北山 丈二

Massive postoperative polyuria is rare, except in neurosurgery patients. Here we report excessive polyuria in a 59-year-old woman following total gastrectomy for advanced gastric cancer. The etiology of the patient's polyuria was unknown. Urine output was measured hourly and replaced with Ringer's lactate solution at 80% of measured volume. The rate of urine output during 9 postoperative days ranged from 900 to 2700 ml·h-1. Several administrations of an antidiuretic hormone (ADH) analogue were ineffective in reducing urine output, suggesting a possible relationship of the massive polyuria to nephrogenic diabetes insipidus. Following oral administration of a thiazide diuretic, known to exert an antidiuretic action in nephrogenic diabetes insipidus, urine output was dramatically reduced. We conclude that this case of massive polyuria probably resulted from postoperative nephrogenic diabetes insipidus. © JSA 2006.

AIM: To determine the real association between serum lipid levels and colonic polyp formation. METHODS: We performed a large scale retrospective study to analyze the correlation between the incidence of colorectal adenoma or carcinoma and the fasting serum levels of total cholesterol (TC) and triglycericles; (TG) in patients who underwent total colonoscopy for screening for colon cancer. RESULTS: Both levels were significantly elevated in patients with adenomas as compared with patients without any neoplastic lesion (TC 207.6 +/- 29.5 vs 199.5 +/- 34.3, n = 4883, p < 0.001; TG 135.0 +/- 82.2 vs 108.7 +/- 71.5, n = 4874, p < 0.001). The difference was significant in patients with tubular adenoma but not in those with villous or serrated adenoma. Multiple logistic regression analysis including age and sex revealed that TG was an independent correlation factor in male (p < 0.01), but not in female patients. The level of TG in patients with invasive carcinoma did not show a significant elevation from that in patients with adenoma. These findings suggest that hypertriglyceridemia is an independent risk factor for colonic adenoma in men. CONCLUSION: Although a high level of serum triglyceride does not appear to be mechanically involved in the development of carcinoma, reduction of serum TG and intensive surveillance with total colonoscopy may have benefit in men with hypertriglyceridemia. (c) 2006 The WJG Press. All rights reserved.

Background. Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological activities that may affect the progression of various cancers. Malignant ascites contains high levels of LPA as well as vascular endothelial growth factor (VEGF). Although LPA receptors are widely expressed in normal as well as cancer cells, little is known about the effect of LPA on host cells. Therefore, we evaluated the effect of LPA specifically on peritoneal mesothelial cells (PMC), and assessed another aspect of LPA in tumor biology mediated through the host cells. Materials and methods. The effect of LPA on the production of VEGF was evaluated by ELISA and northern blotting. Next, we quantified human- and mouse-VEGF separately in ascitic fluid of nude mice inoculated intraperitoneally with a human gastric cancer, MKN45, and thus evaluated the ratio of host-derived VEGF in malignant ascites. Results. Addition of 10 to 80 mu m LPA enhanced VEGF production by PMC through gene activation. The effect was strongly inhibited by pre-treatment with PTX or Ki16425, indicating that the effect was mainly dependent on the LPA1 signal. Of the VEGF in ascitic fluid at 3 weeks after tumor inoculation, 12.8% was derived from mouse cells. At 6 weeks, however, the ratio of host-derived VEGF was reduced to 5.0%, suggesting that the ratio of host-derived VEGF may be higher in the earlier phase. Conclusion. Because tumor growth is often associated with an increase of LPA concentration in ascites, stimulation of VEGF production in PMC might have an important role in the growth of cancer cells disseminated in the peritoneal cavity. (c) 2006 Elsevier Inc. All rights reserved.

Introduction. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid, derived from activated platelet, that is known to induce diverse cellular responses through at least five G-protein-coupled receptors on various cell types. Abnormal platelet and coagulation activation is often seen in patients with gastric cancer. However, neither the effects of this platelet-derived mediator S1P nor the distribution of S1P receptors on the gastric cancer cell are fully understood. The aim of this study was to examine the possible role of S1P and its receptors in the progression of gastric cancer. Materials and methods. We characterized the expression profiles of S1P receptors in nine human gastric cancer cell lines and evaluated the relationship between the responses to S1P and its receptor expression on cell migration by modified Boyden chamber and cell proliferation by MTS assay. Results. Northern blotting analysis has revealed that S1P2 was expressed in all gastric cancer cell lines to varying degrees, and S1P3 was expressed in four cell lines. S1P1 expression was weak, and no significant expression of either S1P4 or S1P5 was detected. The addition of S1P markedly stimulated the migration of MKN1 and HCG-27 that dominantly expressed S1P3, and the effect was potently inhibited by pertussis toxin or wortmannin. In contrast, S1P significantly inhibited the migration of AZ-521 that expressed S1P2 exclusively. This indicates that the balance between S1P2- and S1P3-mediated signals might be critical in determining the metastatic response of gastric cancer cells to S1P. S1P elicited weak but significant antiproliferative effects on all of the three cell lines, although the effects were not major. In these cells, S1P induced extracellular signal-regulated kinase (ERK) phosphorylation with transient Akt dephosphorylation that may cause the weak effects on proliferation. Conclusions. Our results suggest that the S1P receptor expression may critically determine the biological behavior of gastric cancers and thus therapeutic interventions directed at each S1P receptor might be clinically effective in preventing metastasis in gastric cancer. (c) 2006 Elsevier Inc. All rights reserved.

Background and Objectives: Lysophosphatidic acid (LPA), a natural phospholipid, can modulate diverse cellular responses through LPA receptor, LPA(1-4). Although LPA, is known to be widely expressed in human tissues, the distribution of other LPA receptors is not characterized in malignant tissues. Recently, it was reported that malignant transformation resulted in aberrant expression of LPA(2) in a various type of cancer, suggesting the positive role of LPA2 in tumor development. Methods: We investigated the expression of the LPA2 receptor immunohistochemically in 204 gastric cancers and analyzed the relationship between the expression of LPA2 and clinicopathological features. Results: LPA(2) was preferentially expressed (67%) in intestinal-type cancer that was significantly higher than that in diffuse-type cancer (32%, P < 0.0001). The expression of LPA2 showed correlation with a higher rate of lymphatic and venous invasion, lymphatic metastasis, and resultingly tumor stage in diffuse-type cancer, but not in intestinal-type cancer. Conclusions: Our results highlight the possibility that LPA2 expression is an important process in the carcinogenesis of gastric cancer, especially in intestinal-type cancer. Since LPA can transactivate HGF receptor (c-Met) as well as EGF-receptor, LPA may promote the progression of gastric cancer in diffuse-type with high expression of c-Met. The development of LPA(2)-specific antagonists might have future therapeutic relevance in the treatment as well as prevention of gastric cancer.

