Expression Of Microvascular Density Research Articles

Anti-angiogenic effect of the combination low-dose sorafenib and EGCG in HCC-induced Wistar rats.

Background: Sorafenib is an expensive standard drug used for advanced hepatocellular carcinoma. Its combination with epigallo-3-catechin gallate leads to a reduced cost but equally effective anti-angiogenic effect. Therefore, this study aims to assess the anti-angiogenic effect of standard-dose Sorafenib compared to the combination of low-dose Sorafenib and epigallo-3-catechin gallate. Methods: A total of 25 male Wistar rats (7-weeks-old) were randomly divided into 4 groups, namely Sham (K), Control (O), combination of low-dose Sorafenib and epigallo-3-catechin gallate group (X1), and standard-dose Sorafenib group (X2). All groups were injected with N-Nitrosodiethylamine 70 mg/kg bodyweight (BW) intraperitoneally for 10 weeks, except the Sham group. After the development of hepatocellular carcinoma, X1 and X2 were treated for 2 weeks. Subsequently, the level of vascular endothelial growth factor (VEGF) and expression of microvascular density was examined using liver tissues. Results: There was a significant difference (p=0.007) in the level of VEGF between the group X1 (106,682 ± 41,024) and X2 (214,5162 ± 67,71652). However, the differences in VEGF level of group X1 and X2 compared to group O (318,101 ± 55,078) were significantly lower, with values p=0.000136 and p=0.019, respectively. The expression of microvascular density between groups X1 (36 ± 4,416) and X2 (26,2 ± 4,55) was not significantly different. Meanwhile, a significant difference (p<0.05) was discovered when both groups were compared with group O (176 ± 19). Conclusion: The combination of low-dose Sorafenib with epigallo-3-catechin gallate is superior in reducing the level of VEGF compared to standard-dose Sorafenib and is better than the control. Standard-dose Sorafenib as well as the combination of low-dose Sorafenib and epigallo-3-catechin gallate have similar effectivity to reduce the expression of microvascular density.

IL-32 expression associated with lymph vessel invasion in intestinal type of gastric cancer

Background/Aim. Gastric cancer (GC) is fourth most frequent malignant tumor worldwide, frequently diagnosed at advanced stages with poor prognosis. The aim of study was to determine expression of interleukin (IL)-32, proinflammatory and angiogenic mediators in the tumor, peritumor and healthy tissue, in patients with intestinal gastric cancer and the relationship with the disease severity. Methods. The tissue samples of intestinal type of the tumor of 60 patients with GC were analyzed. Expression of IL-32, vascular endothelial growth factor (VEGF), IL-17 and CD31 were measured by immunohistochemistry. Results. IL-32, VEGF and IL-17 expression as well as microvascular density (MVD) were diminished in adjacent tumor tissues compared with the tumor ones. Further, more intense expression of IL-32 and VEGF and enhanced MVD were noticed in patients with severe (TNM stages III and IV) and more progressive GC (lymph vessel invasion). Conclusion. Higher expression of IL-32, VEGF and intense MVD in the tumor tissue of GC patients with detectable lymph vessel invasion may be considered as a sign of the tumor?s malignant progression. This indicates a protumorogenic and proangiogenic role of IL-32 in biology of intestinal type of gastric cancer.

