Angiogenesis In Gastric Cancer Research Articles

Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis-related molecules

BackgroundAlthough FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis. The present study was performed to investigate the correlation between the constitutive expression of phosphorylated FOXO1 (pFOXO1) and angiogenesis in gastric cancer.MethodsImmunohistochemistry was performed on tissue array slides containing 272 gastric carcinoma specimens, and the correlations between the cytoplasmic pFOXO1 expression in gastric cancer cells and CD34-immunopositive microvessel area (MVA) or the expressions of angiogenesis-related molecules were analyzed. In vitro analyses with Western blotting and semiquantitative reverse transcription-polymerase chain reaction were performed using the stable SNU-638 gastric cancer cell line transfected with lentivirus-delivered FOXO1 short hairpin RNA.ResultsThe cytoplasmic expression of pFOXO1 in tumor cells was observed in 85% of gastric carcinoma cases, and was found to be positively associated with higher MVA (P = 0.048). Moreover, pFOXO1 expression was positively correlated with the expressions of several angiogenesis-related proteins, including hypoxia inducible factor-1α (HIF-1α, P = 0.003), vessel endothelial growth factor (P = 0.004), phosphorylated protein kinase B (P < 0.001), and nuclear factor-κB (P = 0.040). In contrast, the expression of pFOXO1 was not correlated with that of phosphorylated signal transducer and activator of transcription 3 or β-catenin. In addition, cell culture experiments showed that FOXO1 suppression increased the mRNA and protein expressions of HIF-1α.ConclusionOur results suggest that pFOXO1 expression in cancer cells plays a role in gastric cancer angiogenesis via mechanisms involving various angiogenesis-related molecules. Animal experiments are needed to confirm the anti-angiogenic role of FOXO1 in human gastric cancer.

Sinomenine inhibits proliferation of SGC-7901 gastric adenocarcinoma cells via suppression of cyclooxygenase-2 expression

Sinomenine (SIN) is a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum. Results of studies have shown that the anti-inflammatory, immunosuppressive and anti-arthritic effects of SIN are partially attributed to the inhibition of cyclooxygenase-2 (COX-2) expression. COX-2 overexpression is associated with enhanced proliferation and angiogenesis of gastric cancer (GC). SGC-7901 cells were treated with different concentrations of SIN in order to observe its effect on the proliferation of human gastric adenocarcinoma cells and to explore the potential underlying molecular mechanism via the detection of COX-2 expression. Celecoxib was used as the positive control. Morphological alterations of the cells were observed microscopically. Cell proliferation was evaluated using MTT assay. COX-2 expression was detected using semi-quantitative RT-PCR and Western blotting. The results showed that SIN inhibited the proliferation of SGC-7901 cells in a time- and dose-dependent manner. In the presence of SIN or celecoxib, SGC-7901 cells became round and detached morphologically, indicating cell apoptosis. The expression of COX-2 was inhibited by SIN in a dose-dependent manner at both the mRNA and protein levels. Our findings indicate that the protective effects of SIN are mediated through the inhibition of COX-2 expression. These findings suggest a novel therapy to treat inflammation-mediated gastric adenocarcinomata.

Abstract LB-290: Glycogen synthase kinase-3β inhibits tumor growth and angiogenesis of gastric cancer

Abstract Objective: The mechanisms underlying angiogenesis in cancer are diverse. Although in vitro studies have shown that glycogen synthase kinase-3β (GSK-3β) inhibits the expressions of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in several cancer cells, the implication of GSK-3β in cancer angiogenesis in vivo has not been shown. We examined the effects of GSK-3β on angiogenesis and human gastric cancer growth. Methods: Human gastric cancer cell lines SNU-638 and SNU-484 were stably transfected with either human wild-type (WT)-GSK-3β or kinase-dead (KD)-GSK-3β, and the effects of GSK-3β on tumor growth and angiogenesis were examined in in vivo experiments. Gastric cancer cells were injected into nude mice subcutaneously and the size of xenografted tumors was measured. The effects of GSK-3β inhibition on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, Western blotting and semiquantitative reverse transcription-polymerase chain reaction. In addition, GSK-3β effects on the HIF-1α degradation and synthesis were examined. Results: Xenografts in nude mice derived from stable gastric cell lines over-expressing KD-GSK-3β showed larger tumor volumes and higher microvessel density than those over-expressing WT-GSK-3β. Immunohistochemistry and Western blot analysis using xenografted tumor tissues showed that KD-GSK-3β over-expression increased immunoreactivity for Ki-67, HIF-1α, VEGF or CD31 compared with WT-GSK-3β over-expression. In addition, KD-GSK-3β over-expression enhanced HIF-1α expression under hypoxic conditions at the translational level, but not under normoxic conditions. Conclusion: These results indicate that GSK-3β inhibits gastric tumor growth and angiogenesis by regulating the expression of HIF-1α and VEGF in gastric cancer cells under hypoxic conditions. Our results suggest the potential usefulness of GSK-3β/HIF-1α/VEGF pathway to find molecular targets in gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2011-LB-290