To determine the clinical efficacy of Roux-en-Y reconstruction (RY) after distal gastrectomy, we compared postoperative outcomes of patients who underwent RY or conventional Billroth I reconstruction (B-I). A total of 50 patients were prospectively randomized to either B-I or RY reconstruction, and complications, postoperative course, and nutritional status were compared. Bile reflux and inflammation in the remnant stomach and lower esophagus were evaluated by postoperative follow-up endoscopy at 6 months. Operative time and blood loss as well as postoperative nutrition did not show significant differences between the two groups. As anticipated, 5 of 24 patients with RY reconstruction developed gastrojejunal stasis in the early postoperative period, which led to a longer postoperative hospital stay as compared with the B-I group (mean +/- S.D; B-I; 19.0 +/- 6.2, RY; 31.8 +/- 21.7 days) (P < 0.05). Endoscopic examination revealed that the frequency of bile reflux (P < 0.01) and degree of inflammation in the remnant stomach (P < 0.05) were less in the RY group than in the B-I group. However, inflammatory findings in the lower esophagus were observed in 7 (27%) of B-I, and 8 (35%) of the RY group, suggesting that late phase esophagitis was not improved in the RY group. Roux-en-Y reconstruction was effective in preventing duodenogastric reflux and resulting gastritis, but it did not prevent esophagitis. Because RY reconstruction induces the frequent complication of Roux-en-Y stasis, causing longer postoperative hospital stay, this method has limited advantages over B-I anastomosis after distal gastrectomy.

Inhibitor of DNA binding (Id) proteins are essential for cell differentiation, proliferation, migration, invasion and angiogenesis. Recently, they have been shown to correlate with less differentiated phenotypes, high malignant potential and poor clinical outcome in various kinds of tumors. In an attempt to develop new strategies for the treatment of peritoneal metastasis of gastric cancer, we prepared an Id1, 3 double-knockdown gastric cancer cell line, MKN45, by RNA interference and investigated its effects on the development of metastatic nodules in the peritoneal cavity. Both cell proliferation and migration capabilities were decreased in Id1, 3 double-knockdown cells, as was their ability to bind to laminin, which could be explained by the decreased expression of integrin alpha 6. These are important steps in the metastatic process. In a mouse model, the number of peritoneal metastatic nodules formed by Id1, 3 double-knockdown cells was reduced compared to mock-transfected control cells, as was the size of individual tumors. In this study, we clearly demonstrated that Id1, 3 double-knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis. Id should be considered an ideal target for the treatment and prevention of gastric cancer, and RNA interference is an attractive and promising strategy to achieve it.

Background: Although abnormal hemostasis has been described in cancer patients, the precise association between the plasma fibrinogen level and lymphatic metastasis has not been reported in a large-scale clinical study. Methods: Preoperative plasma levels of fibrinogen as well as C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were retrospectively examined in 649 patients who underwent surgery for gastric cancer, and the correlation between these factors and nodal status was evaluated. Results: Plasma fibrinogen level in patients with gastric cancer showed a positive association with nodal classification (P < 0.0001). Hyperfibrinogenemia (> 310 mg/dl) as well as high CEA (> 5 ng/ml) and CRP (> 0.3 mg/dl) showed a significant association with nodal metastasis in univariate analysis. Multivariate analysis revealed that hyperfibrinogenemia had an independent association with nodal metastasis (odds ratio, 2.004 (1.140-3.521); P = 0.0157), whereas CEA and CRP were not independent factors. Hyperfibrinogenemia showed an independent association even in advanced cancer [odds ratio 2.611 (1.404-4.854), P = 0.0024, n = 319]. When the 649 gastric cancers were classified into intestinal-type and gastric-type adenocarcinomas, plasma fibrinogen level was correlated with nodal metastasis only in the intestinal-type. Conclusions: Our results suggest that hyperfibrinogenemia may provide favorable circumstances for cancer cells to metastasize via the lymphatic system. Preoperative plasma fibrinogen level is a useful predictor of lymphatic metastasis in intestinal-type gastric cancer.

Leptin is known to act as a growth factor through the Janus-activated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogen-activated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal-regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight.

We previously reported that the over-expression of hRFI, a protein preferentially expressed in the digestive tract regions of several cancers, exhibited a tendency to inhibit TNF-alpha induced apoptosis. In this study, we sought to determine the potential effect of hRFI expression on the sensitivity to 5-fluorouracil (5-FU) and/or other fluoropyrimidines. For the whole lysates of 8 colon cancer cell lines, we performed Western blotting with anti-hRFI antibody and analyzed the correlations between the expression level of hRFI and the cell lines' sensitivity to 5-FU induced apoptosis. Furthermore, for a tissue microarray consisting of 32 xenograft derived human cancer cell lines, we examined the expression levels of hRFI and survivin by immunohistochemical staining, and analyzed the correlations between the expression of each protein and the sensitivity to several chemotherapeutic agents in the xenografts examined. Both in colon cancer cell lines and in xenografts, the expression level of hRFI was correlated with resistance to 5-FU and its derivatives. This evidence suggests that hRFI may be a marker predicting the response to fluorouracil derived chemotherapeutic agents and that the reduction of the expression level of hRFI might improve the outcome of chemotherapy.