Association of p53, VEGF and Microvascular Density in Colorectal Carcinoma

Introduction: Colorectal Cancer (CRC) is third most common malignancy worldwide. Various genomic alterations play fundamental role in initiation and progression of CRC. Among these, p53 mutation has a crucial role in survival and metastasis and its point mutation induces Vascular Endothelial Growth Factor (VEGF) promoting vascular permeability, migration and differentiation. The degree of angiogenesis can be measured by Microvascular Density (MVD) using CD34, which is helpful in identifying high risk patients for recurrence and metastasis. Aim: The aim of the study was to analyse the expression of p53, VEGF and MVD in CRC and their association with clinicopathological parameters. Materials and Methods: The ambispective study of 2 year duration was conducted from September 2015 to July 2017 in the Department of Pathology, Kalinga Institute of Medical Sciences and PBMH, Bhubaneswar. It included CRC resection specimens and archival tissue blocks. Tissue microarray blocks were prepared manually for IHC application in total 70 cases (58 (82.9%) adenocarcinomas and 12 (17.1%) adenomas) which were histologically staged and graded as per American Joint Committee on Cancer (AJCC) and World Health Organisation (WHO) guidelines. Pearson chi-square test and fisher’s-exact method were used to find significance of p53, VEGF and CD34 expression in adenomas and adenocarcinomas with respect to clinicopathological parameters. Results: No significant statistical association was found between p53, VEGF and MVD with tumour grade and nodal status. Majority, 41 (70.69%) cases were hypervascular (MVD-High). Adenomas 9 (75%) cases, were mostly hypovascular (MVD-Low) with p-value of 0.003. There was significant statistical association between VEGF and MVD with a p-value of 0.01. VEGF and MVD were more expressed on left-sided colon cancers. There was significant statistical association (p=0.01) between p53 graded expression and diagnosis in the present study. MVD and tumour nodal status had an inversely significant relationship (p=0.03). Conclusion: p53 and VEGF expressed more on carcinomas than adenomas. Both p53 and VEGF induce angiogenesis which can be effectively measured by CD34 expression (MVD). There is a directly proportional relationship of angiogenesis and malignant transformation. So these three IHC markers together can be considered a significant prognostic factor involved in CRC.

Aberrant Cyclin E and Hepatocyte Growth Factor Expression, Microvascular Density, and Micro-Lymphatic Vessel Density in Esophageal Squamous Cell Carcinoma.

Cyclin E and hepatocyte growth factor (HGF) have been observed as a multifaceted factor in many cancers, and the assessment of microvascular density (MVD) and micro-lymphatic vessel density (MLVD) has been used to quantify tumor angiogenesis and lymphangiogenesis. The aim of this study was to explore the association between expression of cyclin E, HGF, MVD, and MLVD, and clinicopathologic parameters in esophageal squamous cell carcinoma (ESCC). The expression of cyclin E, HGF, MVD, and MLVD were detected using immunohistochemically anticyclin E, HGF, CD34, and lymphatic vessel endothelial hyaluronan receptor 1 in 168 surgically resected ESCC cases and 30 normal esophageal mucosal samples. The expression levels of cyclin E, HGF, MVD, and MLVD were higher compared to controls. High cyclin E and HGF expression was found more frequently in the tumors larger than 5 cm (P < .001), with poorer differentiation (P = .034) and higher tumor node metastasis (TNM) staging (P = .009) compared to their counterparts. Both MVD and MLVD values were found to be higher in the tumors larger than 5 cm (P < .001), with poorer differentiation (P < .001) and higher TNM staging (P < .001) compared to their counterparts. Furthermore, the expression of MVD and MLVD in both the high cyclin E and high HGF expression groups was significantly higher compared to the low cyclin E and HGF expression groups (P < .001). This study demonstrated that high cyclin E and HGF expression is closely correlated with tumor size, tumor differentiation degree, and TNM stage in patients with ESCC. These findings proposed that cyclin E and HGF could serve as novel molecular markers for preoperational evaluation of ESCC.

Cyclooxygenase-2 induces angiogenesis in pancreatic cancer mediated by prostaglandin E2.