Abstract 5139: Thymidine phosphorylase expression correlate with lymphangiogenesis and angiogenesis in metastatic gastric cancer

Abstract Thymidine Phosphorylase (TP) (platelet-derived endothelial cell growth factor, PD-ECGF) is known as a proangiogenic factor. High TP expression in the primary tumor has been thought as a risk factor for hepatic and lymph node metastasis in patients with gastric adenocarcinoma. However, the molecular basis for induction of invasion and lymph node metastasis by TP and its therapeutic implication is largely unknown. First, as a pilot study, the (lymph)angiogenic activity (D2-40, LYVE-1, VEGFC, VEGFR3) and TP expressions were evaluated in resected tumor samples. Sixty patients of gastric cancer with metastatic lymph nodes and in 46 patients without lymph node metastasis were included. With immunohistochemical study, we demonstrated that tumoral and stromal TP expressions were moderately correlated (Pearson correlation = 0.455). TP expression was also correlated with depth of invasion and nodal stage. TP-positive tumors had also increased lymphovascular invasion compared with TP-negative tumors (P = 0.044), and node positive tumor had higher density of lymphatic vessels, and it is correlated with TP expression (P = 0.023). Then, we have shown that nude mice injected intraperitoneally with TP-overexpressing MKN-45 cells (MKN-45/TP) had decreased survival times compared with those injected with control cells (MKN-45/CV). MKN-45/TP tumors were more angiogenic (positive for CD31) and lymphangiogenic (positive for D2-40 and LYVE-1), and they were more invasive than MKN-45/CV tumors. A specific TP inhibitor, TPI, partially extended the survival period of TP tumor bearing mice, and its angiogenic activity was significantly reduced. All these findings imply that TP expression may be related to lymphangiogenesis in gastric cancer, and it could be further investigated as therapeutic targets for anti-metastatic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5139. doi:10.1158/1538-7445.AM2011-5139

Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients

Increased nitric oxide synthase expression plays a key role in tumor progression. To examine inducible nitric oxide synthase expression and its correlation with clinical variables, such as tumor progression, angiogenesis, lymphangiogenesis, and prognosis in gastric cancer, we studied inducible nitric oxide synthase expression in gastric cancer samples from 211 patients with 5-year follow-up. CD105 and D2-40 were adopted as biomarkers for tumor angiogenesis and lymphangiogenesis, respectively. Inducible nitric oxide synthase staining was mainly found in the cytoplasm of gastric cancer tumor cells. Positive inducible nitric oxide synthase immunoreactivity was seen in 54.03% of gastric cancer specimens, which was correlated with lymph node metastasis, vascular invasion, distant metastasis, and TNM stage. Compared with inducible nitric oxide synthase negative patients, inducible nitric oxide synthase-positive patients had significantly shorter survival times and higher microvessel density and lymphatic vessel density. Intratumor and peritumor blood microvessel density and lymphatic vessel density correlated with inducible nitric oxide synthase expression (Spearman ρ test, P < .05). We conclude that inducible nitric oxide synthase expression correlates with lymph node metastasis, vascular invasion, distant metastasis, TNM stage, and poor survival rate in gastric cancer. We propose that synthesized inducible nitric oxide synthase increases angiogenesis, and lymphangiogenesis thus promotes tumor progression. Inducible nitric oxide synthase expression may be a good biomarker for poor prognosis in gastric cancer.