We report the case of a patient with nasopharyngeal carcinoma who was diagnosed as having metastasis in mediastinal lymph nodes and successfully underwent systemic chemotherapy without surgery. A 61- year- old male with a history of nasopharyngeal carcinoma presented with odynophagia. Examination revealed two palpable lymph nodes in the right neck. Pharyngoscopy showed a mass in the left inferior pharyngeal mucosa, and upper gastrointestinal endoscopy showed only chronic gastritis, with no sign of esophageal disease. Chest CT confirmed the presence of a non- enhancing 20- mm soft tissue mass in the paraesophageal area, with increased attenuation compared with the adjacent esophagus. To evaluate this lesion we applied endoscopic ultrasonography- guided fine- needle aspiration biopsy ( EUS- FNA). Two passes were made with a 21- gauge fine needle and the patient tolerated the procedure well, without complications. Cytological findings were compatible with metastatic squamous cell carcinoma from a nasopharyngeal tumor, and the clinical stage was determined as T3N2bM1 ( stage IVC) because of mediastinal lymph node metastasis. We thus determined the nodal status of a head and neck tumor by means of EUS- FNA. In conclusion, EUS- FNA is a safe and reliable technique for evaluation of mediastinal lymphadenopathy, and is especially valuable for head and neck tumors with suspected metastasis.

AIM: To examine whether lysophosphatidic acid (LPA) induces phosphorylation of c-Met and epidermal growth factor receptor (EGFR), both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 (COX-2) expression in human colon cancer cells. METHODS: Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS: Immunoprecipitation analysis revealed that 10 mu mol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 mu mol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION: Our results suggest that LPA acts upstream of various receptor tyrosine kinases (RTKs) and COX-2, and thus may act as a potent stimulator of colorectal cancer. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

Background: CD11b belongs to the integrin family and is expressed on neutrophils, monocytes, natural killer cells, and a subset of lymphocytes. Although CD11b expressed on neutrophils and monocytes has been extensively investigated and has been reported to play an important role in the migration of these subsets of leukocytes, the function of CD11b expressed on a subset of B cells has not yet been clarified. Objective: To elucidate the functional activity of CD11b expressed on B cells, we characterized the CD11b-expressing cells among the B-cell population and investigated their migratory ability. Methods: Isolated peripheral blood CD19(+) B cells were analyzed by flow cytometry. The migratory ability of B cells was evaluated by the transwell assay, and the contribution of CD11b to this ability was investigated by using an anti-CD11b blocking mAb. Results: The majority of CD27(-)IgD(+) naive B cells were CD11b(-), whereas most CD27(+) memory cells were CD11b(+). Among the CD27(+) memory cells, expression of CD11b was stronger on the IgD(-) cells than on the IgD(+) cells. In the transwell assay, the migrating cells were predominantly CD27(+)IgD(-) cells, most of which expressed CD11b. The addition of an anti-CD11b blocking mAb resulted in the significant reduction of the number of migrating B cells. Conclusion: Memory B cells express CD11b and, in contrast with naive B cells, have high migratory ability. CD11b plays an essential role in the homing process of memory cells.

Background: hRFI is a newly discovered gene encoding a Ring Finger domain highly homologous to that of the X-chromosome-linked inhibitor of apoptosis protein, which is among the most potent inhibitors of apoptosis. The hRFI protein is preferentially expressed in colorectal cancers, although its actual function is unknown. The aim of this study was to determine whether hRFI possesses an anti-apoptotic function in colorectal cancer cells against chemotherapeutic agents. Materials and Methods: HCT116 colorectal cancer cells were exogenously transfected with hRFI or LacZ as a control. After exposure to either cisplatin, irinotecan or 5-fluorouracil, apoptosis and caspase-3 activity were evaluated by flow cytometry analysis. Results: The hRFI transfectant exhibited significant resistance to apoptosis induced by each of the three agents, along with inactivation of caspase-3. Growth in the normal medium was not altered. Conclusion: hRFI plays an important role in the resistance to chemotherapeutic agent-induced apoptosis in colorectal cancer cells.

The acquisition of antiapoptotic properties is one of the essential mechanistic steps in colorectal carcinogenesis and is closely correlated with a loss of chemosensitivity and radiosensitivity. Human ring finger homologous to inhibitor of apoptosis protein type (hRFI) is a newly discovered gene encoding a ring finger domain highly homologous to that of X chromosome-linked inhibitor of apoptosis protein. Immunohistochemistry has revealed that the expression of hRFI increased in transition from normal colorectal mucosas to adenomas and from adenomas to carcinomas, suggesting an essential role in the early stage of colorectal carcinogenesis. However, the function role of hRFI in colorectal carcinoma has not been elucidated. To determine whether hRFI possesses an antiapoptotic function in colorectal cancer cells, HCT116 colorectal cancer cells stably overexpressing hRFI were established. The hRFI transfectant exhibited significant resistance to apoptosis induced by tumor necrosis factor-ex or tumor necrosis factor-related apoptosis-inducing ligand compared with control. This antiapoptotic response was associated with decreased activity of caspase-3, -8, and -9. We also established an antisense down-regulation of hRFI, which effectively reversed the antiapoptotic activity of the hRFI transfectant. This confirmed that the antiapoptotic property of the hRFI transfectant was not due to the clonal effect but in fact dependent on hRFI function. In conclusion, hRFI possesses an antiapoptotic function in HCT116 colorectal cancer cells. Considering the progressive increase of hRFI expression in the advance of the colorectal adenoma-carcinoma sequence, hRFI is one of the important players in colorectal carcinogenesis through its effect on apoptosis regulation.

We have investigated a potential anti-angiogenic effect of plaunotol, an extract from the leaves of Plau-noi, in an angiogenesis model consisting of human umbilical vein endothelial cells (HUVECs). Plaunotol inhibited the proliferative activity of HUVECs in a dose-dependent manner. In addition, it caused a remarkable decrease of the ability of HUVECs to adhere and spread on gelatin and vitronectin, but not fibronectin. Tube-like formation in Matrigel was also inhibited in a dose-dependent way. These results strongly suggest the specific inhibition of integrin alpha(v)beta(3) to be the main event of plaunotol-induced suppression of angiogenesis. The alpha(v)beta(3) antagonists are known to be potent inhibitors of tumor angiogenesis and plaunotol, by causing the functional inhibition of alpha(v)beta(3), should be considered a promising new anti-angiogenic drug. (c) 2005 Lippincott Williams W Wilkins.