The purpose of the present study was to elucidate the effects of cyclooxygenase 2 (COX-2) on the expression of vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) in pancreatic cancer in vitro and in vivo, and to clarify the potential mechanism of COX-2-induced angiogenesis of pancreatic cancer. The study analysis was conducted in the pancreatic cancer PC-3 cell line. The expression of COX-2 and VEGF in human pancreatic cancer tissue was analyzed by immunohistochemistry. Angiogenesis was detected using immunohistochemistry with anti-collagen IV antibodies, and was calculated according to the microvascular density (MVD). In vitro analysis was performed using ELISA or radioimmunoassay (RIA). The effect of exogenous PGE2 on the downregulation of VEGF by Celebrex was also assessed. In vivo analysis was performed using western blotting or RIA. Concurrently, MVD was also investigated in nude mice using immunohistochemistry with anti-collagen IV antibodies. COX-2 was overexpressed in pancreatic cancer tissues, with an overall positive rate of 87.5%. There was a positive association between the expression of COX-2 and MVD. The in vitro study indicated that Celebrex suppressed the expression of VEGF and PGE2 in PC-3 cells in a dose- and time-dependent manner, while exogenous PGE2 rescued the expression of VEGF, which was suppressed by Celebrex, in a dose-dependent manner. The in vivo study revealed that the administration of Celebrex to xenograft nude mice significantly inhibited the expression of VEGF and PGE2. These data provide evidence that PGE2 may be an important mediator between COX-2 and VEGF expression in the process of angiogenesis in pancreatic cancer.

Expression and clinical significance of hypoxia inducible factor-1α, matrix metalloprotein-9 and microvascular density in bladder cancer

Objective To investigate the expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloprotein-9 (MMP-9) and microvascular density (MVD) in bladder cancer and its clinical significance. Methods 51 tissues diagnosed as bladder cancer cured in department of urology of our hospital from February 2013 to November 2015 were selected as research objects, and 30 cases of non-bladder cancer patients with normal bladder specimens used as negative control group. Immunohistochemical method was implemented to observe the expression of HIF-1α, MMP-9 and MVD in bladder tissues. Results The positive rate of MMP-9 and HIF-1α was significantly higher than that in normal bladder tissues [60.78% (31/51) vs. 0.00% (0/30), P=0.000; 70.58% (36/51) vs. 16.67% (5/30), P=0.000]; The score of the expression of HIF-1α, MMP-9 in bladder tissues were significantly higher than those in normal bladder tissues (4.31±1.03 vs. 1.12±0.07, P=0.000; 4.64±0.98 vs. 1.53±0.21, P=0.000). The expression of MVD in bladder cancer tissues were significantly higher than those in normal bladder tissues (38.06±9.04 vs. 19.17±5.19; t=11.946, P=0.000). The expressionof HIF-1α, MMP-9 and MVD in bladder cancer whose diameter more than 3 cm was significantly higher than that in tumor diameter whichless than 3 cm (P=0.025, 0.009, 0.011). The expression of HIF-1α, MMP-9 and MVD in invasive bladder cancerwas significantly higher than that of superficial bladder cancer tissue (P=0.000, 0.000, 0.035). Spearman correlation analysis results demonstrated that HIF-1α, MMP-9 expression showed a significant positive correlation with MVD expression levels (P=0.000, 0.001). Conclusion HIF-1α, MMP-9 and MVD in bladder cancer expression was significantly up-regulated and for assessment tumor size, clinical stage and pathological grade, which has good prospects for clinical application. Key words: Hypoxia inducible factor-1α; Matrix metalloprotein-9; Microvascular density; Bladder cancer; Expression; Clinical significance

Nuclear survivin expression correlates with endoglin-assessed microvascularisation in laryngeal carcinoma

AimsSurvivin—a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis—is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent...

Angiogenesis correlates with macrophage and mast cell infiltration in lung tissue of animals exposed to fluoro-edenite fibers

Angiogenesis plays a crucial role in progression of pleural malignant mesothelioma. A significantly increased incidence of pleural mesothelioma has been attributed to exposure to fluoro-edenite, a fibrous amphibole extracted from a local stone quarry. In this study, we have investigated the expression of CD68-positive macrophages, tryptase-positive mast cells and CD31 positive areas, as expression of microvascular density, in lung tissue of sheeps exposed to fluoro-edenite fibers vs controls, by immunohistochemical, morphometric and Western blot analysis. The result have evidenced a significant increase in the expression of CD68-positive macrophages, tryptase-positive mast cells as well as a significant increase in microvascular density evaluated as CD31 positive areas in lung tissue of of sheeps exposed to fluoro-edenite fibers vs controls. These data confirmed the important role played by tumor microenvironment components, including macrophages and mast cells, in favour of angiogenesis in pleural mesothelioma induced by fluoro-edenite exposure.

