Invasion Of Gastric Carcinoma Research Articles

The altered expression of ING5 protein is involved in gastric carcinogenesis and subsequent progression

ING5 can interact with p53, thereby inhibiting cell growth and inducing apoptosis. To clarify the roles of ING5 in gastric tumorigenesis and progression, its expression was examined by immunohistochemistry on a tissue microarray containing gastric nonneoplastic mucosa (n = 119), dysplasia (n = 50), and carcinomas (n = 429), with its comparison with clinicopathologic parameters of the carcinomas. ING5 expression was analyzed in gastric carcinoma tissues and cell lines (MKN28, MKN45, AGS, GT-3 TKB, and KATO-III) by Western blot and reverse transcriptase-polymerase chain reaction. ING5 protein was found to distribute to the nuclei of gastric carcinoma cells with similar messenger RNA levels. An increased expression of ING5 messenger RNA was observed in gastric carcinoma in comparison with paired mucosa (P < .05). Lower expression of nuclear ING5 was detected in gastric dysplasia and carcinoma than that in nonneoplastic mucosa (P < .05). Gastric nonneoplastic mucosa and metastatic carcinoma showed more expression of cytoplasmic ING5 than did gastric carcinoma and dysplasia (P < .05). Nuclear ING5 expression was negatively correlated with tumor size, depth of invasion, lymph node metastasis, and clinicopathologic staging (P < .05), whereas cytoplasmic ING5 was positively associated with depth of invasion, venous invasion, lymph node metastasis, and clinicopathologic staging (P < .05). Nuclear ING5 was more expressed in older than younger carcinoma patients (P < .05). There was a higher expression of nuclear ING5 in intestinal-type than diffuse-type carcinoma (P < .05), whereas it was the converse for cytoplasmic ING5 (P < .05). Survival analysis indicated that nuclear ING5 was closely linked to favorable prognosis of carcinoma patients (P < .05), albeit not independent. It was suggested that aberrant ING5 expression may contribute to pathogenesis, growth, and invasion of gastric carcinomas and could be considered as a promising marker to gauge aggressiveness and prognosis of gastric carcinoma.

Fatal aspiration of barium sulfate

Five weeks after a laparoscopic cholecystectomy an obese 64-year-old woman swallowed 100 ml of barium sulfate as part of a diagnostic radiographic contrast medium examination for a suspected invasive gastric carcinoma. After drinking the medium, she suddenly started vomiting while lying supine with resultant aspiration and minimal coughing. She was transferred to the Intensive Care Unit (5 h later). Chest X-rays showed bilateral alveolar opacities, predominantly on the right (Fig. 1) and bronchoscopy revealed white foamy barium residue in both lungs. Due to increasing dyspnea, she underwent endotracheal intubation with controlled artificial respiration. Subsequent radiographs showed bilateral aspiration pneumonia. Her clinical course was marked by adult respiratory distress syndrome (ARDS) with death 35 h after the event due to respiratory insufficiency from aspiration of barium sulfate complicated by aspiration pneumonia. A medicolegal autopsy confirmed the clinical findings with extensive pneumonia caused by contrast medium aspiration, particularly of the right lung, and a malignant gastric neoplasm with widespread lymphatic node metastases. Histology of the lungs showed polarizing rhomboid crystalline accumulations within the alveolar spaces with granulocytic infiltration, and hyaline membrane formation. Macrophages had also incorporated barium sulfate particles (Fig. 2).