The occurrence of early gastric carcinoma with invasion to the duodenum is supposed to be very low, although advanced cancers arising in the antrum can often invade the duodenal area. Generally, malignant invasion of the duodenum is difficult to diagnose preoperatively, as spread of gastric cancer to the duodenum is often infiltrative and invades through the submucosal or subserosal layer. We report an unusual case of an intramucosal gastric carcinoma with extensive duodenal invasion that was preoperatively diagnosed by endoscopy.

High-level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. Selective inhibition of COX-2 was shown to reduce colorectal tumorigenesis in different models of carcinogenesis and to prevent metastasis in xenograft tumor models, as well as to suppress in vitro induced angiogenesis. Recently, COX-2 was reported to be expressed not only in malignant epithelial cells, but also in the neovasculature that feeds the tumor in a variety of solid human cancers. Thus, one of the possible mechanisms by which selective COX-2 inhibitor reduces tumor growth and metastasis is through inhibition of tumor angiogenesis. Although a report suggested a possible role of endothelial COX-I in the process of angiogenesis, in a recent study, the selective inhibition of COX-2 was shown to strongly inhibit angiogenesis by inducing endothelial cell (EC) apoptosis. In the present study, using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the potential antiangiogenic effect of the selective COX-2 inhibitor and its mechanism of action, and clearly demonstrated that selective inhibition of COX-2 caused a dose-dependent decrease in the proliferative activity of ECs, as well as an inhibition of capillary-like tube formation. The inhibitory effect on EC proliferation was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis. (C) 2004 Wiley-Liss, Inc.

The ligand-less receptor HER2/neu (erbB-2) has been proposed as a prognostic marker of gastric cancer that correlates with poor clinical outcome, indicating that HER2 signals play an important role in gastric cancer progression. This study demonstrated that two Major natural lysophospholipids, lysophosphatidic acid (LPA) and sphingosine I-phosphate (SIP), induce rapid and transient phosphorylation of HER2 in two human gastric cancer cell lines, MKN28 and MKN74 cells. We also revealed that tyrosine phosphorylation of HER2 induced by both lysophospholipids was significantly attenuated by two inhibitors, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This suggests that the pathway of HER2 transactivation induced by these lysophospholipids is dependent on the proteolytically released EGFR ligands. Our results indicate that LPA and SIP act upstream of HER2 in gastric cancer cells, and thus may act as potent stimulators of gastric cancer. (C) 2004 Elsevier Inc. All rights reserved.

High level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX-2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell-surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high-COX-2 (high level COX-2 expression) colon cancer cell line, HT-29, and a low-COX-2 (low level COX-2 expression), DLD-1, were used to investigate the anticolon cancer effect of the selective COX-2 inhibitor, JTE-522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE-522 caused a dose-dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down-regulation of beta 1-integrin expression, which was evident in HT-29, the high-COX-2 colon cancer cells, but not the low-COX-2, DLD-1. In addition, prostaglandin E2 almost completely reversed the effect of JTE-522, strongly suggesting the involvement of a COX-2-dependent pathway. In conclusion, for the first time, we could demonstrate the down-regulation of beta 1 integrin caused by COX-2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop.

Background: Vascular endothelial growth factor (VEGF)-C is implicated in lymphangiogenesis, however the exact role of VEGF-C in promoting lymphatic spread of cancer cells remains largely unknown. Methods: The expression of VEGF-C was immunohistochemically determined in 97 endoscopic biopsy specimens from 46 patients with submucosal gastric carcinoma (SGC). Nodal metastases including micrometastasis and isolated tumor cells (ITC) were evaluated by immunohistochemical staining for cytokeratin in 1650 lymph nodes, and tumor cells in these metastatic nodes were also examined for VEGF-C expression. Results: In biopsy samples, VEGF-C was positively detected in 21 (47%) patients. Metastases were identified in 46 (2.8%) nodes from 15 (33%) patients. Metastases were detected in 39 nodes by hematoxylin-eosin (H&amp E) staining and in additional 7 nodes as ITC by immunohistochemical staining. The rate of lymph node metastases was significantly correlated with VEGF-C expression in biopsy samples (p &lt 0.05). The positive and negative predictive values of VEGF-C in biopsy specimens for nodal metastasis were 44 %(10/21) and 80% (20/25), respectively. Among the 46 metastatic nodes, tumor cells in 29 (63%) nodes positive patients expressed VEGF-C, whereas those in 17 (37%) nodes did not. VEGF-C expression was high in macronodular foci in medullary areas, whereas more than half of ITC or micrometastasis located in peripheral sinus lacked the expression of VEGF-C. Conclusions: Despite the significant correlation, immunodetcetion of VEGF-C in endoscopic biopsy specimens could not accurately predict the nodal status, and thus cannot be applied for the decision of the treatment for SGC. VEGF-C may not be essential for lymphatic transport, but rather important to develop the macronodular lesion in metastatic nodes. © 2005 Ishikawa et al licensee BioMed Central Ltd.

Lysophosphatidic acid (LPA), which interacts with at least three G protein-coupled receptors, LPA1/Edg-2, LPA2/Edg-4, and LPA3/Edg-7, is a lipid mediator with diverse effects on various cells. Nothernblot analysis showed that MKN1, NUGC-3, AZ521, HGC-27, and GCIY, preferentially expressed LPA1, whereas MKN28, MKN45, MKN74 and KATO III expressed LPA2 exclusively. Using a Boyden chamber assay, LPA markedly increased cell migration of LPA1 expressing cells, but not of LPA2 expressing cells. However, when hepatocyte growth factor (HGF) was placed with LPA in the lower chamber, LPA strongly augmented migration of LPA2 expressing cells. Immunoprecipitation revealed LPA induce transient tyrosine phosphorylation of the c-met in MKN28, suggesting the transactivation of c-met by LPA. Our results indicate that LPA regulates migration and metastatic potential of gastric cancer in receptor specific manner.