Comparative study of rabbit VX2 tumor angiogenesis in fatty liver and normal liver and correlation with contrast-enhanced ultrasound quantitative parameters

Objective To comparative analysis the rabbit VX2 tumors angiogenesis in fatty liver and normal liver,and investigate the correlation of contrast-enhanced ultrasound (CEUS) parameters and their angiogenesis.Methods Rabbit models of fatty liver and normal liver with implanted VX2 tumors were established.Two groups of hepatic backgrounds and VX2 tumors were analyzed by QontraXt quantitative software of CEUS.The expression level of tumor microvascular density (MVD) and vascular endothelial growth factor (VEGF) were detected with immunohistochemical techniques and real-time fluorescence quantitative PCR (FQ-PCR).Results ①No significant difference was found in MVD,VEGF protein and gene expression between VX2 tumors in normal liver and fatty liver.The expression of VEGF gene in fatty liver parenchyma were lower than normal liver parenchyma (P ＜0.05).②There was positive correlation between MVD and peak intensity (r =0.494,P ＜0.05; r =0.591,P ＜0.01) both in fatty liver and normal liver VX2 tumors.The expression of VEGF protein were not correlated with TIC parameters (all P ＞ 0.05).③The MVD had positive correlation with expression of VEGF protein in fatty liver and normal liver VX2 tumors (r =0.508,P ＜0.05; r =0.570,P ＜0.01).Conclusions The expression of MVD and VEGF had no significant difference between fatty liver and normal liver VX2 tumors.The peak intensity of VX2 tumors CEUS had positive correlation with MVD both in fatty liver and normal liver,which can indirectly reflect MVD expression level and help to evaluate tumor angiogenesis. Key words: Ultrasonography; Microbubbles; Liver neoplasms, experimental; Fatty liver; Neovascularization, pathologic

Significance of the expression of integrin β1, VEGF and MVD in hypopharyngeal squamous cell carcinoma.

This study aimed to determine the expression of integrin β1 and vascular endothelial growth factor (VEGF) and microvascular density (MVD) by CD105 staining in hypopharyngeal squamous cell carcinoma to determine their association with clinicopathologic characteristics, and to determine their role and the effects of their interactions in the development and progression of hypopharyngeal squamous cell carcinomas. The expression of integrin β1 and VEGF and MVD in hypopharyngeal squamous cell carcinomas and normal hypopharyngeal tissues were evaluated using immunohistochemistry. The Image-Pro Plus software was used to determine the mean optical density of the immunohistochemical images. Integrin β1 expression was significantly higher in hypopharyngeal squamous cell carcinoma tissues (78.00%) than in normal hypopharyngeal tissues (35.00%; P = 0.001) and significantly differed across pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). VEGF expression was significantly higher in hypopharyngeal squamous cell carcinoma tissues (74.00%) than in normal hypopharyngeal tissues (30.00%; P = 0.002), VEGF overexpression differed significantly across different pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). The MVD count was significantly higher in hypopharyngeal squamous cell carcinoma tissues (37.10 ± 5.95) than in normal hypopharyngeal tissues (8.70 ± 3.34; P = 0.000). MVD differed significantly across different pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). The expression of integrin β1 and VEGF and the MVD count exhibited no significant differences in terms of age, gender, history of smoking, and clinical stages (P > 0.05). VEGF expression was positively associated with the MVD count of hypopharyngeal squamous cell carcinomas (r = 0.582, P = 0.000); however, integrin β1 was not associated with VEGF or MVD (P > 0.05). Integrin β1 and VEGF are overexpressed and MVD increased in hypopharyngeal squamous cell carcinomas. VEGF is positively correlated with MVD.