Role of CD97 isoforms in gastric carcinoma

The aim of this study was to elucidate the role of CD97 isoforms in gastric carcinoma. Out of four gastric cancer cell lines investigated, BGC-823 cells demonstrating low CD97 protein expression were stably transfected with pcDNA3.1 vector containing CD97/EGF1,2,5 or CD97/EGF1,2,3,4,5 inserts. Behavior of transfected cells was systematically investigated by employing proliferation, motility and invasive assays. As a result, we found that over-expression of CD97/EGF1,2,5 isoform correlated with increased motile and invasive ability of the clones. Furthermore, CD97/EGF1,2,5 isoform over-expression (3.8 times higher) was followed by significant decrease of CD97/EGF1,2,3,4,5 isoform (10.3 times lower). In contrast, CD97/EGF1,2,3,4,5 clones revealed significantly reduced invasive properties as compared with corresponding controls. The changes in acetylation status were one of the possible mechanisms affecting behavior of transfected cells. We concluded from the study that CD97 is closely related with advanced stages and higher invasiveness of gastric carcinoma. The study further lightened the tumor promoting role of CD97 small isoform in cancer progression and indicated the possible suppressive properties of the full length isoform of CD97.

Human Macrophage Metalloelastase Correlates with Angiogenesis and Prognosis of Gastric Carcinoma

The function of human macrophage metalloelastase (HME) also known as matrix metalloproteinase 12, in tumorigenesis is contradictory. The current study was designed to investigate the association of HME expression with angiogenesis and prognosis of gastric carcinomas. In situ hybridization and immunohistochemistry were used to detect HME in human gastric carcinomas, chronic gastritis with atypical hyperplasia, and normal gastric epithelium mucosa. The results were further confirmed by RT-PCR or semi-quantitative reverse transcription polymerase chain reaction and Western blotting in gastric carcinomas and paired noncancerous tissues. VEGF and microvessel density count were also detected by immunohistochemical staining in all carcinoma tissues. The prognostic significance of HME was assessed with multiple linear regression analysis and Cox proportional hazards model. High expression of HME protein/mRNA was observed in gastric carcinomas and atypical hyperplasia tissues compared with normal gastric epithelium mucosa, or paired noncancerous tissues. HME protein/mRNA were negatively correlated with MVD (p<0.01), VEGF (p<0.01), tumor differentiation grade (p<0.05), vascular invasion (p<0.01), and recurrence (p<0.05-0.01). HME protein was an independent influential factor of MVD (p<0.01). HME protein/mRNA was an independent prognostic factor of gastric carcinoma (p<0.05-0.01). Patients with overexpression of HME protein/mRNA demonstrated a significantly better survival rate compared with those who did not (p<0.05-0.01). Overexpression of HME is strongly correlated with the reduced angiogenesis and vascular invasion of gastric carcinoma, and may serve as a useful predictive indicator in patients with this disease.

Downregulation of ZIP kinase is associated with tumor invasion, metastasis and poor prognosis in gastric cancer

Deletion of 19p13 is one of the most frequent genetic changes in gastric carcinoma (GC), implying the existence of a tumor suppressor gene (TSG) that plays an important role in GC development. To identify the candidate TSG at 19p, array-comparative genomic hybridization (CGH) was applied to study DNA copy-number changes on chromosomes 3, 5p, 13, 16q and 19. The result showed that gains of 16q21, 19q13.1, 5p15.1 and 3q26.31, and losses of 3p21.32, 3p22.2, 19q13.33 and 19p13.3, were frequently detected by array-CGH. One candidate TSG, ZIP kinase (ZIPK), at 19p13.3 was further characterized by immunohistochemistry using a tissue microarray containing 172 primary GCs. Downregulation of ZIPK was detected in 111/162 informative GCs, which was significantly associated with invasion, metastasis and poorer prognosis of GC. To investigate the association of the downregulation of ZIPK with apoptosis, apoptosis assay (TUNEL) was used to compare the apoptotic index between GCs with normal expression and downregulation of ZIPK. TUNEL assay showed that the apoptotic index in GCs with normal ZIPK expression was significantly higher than that in GCs with downregulation of ZIPK (p < 0.001), indicating that ZIPK plays an important pro-apoptotic role in GC. Taken together, we demonstrated here that ZIPK is a tumor suppresser gene and plays an important role in GC development through its pro-apoptotic function. Downregulation of ZIPK can be used to evaluate tumor invasiveness, metastasis and to predict survival of GC.