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

Gastric cancer is often diagnosed in locally advanced or metastatic stages, which preludes a poor prognosis. As only 10% of patients with advanced gastric cancer treated with chemotherapy survive 2 years, new approaches for preventing and controlling the disease are required. We therefore, assessed in gastric cancer cells the chemotherapeutic potential and mechanism of deguelin, a rotenoid of the flavonoid family isolated from several plant species. The effect of deguelin on the proliferation and apoptosis in the gastric cancer cells were assessed by MTT and flow cytometry. The growth of gastric cancer cells (SNU-484, AGS and MKN-28) was inhibited by deguelin in a dose-dependent manner. G2/M phase arrest was induced by deguelin in gastric cancer cells. deguelin (1 µM) induced chromatin condensation and DNA fragmentation. Also the exposure to 1 µM deguelin resulted in the increase in early-apoptotic cells (Annexin V-positive/Propidium iodide-negative) after 24 h, compared to the cells in the control medium (31 versus 12%). Deguelin-induced apoptosis involved the caspase-9 and caspase-3 pathways in gastric cancer cells. Akt phosphorylation, hypoxia-inducible factor-1α accumulation, and vascular endothelial growth factor expression in gastric cancer cells was inhibited by deguelin. Taken together, deguelin showed anticancer activity in gastric cancer cells, which is correlated with the inhibition of angiogenesis and induction of apoptosis. Deguelin may be a potential agent in inhibiting the progression of gastric cancer by virtue of its activity on these crucial cell characteristics.

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

Gastric cancer is often diagnosed in locally advanced or metastatic stages, which preludes a poor prognosis. As only 10% of patients with advanced gastric cancer treated with chemotherapy survive 2 years, new approaches for preventing and controlling the disease are required. We therefore, assessed in gastric cancer cells the chemotherapeutic potential and mechanism of deguelin, a rotenoid of the flavonoid family isolated from several plant species. The effect of deguelin on the proliferation and apoptosis in the gastric cancer cells were assessed by MTT and flow cytometry. The growth of gastric cancer cells (SNU-484, AGS and MKN-28) was inhibited by deguelin in a dose-dependent manner. G2/M phase arrest was induced by deguelin in gastric cancer cells. deguelin (1 microM) induced chromatin condensation and DNA fragmentation. Also the exposure to 1 microM deguelin resulted in the increase in early-apoptotic cells (Annexin V-positive/Propidium iodide-negative) after 24 h, compared to the cells in the control medium (31 versus 12%). Deguelin-induced apoptosis involved the caspase-9 and caspase-3 pathways in gastric cancer cells. Akt phosphorylation, hypoxia-inducible factor-1alpha accumulation, and vascular endothelial growth factor expression in gastric cancer cells was inhibited by deguelin. Taken together, deguelin showed anticancer activity in gastric cancer cells, which is correlated with the inhibition of angiogenesis and induction of apoptosis. Deguelin may be a potential agent in inhibiting the progression of gastric cancer by virtue of its activity on these crucial cell characteristics.

Effect of silencing heparanase on the biological behavior of gastric carcinoma in nude mice

To investigate the effects of silencing heparanase (HPA) on growth, angiogenesis and metastasis of human gastric carcinoma transplanted in nude mice. Human gastric carcinoma SGC-7901 cells and those cells with silenced HPA (gastric carcinoma SGC-7901-HPA(-)) were separately transplanted subcutaneously in 6 nude mice. The time, size and speed of tumor growth were recorded. RT-PCR and Western-blot were used to detect the expression of HPA mRNA and protein in the subcutaneous tumors of the two groups. Immunohistochemical staining was used to detect microvessel density (MVD) in the subcutaneous tumors of the two groups. Cells of the subcutaneous transplanted tumors of the two groups were separately injected into the peritoneal cavity of nude mice, 6 mice each. The growth of metastatic tumors in nude mice was observed. Human gastric carcinoma SGC-7901 cells and SGC-7901-HPA(-) cells were subcutaneously inoculated in nude mice, and tumors appeared at 4 days and 7 days after inoculation, respectively. The MVD was (20.69 ± 1.20)/HP and (11.35 ± 1.94)/HP, respectively (P < 0.05). The expressions of HPA mRNA and protein of the subcutaneously transplanted SGC-7901-HPA(-) tumor were decreased. Four voluminous metastatic tumors caused by SGC-7901 cells occurred in 3 mice in the liver, right kidney, omentum and intestine. Two smaller abdominal metastatic tumors of SGC-7901-HPA(-) cells were found in the liver and right kidney. Silencing HPA can inhibit the tumor growth, angiogenesis and metastasis of human gastric cancer in nude mice. It suggests that HPA might become a new target for prevention and treatment of gastric cancer.