Pigment epithelial-derived factor expression in endometriotic lesions in a rat model of endometriosis

Angiogenesis is a prerequisite for endometriotic lesion formation and development. Pigment epithelium-derived factor (PEDF) is a potential inhibitor of angiogenesis. The objective of this study was to detect PEDF immunolocalization in endometriotic lesions and the correlation with vascular endothelial growth factor (VEGF) and microvascular density (MVD) in a rat model of endometriosis. A subcutaneous endometriosis rat model was established by using auto-transplantation. Expression of PEDF, VEGF and MVD labeled by von Willebrand factor (v-WF) in endometriotic lesions and endometrial tissues was evaluated using immunohistochemical staining. We detected lower PEDF immunostaining and higher VEGF and MVD immunostaining in active lesions in a rat model of endometriosis than that in endometriosis endometrium or control endometrium (P<0.05), but no differences between endometriosis and control endometrium were found (P>0.05). In lesions, PEDF expression was negatively correlated with VEGF expression, MVD or sizes of cysts (P<0.01). On the contrary, both VEGF expression and MVD were positively correlated with lesion sizes (P<0.05). In addition, VEGF expression was positively correlated with MVD (P<0.01). Our results suggest that PEDF might be involved in the pathogenesis of endometriosis and may lead to novel treatment for this disease.

VEGF expression and microvascular density in relation to high-risk-HPV infection in cervical carcinoma – An immunohistochemical study

BackgroundThe poor outlook of cervical carcinoma, a human papillomavirus (HPV)-related cancer mandates the search for new treatment modalities. Therapeutic targeting of tumor vasculature is a promising strategy. The aim was to study angiogenesis in cervical carcinoma in terms of VEGF expression and assessment of microvascular density (MVD) in relation to HPV antigen expression. MethodsThirty paraffin blocks of cervical carcinoma were studied for the immune expression of VEGF and MVD utilizing CD34 monoclonal antibody. Statistical analysis of these immunophenotypes in relation to tumor type, grade and HPV antigen expression was performed. ResultsThis retrospective study comprised of 17 squamous cell carcinomas, 11 adenocarcinomas and two adenosquamous carcinomas. Eleven cases were low grade and 19 were high-grade cases. VEGF expression was detected in 100% of cases. The relation between carcinoma grade and VEGF expression and MVD was statistically significant. There was no relation between VEGF intensity and tumor type although more intense VEGF staining tended to occur in cervical adenocarcinomas. VEGF density was significantly lower in squamous cell carcinomas compared to adenocarcinomas. Mean MVD was 50.37±20.0. The relation between MVD and VEGF expression was statistically significant. HPV immune expression was detected in 93.33% of cases. The relation between HPV antigen expression and each of tumor histotype and grade was not statistically significant. There was a statistically significant relation between HPV antigen expression and each of MVD and VEGF intensity. Multivariate statistical analysis showed MVD as an independent predictor of carcinoma grade. ConclusionVEGF was expressed in 100% of studied cervical carcinoma. There was a statistically significant relation between VEGF expression and MVD. Since HPV antigen expression was significantly correlated with MVD and VEGF staining intensity, we provide evidence that HPV infection may augment tumor angiogenesis in cervical carcinoma. MVD emerged as an independent predictor of cervical carcinoma grade and hence of progressive behavior.

Inhibitory effect of endostar in combination with radiotherapy in a mouse model of human CNE2 nasopharyngeal carcinoma