Intratumoural heterogeneity of intestinal expression reflects environmental induction and progression‐related loss of induction in undifferentiated‐type gastric carcinomas

Gene expression in tumours is regulated by environmental as well as genetic/epigenetic factors. This study assessed the environmental factors in intestinal expression of gastric cancers. We immunohistochemically examined intratumoural heterogeneity in the expression of Cdx2, MUC2, MUC5AC and MUC6 in 39 intramucosal and 49 extramucosally invasive undifferentiated-type gastric carcinomas (UGCs), consisting of signet ring cell carcinomas showing a layered structure (LS) in the mucosa and dedifferentiated tubular adenocarcinomas without LS and with minor tubular components (TC). The LS retains mucosal vertical polarity with superficial MUC5AC expression. Loss of this polarity was independent of intestinal expression and associated with extramucosal invasion. In LS(+) UGCs, intestinal expression was enhanced as the size of mucosal spread increased and was significantly reduced with deeper extramucosal invasion, whereas, in LS(-)/TC(+) UGCs, intestinal expression was frequent and predominant in the mucosa and was insignificantly reduced with deeper extramucosal invasion. In LS(+) UGCs, intestinal expression showed dynamic alteration probably by environmental induction and progression-related loss of induction, whereas it was relatively stable in LS(-)/TC(+) UGCs. Thus, intestinal expression in UGCs is not useful as a marker of tumour progression because it is also affected by environmental factors and genetic lineage.

Expression of UDP-N-acetyl-D-galactosamine: Polypeptide N-acetylgalactosaminyltransferase-6 in Gastric Mucosa, Intestinal Metaplasia, and Gastric Carcinoma

Aberrant mucin O-glycosylation is often observed in cancer and is characterized by the expression of immature simple mucin-type carbohydrate antigens. UDP-N-acetyl-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase-6 (ppGalNAc-T6) is one of the enzymes responsible for the initial step in O-glycosylation. This study evaluated the expression of ppGalNAc-T6 in human gastric mucosa, intestinal metaplasia, and gastric carcinomas. Our results showed that ppGalNAc-T6 is expressed in normal gastric mucosa and in intestinal metaplasia. A heterogeneous expression and staining pattern for this enzyme was observed in gastric carcinomas. ppGalNAc-T6 was expressed in 79% of the cases, and its expression level was associated with the presence of venous invasion. Our results provide evidence that ppGalNAc-T6 is an IHC marker associated with venous invasion in gastric carcinoma and may contribute to the understanding of the molecular mechanisms that underlie aberrant glycosylation in gastric carcinogenesis and in gastric carcinoma.

Expression transformation of claudin-1 in the process of gastric adenocarcinoma invasion

To investigate the relation of expression transformation of claudin-1 with invasiveness and metastasis of gastric carcinoma. By using immunohistochemistry, expression of claudin-1 in mucosa and invasive front of 136 gastric adenocarcinoma cases and proliferative index (Ki-67) were detected and analyzed. In mucosa, the claudin-1 over-expression rate of mucinous adenocarcinomas (including signet-ring cell carcinomas) was the highest. It was negatively related with the differentiation but positively related with the invasiveness and metastasis of gastric cancer. In invasive front, the claudin-1 over-expression rate was positively related with the differentiation, invasiveness and metastasis of gastric carcinoma. The expression transformation of claudin-1 was found in gastric carcinoma. The expression of claudin-1 in invasive front was transformed in 28/136 gastric carcinoma cases. The transformation rate in highly differentiated tubular adenocarcinomas was the highest (51.5%, 17/33). The deeper was the invasiveness, the higher was the transformation rate. The claudin-1 expression transformation rate in serosa and omenta was significantly higher (92.9%) than in tunica muscularis of invasive gastric cancer cases, as well as in patients with lymph node metastasis than in those without lymph node metastasis. Up-regulation of claudin-1 expression and its transformation in invasive and metastatic gastric carcinoma suggest that claudin-1 participates in the transformation of biological behaviors in neoplasms. Further study is needed to elucidate the precise mechanism and the relation of claudin-1 expression with the neoplasm progress.