Leptin in gastric cancer

Leptin promotes proliferation of cancer cells via various signal transduction pathways and contributes to angiogenesis in gastric cancer. Leptin expression level is significantly higher in gastric cancer than in normal gastric mucous tissues, and correlates with clinicopathological features such as differentiation,tumor size and distant metastasis. Leptin has become a prognostic factor and a new therapy target of gastric cancer. Key words: Leptin ; Stomach neoplasms ;

Mast cells and angiogenesis in gastric carcinoma

Previous studies have shown that increased vascularity is associated with haematogenous metastasis and poor prognosis in gastric cancer. The role of mast cells in gastric cancer angiogenesis has not been clarified completely. In this study, we correlated microvascular density and tryptase- and chymase-positive mast cells with histopathological type in gastric cancer. Specimens of primary gastric adenocarcinomas obtained from 30 patients who had undergone curative gastrectomy were investigated immunohistochemically by using anti-CD31 antibody to stain endothelial cells and anti-tryptase and anti-chymase antibodies to stain mast cells. The results showed that stage IV gastric carcinoma has a higher degree of vascularization than other stages and that both tryptase- and chymase-positive mast cells increase in parallel with malignancy grade even if the density of chymase-positive mast cells was significantly lower than the density of tryptase-positive mast cells and is highly correlated with the extent of angiogenesis. This study has demonstrated that mast cell density correlates with angiogenesis and progression of patients with gastric carcinoma. Understanding the mechanisms of gastric cancer angiogenesis provides a basis for a rational approach to the development of an antiangiogenic therapy in patients with this malignancy.

Infiltration of thymidine phosphorylase-positive macrophages is closely associated with tumor angiogenesis and survival in intestinal type gastric cancer

Thymidine phosphorylase (TP), an enzyme catalyzing the reversible phospholysis of thymidine, deoxyuridine and their analogs at their respective bases and 2-deoxyribose-1-phosphate, thus promoting angiogenesis, is often expressed in macrophages present in tumor stroma. In this study, we investigated whether infiltration of TP-positive macrophages as well as tumor-associated macrophages affected tumor angiogenesis. TP was expressed in human macrophage-like cells, but not in gastric cancer cells in culture. The expression level of TP, the number of infiltrating CD68+ and CD163+ macrophages, and microvessel density (MVD) in the tumor were further analyzed by immunohistochemistry in 111 patients with gastric cancer. Biostatistical analysis of digitized data obtained by image analysis showed that TP expression was significantly correlated with the number of infiltrating macrophages and MVD in intestinal type gastric cancer (p<0.05). The number of infiltrating macrophages was also correlated with MVD in both the intestinal and diffuse types (p<0.05). An increased number of CD68+ macrophages was significantly associated with poor outcome in patients with intestinal type (p<0.001), but not diffuse type cancer. TP could be a specific marker enzyme that is expressed in tumor-infiltrating macrophages, being associated with tumor angiogenesis and poor prognosis in patients with intestinal-type gastric cancer.

Abstract 1370: RO5323441, a humanized monoclonal antibody against the placenta growth factor, blocks PlGF-induced VEGFR-1 phosphorylation in vitro and tumor growth in vivo

Abstract Solid tumor growth requires new blood vessel formation or angiogenesis. Inhibition of angiogenesis as a therapeutic strategy in oncology has been validated by treatments that block vascular endothelial growth factor (VEGF) or its receptors, such as bevacizumab (Avastin®), which is an anti-VEGF antibody that prolongs survival in colorectal, lung and other cancer patients in combination with chemotherapy. However, since not all tumors are sensitive to VEGF blockade and resistance mechanisms to VEGF therapies can develop, inhibition of additional targets may be necessary in order to control tumor growth and achieve better clinical effects. PlGF is a member of the VEGF family that is found only in very low levels under normal physiological conditions, but is up-regulated in almost all major malignant diseases. PlGF expression has shown to correlate with tumor stages and patient survival in breast cancer, CRC and gastric cancer [1-3]. Pre-clinical data support a role for PlGF in tumor angiogenesis, and demonstrate that blocking PlGF can inhibit tumor growth [4]. RO5323441, a humanized IgG1 monoclonal antibody directed against PlGF, has demonstrated anti-tumor activity in human tumor xenograft models in mice, has a benign preclinical toxicology profile and is being developed for the treatment of multiple advanced cancer indications. RO5323441 binds to both PlGF-1 and PlGF-2 in a dose dependent manner, and is not cross-reactive with murine PlGF or human VEGF. RO5323441 inhibits the binding of human PlGF-1 or PlGF-2 to VEGFR −1 with IC50 values of 0.1 and 0.2 nM, respectively. RO5323441 blocks PlGF-induced VEGFR-1 phosphorylation in Flt-1-transfected HEK293 cells. Antitumor activity has been demonstrated in mutliple tumor models including ACHN and Caki-1 renal cell carcinoma and Huh-7, hepatocellular carcinoma xenografts. Inhibition of established tumors ranged from 43-97% with twice weekly dosing. A refractory model of non-small cell lung cancer has also been identified. Studies to understand the mechanism of action and to identify pharmacodynamic markers and have been carried out in ACHN-tumor bearing mice.