Background: Monocytes are the main effector cells of the immune system, and the regulation of their survival and apoptosis is essential for monocyte-involved immune responses. Green tea polyphenol catechin has been reported to have antiallergic and antiinflammatory activities, but its effect on monocytes has not yet been explored. Objective: To elucidate the mechanisms of the anti-inflammatory effect of catechin, we studied the effect of catechin, especially epigallocatechin gallate (EGCG), on the apoptosis of monocytes. Methods: Isolated peripheral blood monocytes were incubated without or with catechin, and apoptosis was evaluated by annexin V and propidium iodide double-staining or terminal deoxynucleotidyl assay. The activation of caspases 3, 8, and 9 was also evaluated by flow cytometry. The influence of GMCSF or LPS, the known monocyte survival factors, on the EGCG-induced apoptosis of monocytes was investigated. Results: Among the 4 catechin derivatives tested, EGCG and epicatechin gallate induced apoptosis of monocytes. Caspases 3, 8, and 9, which play a central role in the apoptotic cascade, were dose-dependently activated by EGCG treatment. The EGCG-induced apoptosis of monocytes was not affected by GM-CSF or LPS. Conclusion: Catechin, especially EGCG, by promoting monocytic apoptosis, may be a new promising antiinflammatory agent, and should be tested in clinical trials.

Background. Recently, increased body weight has been associated with an increased risk of cancers at multiple specific sites, including gastric cancer. Adiponectin is a peptide hormone secreted by adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Moreover, the circulating level of adiponectin has been reported to be inversely related to body mass index. Methods: Fasting plasma levels of adiponectin were determined in 75 patients with gastric cancer and 52 healthy controls using an ELISA. In these patients, we analyzed the association between plasma adiponectin level and gastric cancer risk as well as various clinicopathologic characteristics. Results: Plasma adiponectin level was significantly lower in patients with gastric cancer than in healthy controls (9.1 +/- 6.2 versus 13.3 +/- 9.4 ng/mL, P < 0.01) and showed a significant modest inverse relation with the gastric cancer (odds ratio, 0.92; 95% confidence interval, 0.85-0.97; adjusted odds ratio, 0.89; 95% confidence interval, 0.84-0.95], although body mass index was not different. In addition, adiponectin level was extremely low in patients with upper gastric cancers (upper, 5.5 +/- 4.1 ng/mL; middle, 9.7 +/- 6.4 ng/mL; lower, 10.7 +/- 4.1 ng/mL; P = 0.012). Furthermore, adiponectin level tended to decrease as the tumor stage increased (stage I, 9.9 +/- 6.9 ng/mL; stage II, 8.7 +/- 5.5 ng/mL; stage III, 8.6 +/- 4.1 ng/mL; stage IV, 5.2 +/- 6.2 ng/mL; P = 0.34). Interestingly, in 32 patients with undifferentiated cancer, serum adiponectin showed a negative correlation with pathologic findings such as tumor size, depth of invasion, as well as tumor stage (P < 0.05), but no correlation in the remaining 43 patients with differentiated cancer. Conclusions: Our results suggest that a low plasma adiponectin level is associated with an increased risk for gastric cancer and raise the possibility that adiponectin has a potential role in the progression of gastric cancer, especially in undifferentiated type cancers in the upper stomach.

Objective: UDP-N-acetyl-alpha-D- galactosamine-polypeptide N-acetylgalactosaminyl transferase-3 (GalNAc-T3) regulates the initial glycosylation of mucin-type O-linked proteins. Although a different expression of GalNAc-T3 has been reported in various cancers, the expression has not been characterized in squamous cell carcinoma (SCC) of the esophagus. Methods: We have also evaluated the expression of this enzyme in surgically resected esophageal mucosa. By immunohistochemical staining using a specific antibody, we evaluated the expression of GalNAc-T3 in 66 esophageal SCC and 28 dysplasia samples, and analyzed the relationship between the expression of GalNAc-T3 and clinicopathological features. Results: GalNAc-T3 was positively detected in the majority of the cases of SCC, but not in dysplasia as well as the normal counterparts in resected esophagus. GalNAc-T3 was determined to be positive in 37 cases (68.5%) of differentiated carcinomas, but only in 4 cases (33.3%) of undifferentiated carcinomas ( p < 0.05). Hematogeneous metastasis was observed in 13 of 41 (31.7%) GalNAc-T3-positive tumors, which was significantly more frequent than in negative tumors (2/25, 8%; p < 0.05). The number of metastatic nodes was significantly higher in tumors with GalNAc-T3-positive than GalNAc-negative expression (4.2 +/- 3.2 vs. 2.8 +/- 1.3, p < 0.05). The survival rate tended to be lower for patients with GalNAc-T3-positive tumors, although the difference was not statistically significant ( p = 0.18). Conclusion: GalNAc-T3 may play a positive role in the process of carcinogenesis and progression in esophageal SCC. Functional inhibition of GalNAc- T3 may be effective for the prevention and treatment of esophageal SCC. Copyright (C) 2005 S. Karger AG, Basel.

Lysophosphatidic acid (LPA), which interacts with at least three G protein-coupled receptors (GPCRs), LPA I /Edg-2, LPA2/Edg-4, and LPA3/Edg-7, is a lipid mediator with diverse effects on various cells. Here, we investigated the expression profiles of LPA receptors and patterns of LPA-induced migration in gastric cancer cells. Northern blot analysis revealed that various gastric cancer cells expressed variable levels of LPA1, LPA2, and LPA3 without a consistent pattern. Using a Boyden chamber assay, LPA markedly increased cell migration of LPA1-expressing cells, the effects of which were almost totally abrogated by Kil6425, anLPA antagonist against LPA1 and LPA3. In contrast, LPA by itself did not significantly induce migration in MKN28 and MKN74 cells, which exclusively expressed LPA2. However, when hepatocyte growth factor (HGF) was placed with LPA in the lower chamber, LPA induced migration of these cells in a dose-dependent manner. Inummoprecipitation analysis revealed that LPA induced transient tyrosine phosphorylation of c-Met in LPA2-expressing cells, which suggests that the transactivation of c-Met by LPA causes a cooperative migratory response with HGF to these cells. Our results indicate that LPA regulates the migration of gastric cancer cells in a receptor-specific manner and suggest that the expression pattern of LPA receptors may affect the metastatic behavior of gastric cancer. (C) 2004 Elsevier Inc. All rights reserved.