Twist Is Required for Thrombin-Induced Tumor Angiogenesis as Well as Migration.

Twist, a master regulator of embryonic morphogenesis, induces functions that are also required for tumor invasion and metastasis. A recent study (Cell 117: 927, 2004) defined a requirement of Twist for tumor metastasis unrelated to tumor growth and invasion. We now report a requirement of Twist for angiogenesis. It has been speculated that Twist expression might be derepressed during tumor progression. Indeed, high levels of Twist correlate with invasive lobular breast carcinoma, gastric carcinoma, prostate cancer and metastatic nasopharyngeal carcinoma. Since thrombin contributes to the malignant phenotype by upregulating tumor metastasis (as well as growth, invasion and angiogenesis) we proposed that it might be operating through the upregulation of Twist. Five different tumor cell lines [(Human MCF7 Breast, DU145 Prostate and murine 4T1 breast, B16F10 melanoma, undifferentiated cell line (UMCL)] and 2 different endothelial cell lines [HUVEC and Brain microvascular endothelial cell (BMEC)] were examined. Thrombin upregulated Twist mRNA and protein (>2 fold) in all 7 cell lines, indicating a general biologic effect. In Twist knock down (KD) studies of B16F10 tumor growth on a chick choriallantoic membrane we noted an ∼45% decrease in angiogenesis (neoangiogenesis branching), n=8. This suggested that B16F10 cells might contain inducible vascular growth factors and receptors that are present in endothelial cells. Twist was therefore further examined in both HUVEC and tumor cells and compared with known effects of thrombin on angiogenesis. Twist KD in HUVEC led to a 2.8 fold impaired thrombin-induced chemotaxis and 5.6 fold impaired vascular tubule formation in matrigel compared to wild type, empty vector and scrambled vector, n=3. Similar Twist KD results were noted in BMEC. We next introduced a tetracycline-dependent Twist-inducible plasmid into B16F10 cells and vascular factors analyzed by immunoblot. A 3-8 fold upregulation was noted for VEGF and its KDR receptor, Ang-2 and its Tie 2 receptor and the growth-regulated oncogene (GRO-α) chemokine, n=2–3. GRO-α has recently been shown to be responsible for thrombin-induced upregulation of angiogenesis and tumor growth (Cancer Res 66:4125, 2006). In studies on the effect of thrombin on a tetracycline-dependent Twist-inducible plasmid, the mRNA and protein of several vascular growth factors and receptors were shown to be identically upregulated (by Twist or thrombin) 2–3 fold in tumor cells as well as HUVEC (GRO-α, VEGF, KDR, Ang-2, MMP-1 and CD31), n=3–5. These data suggest that the positive effect of thrombin on angiogenesis requires the upregulation of Twist. Since the chemokine GRO-α upregulates the identical vascular growth factors and receptors as Twist, this prompted an examination of the relationship of Twist and GRO-α with thrombin. Utilizing a GRO-α inducible plasmid system in B16F10 cells, Twist mRNA and protein were both shown to be upregulated ∼2 fold. Other vascular growth factor proteins were also upregulated 2–5 fold (Ang-2, KDR, VEGF and CD31), n=2–3. Thus Twist regulates angiogenesis as well as metastasis. Thrombin upregulates Twist which is required for thrombin-induced angiogenesis as measured by tumor angiogenesis index, endothelial cell migration and matrigel tubule formation. Twist upregulates GRO-α which can upregulate Twist resulting in positive feedback. It is suggested that the positive effect of thrombin on angiogenesis is via its upregulation of both Twist and GRO-α.