Abstract 3476: Combined blockade of IGF-I receptor and VEGF for gastric cancer

Abstract Background Insulin-like growth factor-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal (GI) cancers. We have shown successful therapy for GI cancers using adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn). On the other hand, IGF-IR signaling affects on vascular endotherial growh factor (VEGF) expression in some tumors. Here, we sought to evaluate the roles of IGF-IR on tumor angiogenesis and lymphangiogenesis and to develop targeting therapy for gastric cancer. Methods The impact of IGF signals on VEGF-A/C expression in gastric cancer cell was assessed. The effects of IGF-IR/dn alone and with bevacizumab on angiogenesis / lymphangiogenesis in mouse xenogfarts were assessed. Results IGFs induced expressions of VEGFs and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced those expressions and vascular formation. IGF-IR/dn down-regulated tumor size on mice via inhibiting both angiogenesis and lymphangiogenesis. The combination of IGF-IR/dn and bevacizumab was highly effective against tumors on mice. This combination reduced the expression of VEGF and induced apoptosis in the murine tumors most of all. Conclusions IGF-IR is involved in angiogenesis and lymphangiogenesis in gastric cancer. Targeting IGF-IR alone and with blocking VEGF may have therapeutic utility of prevention for gastric cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3476.

Angiogenesis and Lymphangiogenesis of Gastric Cancer

Tumor angiogenesis is the result of an imbalance between positive and negative angiogenic factors released by tumor and host cells into the microenvironment of the neoplastic tissue. The stroma constitutes a large part of most solid tumors, and cancer-stromal cell interactions contribute functionally to tumor growth and metastasis. Activated fibroblasts and macrophages in tumor stroma play important roles in angiogenesis and tumor progression. In gastric cancer, tumor cells and stromal cells produce various angiogenic factors, including vascular endothelial growth factor, interleukin-8, platelet-derived endothelial cell growth factor, and angiopoietin. In addition, Helicobacter pylori infection increases tumor cell expression of metastasis-related genes including those encoding several angiogenic factors. We review the current understanding of molecular mechanisms involved in angiogenesis and lymphangiogenesis of human gastric cancer.

RNAi-mediated inhibition of PDGF-D leads to decreased cell growth, invasion and angiogenesis in the SGC-7901 gastric cancer xenograft model

Platelet-derived growth factor-D (PDGF-D) plays an important role in many types of human cancer. However, little is known about the function of this gene in gastric cancer. Here we demonstrated that PDGF-D is commonly overexpressed in gastric cancer. Silencing of PDGF-D using RNA interference significantly attenuated the proliferation and invasion potentials of SGC-7901 gastric cancer cells in which PDGF-D is overexpressed. Moreover, suppression of PDGF-D expression resulted in less activation of β-catenin and its downstream effector genes, cyclin D1 and matrix metalloproteinases, which are known to be involved in cell proliferation and invasion, respectively. Further, downregulation of PDGF-D remarkably reduced VEGF expression and secretion and proangiogenic activities of SGC-7901 cells in vitro. Most importantly, PDGF-D downregulation caused a significant decrease in tumor growth and angiogenesis in a SGC-7901 xenograft model. Together these findings suggest that PDGF-D is involved in the promotion of gastric cancer growth, invasion and angiogenesis, and RNAi-mediated silencing of this gene may thus offer a promising therapeutic strategy for PDGF-D-overexpressing gastric cancer.