The inhibitory effects of Endostar in combination with radiotherapy in BALB/c nude mice model of human CNE2 nasopharyngeal carcinoma and the mechanism were investigated. In nude mice model of CNE2 nasopharyngeal carcinoma, the inhibitory rate and the sensitizing enhancement ratio (E/O) were calculated according to the tumor volumes in different groups. The expression of microvascular density (MVD) in tumor tissues was examined by using immunohistochemistry staining. The transcription of VEGF gene was detected by using RT-PCR. The inhibitory rate in Endostar+ radiotherapy group was higher than in other groups. In Endostar+radiotherapy group, the tumor volume was significantly decreased and the E/O ratio was 2.335, suggesting that Endostar could be a radiosensitizer. The expression of MVD of tumor tissues in Endostar+radiotherapy group was reduced significantly. The expression of the MVD in treatment groups was significantly different from that in control group (P<0.05). Compared to other groups, VEGF mRNA expression in Endostar+radiotherapy group was decreased remarkably. Endostar in combination with radiotherapy significantly inhibited the growth of CNE2 tumor. The combination therapy decreased the expression of VEGF, and inhibited tumor angiogenesis and proliferation. When combined with radiotherapy, Endostar acted as a radiosensitizer.

Clinicopathological significance of VEGF expression and microvascular density in renal clear cell carci-noma

Objective To evaluate vascular endothelial growth factor (VEGF) expression and micro-vascular density (MVD),and their clinicopathological significance in clear cell renal carcinoma (CCRCC).Methods Immunohistochemistry method was used to examine the expression of VEGF.CD34 staining endo-thelial cells were applied to measure the MVD.Results Sixty-six cases of CCRCC were collected.VEGF ex-pressions in 36(54.5%) cases were positive.No significant relationship was detected between VEGF expres-sion and clinicopathological parameters.The MVD value was 12-96.3.The levels of MVD were significantly lower in advanced TNM staging (P=0.000),high grading (P=0.005) and metastasized tumors (P=0.011).In larger tumors,the cases of MVD 50(26.7%) were much less than those of MVD <50 (73.3%).There was no significant relationship between the expression of VEGF and MVD,and neither of them was correlated with the renal capsule infiltration.Conclusion The overexpression of VEGF in CCRCC shows that it may be the target molecule for treatment.The value of MVD is inversely correlated with the grad-ing and staging of CCRCC,indicating its significance in the prognosis assessment of CCRCC. Key words: Kidney neoplasms; Vascular endothelial growth factors; Immunohistochemistry; Micro-vascular density

Inactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer.

To investigate the expression of PTEN/MMAC(1)/TEP(1) and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer. Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in cancer cells were investigated. PTEN expression significantly decreased (t = 3.98, P<0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P<0.01) in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t = 1.95,P<0.05) whereas VEGF expression (t = 2.37, P<0.05) and MVD (t = 3.28, P<0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t = 3.91, P<0.01), invasion depth (t = 1.95, P<0.05) and age (t = 4.69, P<0.01). MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t = 3.69, P<0.01), and there was a negative correlation between PTEN expression and MVD (gamma= -0.363, P<0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P<0.01), lymph node metastasis (t = 2.31, P<0.05) and TNM stage (t = 3.04, P<0.01). MVD in VEGF-positive gastric cancer was significantly higher than that in VEGF-negative gastric cancer (t = 4.62, P<0.01), and there was a positive correlation between VEGF expression of and MVD (gamma= 0.512, P<0.05). VEGF expression in PTEN-negative gastric cancer was significantly stronger than that in PTEN-positive gastric cancer (t = 2.61, P<0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (gamma= -0.403, P<0.05). Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTEN-related angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.

Effects of mifepristone on invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo.