Predictive Role of Nuclear Factor-κB Activity in Gastric Cancer

The biologic significance of nuclear factor-kappaB (NF-kappaB) activation in human gastric cancer is unclear. We clarify the clinical significance of NF-kappaB activation and its relationship to Helicobacter pylori infection, a well-known pathogenesis of gastric cancer. Moreover, we examine the effects and underlying mechanisms induced by caffeic acid phenethyl ester (CAPE), an inhibitor of NF-kappaB, for gastric carcinoma. NF-kappaB was located immunohistochemically in 90 human gastric cancer specimens and 50 nonmalignant gastric specimens. The correlations between NF-kappaB activation, pathologic staging, and H. pylori infection were analyzed. We also performed electrophoretic mobility gel shift assay, real-time reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay to evaluate the responses of AGS (a gastric adenocarcinoma epithelial cell line) human gastric cancer cells subsequent to H. pylori infection or CAPE treatment. Nuclear expression of NF-kappaB was significantly more frequently observed in gastric cancer tissues than in nonmalignant gastric tissues (31% vs. 4%, P=0.0001). The activity of NF-kappaB and the expressions of MMP-9, IL-1beta, and IL-8 in AGS cells were activated by H. pylori infection. However, the augmented responses could be significantly reversed by CAPE treatment. Moreover, in vitro studies showed that CAPE inhibits tumor growth and capacity for invasion. NF-kappaB activation is related to carcinogenesis, tumor aggression, and H. pylori infection with the increased expression of MMP-9, IL-1beta, and IL-8. Moreover, NF-kappaB inhibitors or anti-inflammatory agents such as CAPE might be new adjuvant agent against invasive gastric carcinoma.

Expression of CD44s mRNA in gastric carcinoma

To study the expression of CD44s mRNA in the occurrence, development and invasion of gastric carcinoma (GC). The expressions of CD44s mRNA in 66 cases of GC, 25 cases of superficial gastritis and 25 cases of atypical hyperplasia were examined by in situ hybridization (ISH). There was no expression of CD44s mRNA in the group of superficial gastritis; the positive rate was 20%(5/25) in the group of atypical hyperplasia and 62.12%(41/66) in the group of gastric carcinoma. The positive rate in poor differentiation group was significantly higher than that in well differentiation group (P<0.05), and the positive rate of lymph node metastasis group was significantly higher than that in negative lymph node metastasis group(P<0.05). The expression of CD44s mRNA was related to cell differentiation degree and lymph node metastasis, the activation of CD44s gene was related to strong invasion of cancer cells and poor prognosis.

Phosphorylation of p68 RNA Helicase Plays a Role in Platelet-derived Growth Factor-induced Cell Proliferation by Up-regulating Cyclin D1 and c-Myc Expression

p68 RNA helicase is a protypical member of DEAD box family RNA helicase. The protein plays an important role in the cell developmental program and organ maturation. We demonstrated previously that, in response to growth factor platelet-derived growth factor (PDGF)-BB stimulation, p68 is phosphorylated at Tyr(593), and the phosphorylation of p68 promotes epithelial-mesenchymal transition via promoting beta-catenin nuclear translocation (Yang, L., Lin, C., and Liu, Z. R. (2006) Cell 127, 139-155). We show here that the tyrosine phosphorylation of p68 also mediates the effects of PDGF in stimulating cell proliferation. The phosphorylated p68 (referred to as phospho-p68) promotes cell proliferation by activating the transcription of cyclin D1 and c-Myc genes. We show that the ATPase/helicase activities of p68 are required for the activation of cyclin D1 transcription. The phospho-p68 participates in the complex assembled at the cyclin D1 and c-Myc promoters, which strongly suggests a direct role in transcriptional regulation. Furthermore, our data demonstrated that the phosphorylation of p68 at Tyr(593) plays a role in mediating the autocrine loop effects of PDGF, suggesting an important role for p68 phosphorylation in cell proliferation.