Analysis of specific properties of tumor endothelium should be useful for development of novel antiangiogenic strategies. However, the isolation of pure endothelial cells from tumor tissues is still a fundamental problem. In this study, we have attempted to develop a reliable method for the isolation of endothelial cells from murine tumors. We found that the labeling with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-acetylated-low density lipoprotein (Dil-Ac-LDL), commonly used for this purpose, can result in the contamination of isolated endothelium by macrophages due to the overlapping staining patterns of these two distinct cell types. Therefore, we chose the CD16, which is expressed on macrophages but not endothelial cells, to better distinguish them when labeled with Dil-Ac-LDL. By using this method, we obtained pure populations of endothelial cells and macrophages from murine colorectal cancer tissues, showing characteristic morphological and functional properties of the either cell type. The endothelial cells were long spindle-shaped, spread on gelatin, formed tube-like structures on Matrigel and expressed MECA-32 but not CD68. In contrast, the macrophages were round-shaped, partially spread on gelatin, formed unorganized aggregates on Matrigel and expressed CD68 but not MECA-32. The additional analysis of normal and tumor tissues revealed a positive correlation between the relative numbers of tumor endothelial cells and macrophages, calculated as % total cells, as well as the respective relative number and tumor weight. The present method is hoped to be useful for the evaluation of tumor angiogenesis and antitumor immunity. (C) 2004 Elsevier B.V. All rights reserved.

Receptor tyrosine kinases (RTKs) are transactivated by the stimulation of G protein-coupled receptors (GPCRs). Sphingosine I-phosphate (SIP), a ligand of GPCR, is known as a tumor-promoting lipid, but its signaling pathways are not fully understood. We here demonstrated that SIP induces rapid and transient tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and c-Met in gastric cancer cells, both of which have been proposed as prognostic markers of gastric cancers. The pathway of SIP-induced c-Met transactivation is Gi-independent and matrix metalloproteinase-independent, which differs from that of EGFR transactivation. Our results indicate that SIP acts upstream of various RTKs and thus may act as a potent stimulator of gastric cancer. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Lysophosphatidic acid (LPA) is a simple bioactive phospholipid with diverse effects on various cells, that interacts with three G protein-coupled transmembrane receptors, LPA1, LPA2, and LPA3. The expression pattern and functions of these LPA receptors in various tumors have not been fully examined, except in ovarian cancer. To evaluate the LPA receptor expression profile in human colorectal cancer and in normal mucosa, we used real-time reverse transcription-polymerase chain reaction (RT-PCR) and measured the expression levels of LPA1, LPA2, and LPA3 messenger RNA (mRNA) in 26 colorectal cancers and 16 corresponding normal tissue samples. Normal epithelium expressed both LPA1 and LPA2 mRNA at similar levels. In comparison, colorectal cancers expressed LPA1 mRNA at a significantly lower level (0.3-fold; P<0.05), and LPA2 mRNA at a significantly higher level (three-fold; P<0.05), as compared with normal tissues. Thus, the ratio of LPA2/LPA1 increased markedly during malignant transformation (18-fold increase). LPA3 mRNA was expressed at only a low level in both normal and cancer tissues. We also assessed LPA2 expression immunohistochemically using a rat anti-LPA2 monoclonal antibody, and confirmed high expression of LPA2 in colorectal cancer at the protein level. As for LPA1, we examined Western blot analysis for 16 matched normal and cancer tissues. It revealed a significant decrease in the expression of LPA1 protein in cancer tissues compared to normal mucosa in nine of 16 cases, and in the remaining seven cases the expression levels was much the same. These results suggested that alteration of LPA receptor expression might be an important event in the development of colorectal cancer, and therefore, LPA and its receptors could be a chemopreventive target against colorectal cancer.

Background: hRFI, which has a relatively high homology to XIAP, is preferentially expressed in esophageal and colorectal carcinomas, and is involved in the initial tumor formation in the colorectal adenoma-carcinoma sequence. Furthermore, its diffuse expression is associated with colorectal carcinogenesis. However, hRFI expression in gastric carcinomas has not been evaluated so far. Methods: We performed immunohistochemical staining on 76 gastric carcinoma samples using the antibody to hRFI and also analyzed the correlation between the staining pattern of hRFI and the clinico-pathological characteristics. Results: All of the samples were stained focally (31 cases, 40.8%) or diffusely (45 cases, 59.2%) in the cancerous region. On the contrary, most of the normal gastric region showed no staining, except for a few cases that showed slight immunoreactivity in speckles. Furthermore, the proportion of blood vessel involvement was significantly higher in carcinomas with diffuse hRFI expression (28/45, 62.2%) than in carcinomas with focal expression (7/31, 22.6%) (P < 0.001). Liver metastasis was consistently observed in five cases (11.1%) in diffuse, but only one (3.3%) in focal type during the average follow up period of 5 years. However, the 3-year survival rate did not show significant difference between these different staining patterns of hRFI. Conclusions: These results suggest that the detection of the expression pattern of hRFI in gastric carcinomas can be another useful predictor of liver recurrence, especially when combined with other factors.

For colorectal carcinomas as well as colonic polyps we investigated the expression of a newly discovered gene, hRFI, which is isolated by the yeast two-hybrid screening using hTid as a bait and expressed highly in esophageal carcinomas. Immunohistochemical staining was performed on 48 colorectal carcinomas and 77 colorectal polyps consisting of 70 adenomas and 7 hyperplastic polyps using the antibody of hRFI. We analyzed the expression of hRFI and the correlation between the percentage of staining of each and their clinico-pathological characteristics. Protein coding by hRFI was specifically and diffusely expressed in most of the cancerous regions of the colorectum. Also, in the early stage of colorectal adenomas, staining of hRFI was focal, and the percentage area of diffuse staining increased as the degree of dysplasia progressed. Although all normal colorectal glands and most hyperplastic polyps (71.4%) showed no staining of hRFI, most colorectal adenomas and carcinomas (93.2%) showed a focal or diffuse staining (P<0.001). Furthermore, the percentage of diffuse staining in carcinomas (81.3%) was significantly higher than in adenomas (5.7%) (P<0.001). hRFI is highly expressed in colorectal carcinomas. In the adenoma-carcinoma sequence, hRFI is involved at the initial tumor formation and its diffuse expression is associated with colorectal carcinogenesis. This evidence suggests that hRFI may act as an oncogenic molecule affecting the apoptotic pathway.