Cancer-Stromal Cell Interaction and Tumor Angiogenesis in Gastric Cancer

Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by a variety of stromal cells. The stroma constitutes a large part of most solid tumors, and cancer-stromal cell interaction contributes functionally to tumor growth and metastasis. Angiogenesis is the result of an imbalance between positive and negative angiogenic factors released by tumor and host cells into the microenvironment of the neoplastic tissue. In gastric cancer, tumor cells and stromal cells produce various angiogenic factors, including vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor. The microenvironment in the gastric mucosa may also influence the angiogenic phenotype of gastric cancer. Helicobacter pylori infection increases expression of several angiogenic factors by tumor cells. Activated fibroblasts and macrophages in tumor stroma also play an important role in angiogenesis and tumor progression. We review the current understanding of cancer-stromal cell interaction as it pertains to tumor angiogenesis in gastric cancer.

Relationship between prognosis and angiogenesis, lymphangiogenesis, proliferative cell distribution in gastric cancer

Objective We investigated the relationship between lymphangiogenesis, angiogenesis and cell proliferation in gastric cancer.

Relationship between Ets-1 expression and angiogenesis, clinicopathological features and survival of patients with gastric carcinoma

To investigate the expression of Ets-1 in gastric carcinoma, para-cancerous tissue and metastatic lymph nodes, and to determine the relationship between Ets-1 expression and clinicopathological features, angiogenesis and survival of patients with gastric carcinoma. Gastric carcinoma tissue microarray was used to determine Ets-1 protein expression by SP immunohistochemical staining in 189 advanced gastric cancer, 54 papacancerous tissues, 41 metastatic lymph nodes and 32 control tissues. The positive rates for Ets-1 expression of the carcinoma, paracancerous and control tissues were 71.4%, 29.6% and 18.8%, respectively, with a significant difference among the three groups (P < 0.01). In the cancer tissues, the positive rate of Ets-1 protein expression was significantly associated with depth of invasion and lymph node metastasis (P < 0.01), but not associated with degree of differentiation, Lauren's histological type, sex, age, and size of tumor (P > 0.05). The positive rates for Ets-1 expression of the 41 gastric cancer and 41 metastatic lymph nodes were significantly different (P < 0.05). In metastatic lymph nodes, the positive rate for Ets-1 expression was higher. The MVD in Ets-1 positive tumors was higher than that in the Ets-1 negative tumors, with a significant difference (P < 0.05). Kaplan-Meier survival analysis showed that the survival time of Ets-1-negative patients was longer than that of Ets-1-positive patients (P < 0.05). Cox regression analysis showed that Ets-1 expression was not an independent prognostic factor of gastric carcinoma. A higher expression of Ets-1 is involved in carcinogenesis, development, invasion, and metastasis of gastric cancer. Ets-1 plays an important role in angiogenesis in gastric cancer. Ets-1 is a useful marker for predicting the outcome for patients with gastric carcinoma, though it is not an independent prognostic indicator.

RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer

This article has been retracted at the request of the Editor-in-Chief.Reason: The Editors have determined that the article is a duplication of the authors’ article in Cancer Biology & Therapy (2005) 4:113-117. This is in violation of the journal’s policy against dual publication. For more information on this policy see: www.landesbioscience.com/journals/cbt/guidelines/#plagiarism.

Expression of Hepatocyte Growth Factor and Basic Fibroblast Growth Factor as Prognostic Indicators in Gastric Cancer

We have investigated the correlations among hepatocyte growth factor (HGF) mRNA expression, basic fibroblast growth factor (bFGF) mRNA expression, tumor microvessel density (MVD), and clinical pathological features of gastric cancer in Chinese patients. In situ hybridization was used to detect the expression of HGF and bFGF mRNAs, and immunohistochemistry was used to detect CD34 in 105 gastric cancer tissues and in 20 normal control tissues. The rate of HGF mRNA expression in normal gastric tissues (25%) was significantly lower than that (57.1%) in tumor tissues (P < 0.01). The rates of HGF mRNA and bFGF mRNA expression and MVD in T3-T4 stage tissues were higher than those in T1-T2 stage tissues (P < 0.01); the HGF mRNA expression rate was directly correlated with the bFGF mRNA expression rate (P < 0.05), and they were also directly correlated with MVD (P < 0.01). The mean survival time and the 5-year survival rate of patients who were positive for expression of HGF mRNA and bFGF mRNA and who had a MVD >or= 39.5/0.72 mm(2) were significantly shorter than those who did not express HGF mRNA and bFGF mRNA and who had a MVD <39.5/0.72 mm(2). Both HGF and bFGF may participate in angiogenesis in gastric cancer and may be involved in tumor invasion and metastasis. HGF and bFGF mRNA expression can be used as useful parameters to evaluate the prognosis of gastric cancer.