Clinicopathological evaluation of biological behavior of submucosal invasive gastric carcinomas: relationship among lymph node metastasis, mucin phenotype and proliferative activity

Gastric carcinomas have been classified into the differentiated and undifferentiated type, on the basis of its tendency to gland formation. As a result of recent advances in mucin histochemistry, mucin phenotypes of gastric carcinomas have been investigated. However, no consensus on the evaluation of the grade of malignancy of early gastric carcinomas regarding mucin phenotype expression has developed. To address this issue, we evaluated the lymph node metastasis rate and proliferative activity of a submucosal invasive (sm) gastric carcinoma according to mucin phenotype expression. In resected surgical specimens from 108 patients with a single sm gastric carcinoma, the association between clinicopathological factors and lymph node metastasis was evaluated. In all cases, immunohistochemical staining with human gastric mucin, Muc-2, and CD10 and mucin histochemical staining by paradoxical concanavalin A staining were performed. The mucin phenotypes were classified into gastric-type (G-type), intestinal-type (I-type), mixed gastric and intestinal type (M-type), or a lack of mucin (LOM), using these as markers. To evaluate the cell proliferative activity of the gastric carcinoma, proliferating cell nuclear antigen (PCNA) staining was also performed. The rate of lymph node metastasis was higher for G-type sm carcinomas. A multivariate analysis showed that the G-type and lymphatic invasion were independent factors of lymph node metastasis. However, the PCNA-labeling index (PCNA-LI) was low for G-type carcinomas irrespective of the presence or absence of lymph node metastasis. In I-type carcinomas, PCNA-LI was significantly higher in cases that were positive for lymph node metastasis than in negative cases. G-type and lymphatic invasion are independent risk factors for lymph node metastasis of an sm gastric carcinoma, and proliferative activity may be a significant parameter for lymph node metastasis in cases with I-type carcinomas.

Relationship between lymph node metastasis and E-cadherin expression in submucosal invasive gastric carcinomas with gastric-phenotype

Recent advances in immunohistochemical staining have led to the proposition of a classification of gastric carcinomas based on cellular phenotypes, and the degree of biological malignancy of gastric-phenotype carcinomas has attracted particular attention. One hundred and seven submucosal (SM) invasive carcinomas encountered in our center were examined for their histological type, cellular phenotype, and E-cadherin expression status to clarify their relationships with lymph node metastasis. Eleven (10.3%) of 107 SM gastric carcinomas were lymph node metastasis-positive. Gastric-phenotype carcinomas accounted for 20.6%, with a lymph node metastasis rate of 27.3% (6/22), which was significantly higher (p<0.05) than those of intestinal-phenotype carcinomas (5.9%) and mixed-phenotype carcinomas (2.9%). In terms of E-cadherin expression, only carcinomas with reduced E-cadherin expression showed lymph node metastasis at a rate significantly higher than that of carcinomas with normal E-cadherin expression (p<0.05). The lymph node metastasis rate (46.2%) of gastric-phenotype carcinomas with reduced E-cadherin expression was significantly higher than those of carcinomas of other phenotypes (p<0.05). Since gastric-phenotype differentiated carcinomas with reduced E-cadherin expression have the potential for becoming undifferentiated, the risk of lymph node metastasis should be considered.

Upregulated EMMPRIN/CD147 might contribute to growth and angiogenesis of gastric carcinoma: a good marker for local invasion and prognosis.

Tumour growth depends on angiogenesis, which is closely associated with vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Extracellular MMP inducer (EMMPRIN) was reported to involve in the progression of malignancies by regulating expression of VEGF and MMPs in stromal cells. To clarify the role of EMMPRIN in progression and angiogenesis of gastric carcinoma, expression of EMMPRIN, ki-67, MMP-2, MMP-9 and VEGF was examined on tissue microarray containing gastric carcinomas (n=234) and non-cancerous mucosa adjacent to carcinoma (n=85) by immunohistochemistry. Additionally, microvessel density (MVD) was assessed after labelling with anti-CD34 antibody. Extracellular MMP inducer expression was compared with clinicopathological parameters of tumours, including levels of ki-67, MMP-2, MMP-9 and vascular endothelial growth factor (VEGF), MVD as well as survival time of carcinoma patients. Gastric carcinoma cell lines (HGC-27, MKN28 and MKN45) were studied for EMMPRIN expression by immunohistochemistry and Western blot. Extracellular MMP inducer expression was gradually increased from normal mucosa to carcinomas through hyperplastic or metaplastic mucosa of the stomach (P<0.05). There was strong EMMPRIN expression in all gastric carcinoma cell lines despite different levels of glycosylation. Extracellular MMP inducer expression was positively correlated with tumour size, depth of invasion, lymphatic invasion, expression of ki-67, MMP-2, MMP-9 and VEGF of tumours (P<0.05), but not with lymph node metastasis, UICC staging or differentiation (P>0.05). Interestingly, there was a significantly positive relationship between EMMPRIN expression and MVD in gastric carcinomas (P<0.05). Survival analysis indicated EMMPRIN expression to be negatively linked to favourable prognosis (P<0.05), but not be independent factor for prognosis (P>0.05). Further analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to influence the relationship between EMMPRIN expression and prognosis. Upregulated expression of EMMPRIN possibly contributes to genesis, growth and local invasion of gastric carcinomas. Altered EMMPRIN expression might enhance growth, invasion and angiogenesis of gastric carcinoma via upregulating MMP expression of both stromal fibroblasts and gastric cancer cells and could be considered as an objective and effective marker to predict invasion and prognosis.