Background/Aims: Vascular endothelial. growth factor C (VEGF-C) and D (VEGF-D) are considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we examined the expression of VEGFC and -D in esophageal carcinoma. Methodology: With immunohistochemical staining using specific antibodies, we classified 26 esophageal carcinoma cases and 11 dysplasia cases. Results: All esophageal carcinomas clearly expressed VEGF-C. In esophageal dysplasia, 9 (82%) cases were positive for VEGF-C, and 2 (18%) were negative. In contrast, none of the normal esophageal mucosa expressed VEGF-C. Seventeen (65%) of 26 cases of esophageal carcinoma were positively stained for VEGF-D and 7 (35%) were negative. VEGF-D was also positive in 2 (18%) cases of esophageal dysplasia, but in no cases of normal tissue. VEGF-C was detected in all carcinomas and dysplastic lesions that expressed VEGF-D. Conclusions: Active production of VEGF-C and -D was observed not only in esophageal carcinomas but also in some dysplastic lesions. This finding raises the possibility that VEGF-C and -D might play positive roles in the early stage of esophageal carcinogenesis.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been developed as lipid-lowering drugs, and are well recognized to reduce morbidity and mortality from coronary artery disease. Several recent experimental studies have focused on the inhibitory effects of HMG-CoA reductase inhibitor on tumor cell growth in vitro and in vivo, dependent on a direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of pravastatin and its mechanism of action. Using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of pravastatin on the various steps of angiogenesis, including endothelial cell proliferation and adhesion to extracellular matrix proteins. Pravastatin induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on the cell cycle arrest to the G(1) phase and not on cell apoptosis. G(1) arrest was due to the decrease of cyclin D, cyclin E and cyclin-dependent kinase 2 levels. In addition, pravastatin inhibited tube formation on Matrigel and adhesion to extracellular matrix, but did not affect matrix metalloproteinase production. The present results demonstrate the anti-angiogenic activity of pravastatin and its potential use as an anticancer drug is suggested. (C) 2004 Lippincott Williams Wilkins.

Purpose: To evaluate leptin and leptin receptor (OB-R) expression in human breast cancer and determine whether it could be effective for the prevention and treatment of breast cancer. Experimental Design: Immunohistochemical staining using specific antibodies was used to evaluate the protein expression of leptin and OB-R in 76 invasive ductal carcinomas and 32 samples of corresponding normal mammary gland, and the relationship between the expression of OB-R and leptin and clinicopathological features was analyzed. Results: Normal mammary epithelial cells did not express a significant level of Ob-R, whereas carcinoma cells showed positive staining for OB-R. in 63 (83%) cases. Both normal epithelial cells and carcinoma cells expressed a significant level of leptin. However, overexpression of leptin, as determined by staining intensity, was observed in 70 cancers (92%) but in no normal epithelium. The expression of OB-R showed a significant correlation with the level of leptin expression. Interestingly, distant metastasis was detected in 21 (34%) of 61 OB-R-positive tumors with leptin overexpression, but in none of the 15 tumors that lacked OB-R expression or leptin overexpression (P < 0.05). Consequently, patients with the former tumors showed significantly lower survival than those with the latter. Conclusions: Leptin may have a promoting effect on the carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Functional inhibition of leptin may be effective for the prevention and treatment of breast cancer.

Background: Although green tea polyphenol catechin has been reported to have antiallergic and anti-inflammatory activities, the precise mechanisms of its effect on the immune system have been poorly investigated. Objective: In this study, we aimed to elucidate the mechanisms of the anti-inflammatory effect of catechin. For this purpose, we studied the effect of 2 kinds of catechin, epigallocatechin gallate (EGCG) and epicatechin gallate, on peripheral blood CD8(+) T cells, which play the key role in immune responses. Methods: Isolated peripheral blood mononuclear cells or CD8(+) T cells were incubated without or with catechin, and the changes in the surface expression of integrin molecules were investigated by flow cytometry and the direct binding of catechin to CD11b molecule by competitive ELISA. Also, the effect of catechin on the ability of CD8(+) T cells to bind intracellular adhesion molecule 1 and to migrate in response to chemokines was evaluated by using the adhesion and migration assays. Results: The 2 catechins directly bound to CD11b expressed on CD8(+) T cells, which caused a consequent decrease of flow-cytometric CD11b expression. The effect was more prominent with EGCG than epicatechin gallate, and the impaired expression of CD11b induced by EGCG resulted in decreased ability of CD8(+) T cells to adhere intercellular adhesion molecule 1, and consequently decreased migration in response to chemokines. Conclusion: We concluded that catechin, especially EGCG, by downregulating CD11b expression on CD8(+) T cells and, in consequence, inhibiting infiltration of these cells into the sites of inflammation, is a promising new potent anti-inflammatory agent.

Although increased dietary fat or cholesterol has been reported to be a risk factor for the development of certain cancers, the effect of the serum lipid level on tumor metastasis has not been well documented. Fasting serum levels of total cholesterol (TC) and triglycerides (TG) were examined in 54 patients with superficial esophageal cancer (SEC) invading lamia musucularis or submucosal layer who underwent esophagectomy with classical lymphadenectomy. The association between lymph node metastasis and the preoperative serum lipid levels as well as the pathological findings was retrospectively analyzed. The levels of TC and TG were significantly higher in 18 node-positive than in 36 node-negative patients (TC: 205.4 +/- 38.9 vs. 174.5 +/- 26.8 mg/dl, P < 0.01; TG: 152.0 +/- 68.5 vs. 88.7 +/- 28.6 mg/dl, P < 0.001). Patients with hypercholesterolemia (TC greater than or equal to 220 mg/dl) and hypertriglyceridemia (TG greater than or equal to 150 mg/dl) showed extremely high rates of nodal metastasis (80 and 91 %, respectively), that were significantly higher than those of patients with normal lipid levels (P < 0.01 and P < 0.001). When hyperlipidemia was defined as the presence of either hypertriglyceridemia or hypercholesterolemia, hyperlipidemia was an independent risk factor for nodal metastasis in SEC. Elevated serum lipid levels might bring favorable circumstances for the development of lymph node metastasis in the early stage of EC. Hyperlipidemia might prompt us to perform more studies to investigate possible metastasis. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