To investigate the effects of mifepristone on the invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 and its mechanisms. After incubation with various concentrations of mifepristone (5, 10, 20 micromol/L), the adhesion to artificial basement membrane, Matrigel, and the migration of MKN-45 cells were assayed using MTT assay and Transwell cell culture chambers, respectively. Enzyme- linked immunoabsorbent assay (ELISA) and flow cytometry were used to determine the expression of vascular endothelial growth factor (VEGF) and integrin beta3 in the cells. After subcutaneous transplantation of MKN-45 cells in nude mice, mifepristone (50 mg/kg.d) was administrated subcutaneously for 8 wk to assess its effects on tumor metastasis. Immunohistochemical analysis was used to detect the expression of VEGF and microvascular density (MVD) in xenografted tumors. Mifepristone dose-dependently inhibited the heterotypic adhesion to Matrigel of MKN-45 cells. The inhibition was accompanied by a significant down-regulation of integrin beta3 expression in the cells. After incubation with 5, 10, 20 micromol/L mifepristone, the number of migrated MKN-45 cells was 72+/-8, 50+/-6, 41+/-5 in experiment group, and 94+/-16 in control group (P<0.01). Meanwhile, secreted VEGF protein of MKN-45 cells in mifepristone-treated group (14.2+/-2.9, 8.9+/-3.1, 5.4+/-2.1 ng/g per liter) was significantly lower than that in control group (22.7+/-4.3 ng/g per liter, P<0.01). In vivo, mifepristone decreased the number of metastatic foci in lungs of nude mice and down-regulated the expression of VEGF and MVD in the xenograted tumors. Mifepristone can effectively inhibit the invasive and metastatic potential of human gastric adenocarcinoma cell line MKN-45 in vitro and in vivo through inhibition of heterotypic adhesion to basement membrane, cell migration and angiogenesis.

Vascular endothelial growth factor and microvascular density in esophageal and gastric carcinomas.

To observe the relationship between the expression of vascular endothelial growth factor (VEGF), microvascular density (MVD) and the pathological characteristics of esophageal and gastric carcinomas. S-P immunohistochemical staining was used to investigate the expression of VEGF in all the specimens. The antibody against factor VIII-related antigen was used to display vascular endothelial cells, and MVD was examined by counting the factor VIII-positive vascular endothelial cells. The positive rates of VEGF expression in esophageal carcinoma and gastric carcinoma were 81.36 % and 67.5 % respectively, and the MVD averaged 41.81+/-8.44 and 34.36+/-9.67 respectively, which were higher than those in benign diseases. The expression of VEGF and MVD were closely correlated with the degree of differentiation, lymphatic metastasis, but not related to depth of cancer invasion. In early stage gastric carcinoma, the rate of expression of VEGF and MVD was lower than that in progressive gastric carcinomas. The expression of VEGF is correlated with tumor angiogenesis, and VEGF plays an important role in new blood vessels formation, the expression of VEGF and MVD play an important role in tumor growth and metastasis. MVD and the expression of VEGF may be two important indexes for patients' prognosis.

Meningioma-associated brain oedema: the role of angiogenic factors and pial blood supply.

Approximately 60% of meningiomas are associated with perilesional brain oedema. Several aspects have been evaluated in order to understand the pathophysiological mechanisms of oedema (age, sex of the patient, size and location of the tumour, histotype, grading), although at present they have yet to be completely clarified. We focused on pial blood supply, microvascular density (MVD) and angiogenic growth factors (i.e. vascular endothelial growth factor--VEGF) in order to evaluate their putative role in the development of brain oedema. We retrospectively studied 55 patients with intracranial meningiomas. Computerized tomography (CT) and angiographic studies were obtained in all cases. The angiograms provided an accurate differentiation between pial and dural blood supply, concomitantly with its semi-quantitative evaluation. The location and the volume of oedema, in relation to the meningioma surface, was evaluated using CT scans, as an oedema index (E/I). We also determined the expression of VEGF and MVD using standard immunohistochemical methods. Thirty-two out of 55 meningiomas presented peritumoural oedema, with an angiographic blush ranging from 2 to 4; VEGF protein was expressed in 27 out of 32 cases, independent of grade or histotype of tumours. In all patients, MVD ranged from 4 to 33.3 vessels (median value: 10.6). A significant relationship was found between the expression of VEGF and MVD (p = 0.0003) and between VEGF and E/I (p = 0.0023). Moreover, the E/I ratio was related to the blush (p = 0.0005). A significant association was also present between VEGF expression and pial blush (p = 0.0001). Our data confirm the central role of VEGF and pial blood supply in the pathogenesis of peritumoural oedema and support the hypothesis that the development of oedema in meningioma is vasogenic in type.