Expression of altered retinoblastoma protein inversely correlates with tumor invasion in gastric carcinoma

To investigate the clinical and pathological significance of altered retinoblastoma (Rb) encoding protein (pRb) in gastric carcinoma. Expression of altered pRb was analyzed in 91 patients with gastric adenocarcinoma by immunohistochemistry. Sixty-five percent (59/91) of the tumors were positively stained and the staining in tumor nuclei of gastric carcinoma ranged 0%-90%. Moreover, strong expression of altered pRb was found in 35% (6/17), 24% (5/21), 17% (8/46) and 0% (0/7) of T1, T2, T3 and T4 gastric carcinomas, respectively. Altered pRb expression was inversely correlated with the depth of tumor invasion (P = 0.047). Degree of immunoreactivity had no significant correlation with tumor grade, node metastasis and distant metastasis. In terms of prognostic significance, univariate analysis showed that poor differentiation [41 (66.1%) vs 34 (42.5%) P = 0.051], advanced tumor stage (P < 0.001) and weakly altered pRb expression [17 (80.5%) vs 58 (49.6%) P=0.044] were associated with worse prognosis in these patients. However, multivariate analysis revealed that advanced tumor stage was the only independent poor prognostic factor (P < 0.001). the mutation of Rb gene is frequent in gastric carcinoma. The expression of altered pRb inversely correlates with tumor invasion and is not an independent prognostic marker in gastric adenocarcinoma.

The expression of CD97EGF and its ligand CD55 on marginal epithelium is related to higher stage and depth of tumor invasion of gastric carcinomas

CD97EGF is a member of the EGF-TM7 family of class II seven-transmembrane (7TM), and its cellular ligand CD55 (also known as decay accelerating factor; DAF) protects host cells from complement attack. To determine whether the expression levels of these two molecules are correlated with the clinicopathological features of gastric carcinomas, a total of 35 gastric carcinomas and their corresponding margins and normal specimens were investigated by RT-PCR, Western blot analysis and immunohistochemistry. Transcript levels of CD97EGFand CD55 were higher in tumors than those in the margin and normal epithelial mucous tissues (P<0.05). However, the expression levels of CD97EGF and CD55 mRNA had no correlation with the clinicopathological features of gastric carcinoma patients. All three groups of specimens were immunoreactive for CD97EGF and the CD55 protein. Strong and specific immunoreactivities of CD97EGF were located in the mucosal epithelia of the marginal basal membrane. Expression of CD97(EGF) in the margins showed a marked difference between the depth of tumor invasion T1 and T2, 3 and 4, and stages I and II/III/IV of gastric carcinomas (P<0.05). The expression of CD55 protein was highly correlated with CD97EGF (R=0.6483, P<0.001). Western blot analysis confirmed the expression and distribution patterns of CD97EGF and CD55. Our findings suggest that CD97EGF may play a role in the development and invasion of gastric carcinomas by binding its cellular ligand CD55. Detection of the CD97EGF expression in the tumor margin could be referred to as the molecular edge of gastric carcinomas.