The prognosis of gastric cancer with peritoneal metastasis has not improved. Despite many promising studies, gene therapy has limited clinical application because of the lack of suitable vector systems to enable selective gene transduction to tumor cells. The aim of this study was to clarify whether gene therapy targeted to peritoneal mesothelial cells (PMCs) can inhibit peritoneal dissemination of gastric cancer. In vitro experiments showed that adenovirus expressing LacZ infected human omental tissue-derived PMCs more efficiently than human gastric cancer cell lines MKN1 and MKN45. When adenovirus expressing LacZ was injected into the peritoneal cavity of nude mice, the expression was detected in the peritoneum for at least 4 weeks. Furthermore, when adenovirus expressing soluble Flt-1 (Ad-sFLT-1) was i.p. administered in vivo, a high level of sFlt-1 protein could be detected in peritoneal lavage for 8 weeks. When MKN45 cells were i.p. inoculated 3 days after adeno-viral vector injection, Ad-sFLT-1 markedly reduced the number of metastatic nodules larger than I mm in diameter on the peritoneal surface, and significantly prolonged the survival of nude mice without any significant side effects. Thus, peritoneal dissemination was significantly suppressed by a single i.p. injection of Ad-sFlt-1. Anti-angiogenic gene therapy targeted to PMCs could be a novel and practical strategy against peritoneal dissemination of gastric cancer, because it does not require tumor-specific gene transfer.

Colon perforation (CP) is still a critical complication after renal transplantation (RT), and idiopathic perforation is extremely rare. Here we describe a successfully treated case of idiopathic rectosigmoid perforation that occurred 7 years after RT. In our research this is the tenth reported case of idiopathic CP after RT and the second case that has occurred in the rectosigmoid. The patient was a 51-year-old Japanese male RT recipient still receiving immunosuppressive medication. He was admitted to the hospital for sudden onset of abdominal pain during defecation. Emergency laparotomy was performed 5 h after the onset, and a longitudinal 1.5 cm perforation with a clear margin was observed in the rectosigmoid, 8 cm above the peritoneal reflection. Hartmann's operation was performed. Macroscopic and histological examination did not reveal any specific findings that may have caused perforation, so the case was diagnosed as idiopathic rectosigmoid perforation.

Background and Objectives: Tumor development usually is accompanied by alterations of O-glycosylation. Initial glycosylation of mucin-type O-linked proteins is regulated by UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 (GalNAc-T3). Although the expression of GalNAc-T3 has been examined in various cancers, the expression has not been characterized in early stages of cancer. Methods: Using the specific antibody, we evaluated the expression of GaINAc-T3 in 125 early gastric cancers that were treated as classical gastrectomy with lymphadenectomy, and analyzed the relationship between the expression of GaINAc-T3 and clinicopathological features. Results: GalNac-T3 was positively expressed in 40 cases (76%) in differentiated carcinomas, whereas in only six cases (8%) in undifferentiated carcinomas (P < 0.001). Positive staining was observed in 17 (26%) intramucosal and in 29 (48%) submucosal carcinomas, indicating that GalNac-T3 tended to be highly expressed as the depth of invasion increased (P < 0.05). Lymph node metastasis tended to be observed more frequently in GalNac-T3 positive than negative cases, and the difference was significant in undifferentiated type cancer (P < 0.05). Conclusions: GaINAc-T3 expression was a useful indicator of tumor differentiation in early gastric cancer, and the expression had positive correlation with depth of tumor invasion and lymph node metastasis. This suggests that the overexpression of GalNAc-T3 may have a role in invasion and metastasis in early stages of gastric cancer. (C) 2004 Wiley-Liss, Inc.

Background/Aims: Vascular endothelial growth factor-C (VEGF-C) is a potent growth factor stimulating lymphangiogenesis. Methodology: We examined the expression of VEGF-C immunohistochemically in neoplastic as well as normal mucosa of colorectal tissues, and evaluated the significance of VEGF-C in colorectal carcinogenesis and as a marker to predict the outcome of colorectal cancer. Results: VEGF-C was strongly stained in 70/79 adenomas (89%), but the staining was focal in all cases, and the expression pattern in adenomas was not significantly related to either dysplasia or size of the adenoma. In the 8/8 intramucosal carcinomas within adenomas, both the carcinomatous and adenomatous lesions were stained focally, but in 6 cases (75%), the VEGF-C-positive area was larger in the carcinomatous lesion than in the adenomatous lesion. In most invasive adenocarcinomas, VEGF-C was clearly stained (83/85; 98%), with both a focal (40%) and diffuse (60%) staining pattern. In invasive carcinomas, the expression of VEGF-C was significantly correlated with lymphatic involvement, lymph node metastasis and tumor size, but not with venous involvement or liver metastasis. Survival rate tended to be lower in the high VEGF-C group than in the low group, although statistical significance was not observed. Conclusions: These results suggest that VEGF-C plays a positive role in lymphatic spread in colorectal carcinomas.

Background: Although increased dietary fat or cholesterol has been reported to be a risk factor for the development of certain cancers, the effect of serum lipid levels on turnout metastasis is not clearly understood. Methods: The association between lymph node metastasis and preoperative serum levels of total cholesterol (TC) and triglyceride (TG) as well as various pathological findings for tumours was examined in 353 patients with early gastric cancer who underwent gastrectomy with classical lymphadenectomy. Results: The rate of lymph node metastasis was significantly higher in patients with early gastric cancer who had hypercholesterolaemia (TC 220 mg/dl or greater) or hypertriglyceridaemia (TG 150 mg/dl or greater). The tendency was more prominent in men, and multivariate analysis showed that hypertriglyceridaemia was an independent risk factor for nodal metastasis in men, in addition to pathological invasion to the submucosal layer or to lymphatic vessels. In contrast, neither hypercholesterolaemia nor hypertriglyceridaemia showed a significant association with nodal status in women with early gastric cancer. Conclusion: Raised serum lipid levels might favour the development of lymph node metastasis in men with early-stage gastric cancer. In patients with early gastric cancer serum lipid levels should be checked before operation, and the use of minimal local treatments must be considered carefully in male patients with hyperlipidaemia.