MT cell line, but was not detected in TMK-1 cells. Six weeks after orthotopic implantation of TMK-1 and TMK-MT xenografts of nude mouse-subcutaneus tumor into the stomach of nude rats, gastric tumors were found in all the animals. Histologically, the lymphatic invasion was found in the submucosa of the TMK-MT gastric tumors. Lymph node metastasis was not detected in nude rats bearing TMK-1 gastric tumor (0/8). In contrast, lymph node metastasis was detected in five out of 8 rats, bearing TMK-MT gastric tumor. MT1-MMP immunoreactivity was found on the cell membrane and cytoplasm of TMK-MT cells not only in the lymph node metastasis but also in the stomach tumor. These results suggest that MT1-MMP overexpression induced by transfection of its gene may promote lymph node metastasis of transformed cells.

Animals↗