Diagnosis of Gastric Cancer with MDCT Using the Water-Filling Method and Multiplanar Reconstruction: CT–Histologic Correlation

The purpose of this study was to assess the utility of MDCT with a thin-sliced multiplanar reconstruction (MPR) technique and water-filling method for the diagnosis of gastric cancers. Sixty-five patients with gastric cancers were preoperatively examined with MDCT using the water-filling method. The abdomen was dynamically scanned at 30 and 80 sec after the start of contrast medium administration. MPR images were reconstructed with a slice width of 1.25 mm and a slice interval of 1 mm. The detection rate and accuracy of T staging for gastric cancer were evaluated on MPR images and compared with 5-mm-slice axial images. In addition, MDCT images were correlated with pathologic findings. The detection rate of all gastric cancers using the MPR technique was 65%. The detection rate of advanced gastric cancers was 96.2% (25 of 26), whereas that of early gastric cancers was 41.2% (14 of 34). There was a statistically significant difference (p < 0.05) in the detection rate of early gastric cancers between MPR and 5-mm-slice axial images. The MDCT appearances of gastric cancers were well correlated with pathologic findings such as mucinous component or differences in infiltration of cancer cells. The overall accuracy of CT staging was 85%. MPR images were superior to axial images for the evaluation of the z-axis extent of tumor. MDCT with the water-filling method has advantages in acceptable evaluation of depth invasion of gastric carcinomas and in visualization of histologic changes in the tumors. MPR images may be a useful guide for the evaluation of the z-axis extent of tumor.

Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathological parameters

In this study, we investigated whether expression of vascular endothelial growth factor (VEGF)-C and/or VEGF-D correlates with clinicopathological features of human gastric carcinoma. We immunohistochemically examined the expression of VEGF-C and VEGF-D in 140 archival surgical specimens of submucosally invasive gastric carcinoma. Of these specimens, 32 (22.9%) and 12 (8.6%) showed intense VEGF-C and VEGF-D immunoreactivity in cancer cells, respectively. VEGF-C immunoreactivity was associated with histological type, lymphatic invasion, lymph node metastasis, and microvessel density. No association was identified between VEGF-D immunoreactivity and clinicopathological variables. These results suggest that VEGF-C is a dominant regulator of lymphangiogenesis in early-stage human gastric carcinoma.

The Expression of a Type II Transmembrane Serine Protease (Seprase) in Human Gastric Carcinoma

Objective: The invasion and metastasis of carcinoma cells require the proteolytic degradation of the extracellular matrix by various cell surface proteases. Among these, seprase is a type II transmembrane serine protease absent in normal tissues and it has been implicated in the invasion of the extracellular matrix by both tumor and stromal cells in human breast carcinoma and melanoma. In the present study, the expression of seprase mRNA, protein and its gelatin-degrading activity in human gastric carcinoma were examined to substantiate the potential role of seprase in gastric carcinoma invasion. Methods: We have examined the seprase expression in human gastric carcinoma (n = 34) by RT-PCR, Western immunoblotting analysis, immunohistochemistry, and gelatin zymography. Results: Immunoblotting analysis using mAb D8 directed against seprase showed that the carcinoma tissues in 26 out of 34 cases of gastric cancer expressed a dimeric form of seprase but their normal counterparts did not. Gelatin zymography confirmed that the isolated seprase exhibited the gelatin-degrading activity and was active. Seprase-expressing carcinoma tissues were more often found in the scirrhous type than in other types of gastric carcinoma. RT-PCR analysis showed that seprase mRNA was present in carcinoma tissues but not in normal tissues. Immunohistochemically, seprase was mainly located in gastric carcinoma cells, weakly in stromal cells and microvessel endothelial cells in the tumor nest, and none in normal cells. Conclusions: Our studies showed the unique expression and localization of seprase in the tumor and stromal cells within human gastric carcinoma but not in normal tissues, suggesting a role of seprase in the invasive and metastatic progression of gastric carcinoma.