Tumor angiogenesis in breast cancer: Its importance as a prognostic indicator and the association with vascular endothelial growth factor expression

Summary The importance of tumor angiogenesis in the process of tumor growth and progression in solid tumors has been widely accepted. We have investigated the significance of tumor angiogenesis as a prognostic indicator in a retrospective study including 328 primary breast cancer patients. The postoperative survey demonstrated that the microvessel density (MVD) evaluated by immunocytochemical staining for factor VIII-related antigen is a potent prognostic indicator. The relapse-free survival (RFS) rate of patients with over 100 microvessels/mm² in a microscopic field was significantly worse compared to that of patients with less than 100 microvessels/mm² (p<0.00001). The significance of MVD was found in both node-negative and node-positve patients (p< 0.005 and p<0.01, respectively). Multivariate analysis confirmed that MVD is an independent prognostic indicator for RFS. In the background factor analysis, MVD was significantly correlated with the number of metastatic nodes (p<0.01). In addition, the immunocytochemical analysis for vascular endothelial growth factor (VEGF) demonstrated a close association between the increase in MVD and the expression of VEGF (p<0.001). VEGF status also was a significant prognostic indicator in univariate analysis for RFS (p<0.01). It was concluded that MVD is a potent prognostic indicator in primary breast cancer. Furthermore, it was also suggested that VEGF plays crucial roles in the promotion of angiogenesis in breast cancer.Abbreviations MVD microvessel density - VEGF vascular endothelial growth factor     

Vascular endothelial growth factor-121 mRNA expression and neomicrovessel density in primary lung cancer

The correlation between vascular endothelial growth factor (VEGF)121 mRNA expression and microvessel density was examined in 42 cases of primary lung cancer. Microvessels in tumors were highlighted by staining endothelial cells for factor VIII, CD31, and BNH9. The microvessel density in a high VEGF121 expressing group was significantly greater than that in the low expressing group in the assessment with anti-CD31 antibody. The difference of survival stratified by the vessel density was significant in patients. with stage I disease. The results suggest a relationship between neomicrovessel density and VEGF121. VEGF121 may be a useful marker of the tumor neovascularization in lung cancer.     

Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.     

早期三阴性乳腺癌与非三阴性乳腺癌VEGF和MVD表达的比较

目的探讨血管内皮生长因子（vascularendothelialgrowthfactor,VEGF）、微血管密度（microvesseldensity,MVD）在早期三阴性乳腺癌组织中与非三阴性乳腺癌组织中的表达水平。方法采用免疫组化染色法检测我院2007年1～12月行根治性手术切除、经病理证实的乳腺癌组织蜡块89例（其中早期三阴性乳腺癌21例,非三阴性乳腺癌68例）癌组织中VEGF的表达及MVD值,分析VEGF的表达及MVD值在早期三阴性乳腺癌和非三阴性乳腺癌组织中的差别,以及VEGF和MVD之间的关系。结果早期三阴性乳腺癌癌组织中VEGF表达的阳性率高于非三阴性乳腺癌（71．43％vs25．00％,P〈O．001）。MVD在早期三阴性乳腺癌与非三阴性乳腺癌组间的差异无统计学意义（P=0．105）。结论VEGF表达与乳腺癌血管生成密切相关,VEGF及MVD在三阴性乳腺癌中的生物学意义值得进一步探讨。     

The Determination of VEGF and MVD,among Patients with Primary Breast Cancer

The purpose of the study was to ascertain the value of assessment of vascular endothelial growth factor (VEGF) levels and microvessel density, and to search for correlations between them, in women with breast cancer. The assessment considered factors such as the stage of clinical disease advancement-according to International Union Against Cancer, the grade of histological malignancy, status of axillary lymph nodes and the size of the primary tumour. The concentration of VEGF was assessed in the plasma of 103 women with breast cancer, using an immunoenzymatic method (Quantikine test of R&D Systems). Assessment of microvessel density was performed using histopathological immunoperoxidase methods, using an anti-von Willebrand factor antibody (DAKO A/S). A statistically significant relationship was found between rising VEGF levels and microvessel density in women with breast cancer, when compared to values from a control group. A correlation was found between VEGF concentration and microvessel density (MVD) values. Statistically significant differences were found between VEGF levels of patients in stages I, II and III of clinical disease advancement. For MVD, differences were found only between stages I and III. A statistical relationship was also found between VEGF and MVD and tumour size. Similar results were found between VEGF concentrations in women with metastases to the axillary lymph nodes and cytokine levels in women with no metastases. The results of the study suggest that the degree of tumour vascularization and the concentration of VEGF may represent valuable indicators for the assessment of the angiogenic process in women with breast cancer.     

Expression of vascular endothelial growth factor in patients with testicular germ cell tumors as an indicator of metastatic disease

BACKGROUND: Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor (PD-ECGF) are involved in increased angiogenic activity and disease progression in solid tumors. However, there is no information regarding the association of these angiogenic factors with clinicopathologic findings in testicular germ cell tumors (GCTs). METHODS: The authors examined the expression of VEGF and TP as well as microvessel density in GCTs and their association with clinicopathologic findings. Expression of VEGF and TP and microvessel density were examined immunohistochemically in 80 GCTs, including 33 seminomas (25 tumors with organ-confined disease and 8 with metastasis) and 47 nonseminomatous testicular GCTs (NSGCTs) (20 tumors with organ-confined disease and 27 with metastasis). Expression of VEGF also was examined in four GCTs and one nonneoplastic testis by immunoblotting. RESULTS: VEGF protein was expressed more highly in GCTs compared with nonneoplastic testes. VEGF expression in GCTs was correlated significantly with microvessel count (P < 0.001). Both VEGF expression and microvessel count were correlated with metastasis in seminoma (P = 0.008 and P < 0.001, respectively), but only VEGF expression was identified as statistically significant by multiple regression analysis (P = 0.006). Conversely, four variables (VEGF expression, microvessel count, the presence of venous invasion, and the presence of embryonal carcinoma elements in the primary tumor) were correlated with metastasis in NSGCT (P < 0.001, P < 0.001, P = 0.004, and P = 0.029, respectively). However, multiple regression analysis revealed that only VEGF expression and microvessel count were significant factors for metastasis (P < 0.007 and P < 0.001, respectively). In contrast, high levels of TP were observed in infiltrating cells, but not in the majority of cancer cells. CONCLUSIONS: The findings of the current study suggest that VEGF expression is involved in tumor development, angiogenesis, and metastasis in GCT.     

Vascular endothelial growth-factor expression and angiogenesis in nonsmall cell lung carcinomas

Vascular endothelial growth factor (VEGF), a secreted endothelial-specific growth factor, and microvessel density was examined in 204 primary non-small cell lung carcinomas. The expression of VEGF was evaluated by immunohistochemical staining using an anti-VEGF antibody. Positive staining was obtained in 125 out of 204 cases (61%). Tumor vascularity was quantitatively assessed by microvessel counting after staining with the endothelial-specific marker factor VIII. The mean microvessel count for all patients was 9.6+/-10.4. Expression of VEGF was closely associated with increment of microvessel density. Postoperative follow-up of patients demonstrated a trend that survival time of patients with VEGF-positive tumors was worse than that of patients with VEGF-negative tumors. In contrast, microvessel density was not a prognostic factor.     

The natural progression of microvasculature in primary tumor and lymph node metastases in a breast carcinoma model: relationship between microvessel density, vascular endothelial growth factor expression, and metastatic invasion

The natural course of tumor microvascularity in rat MTLn3 mammary adenocarcinomas was studied. The relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and histopathology was compared in primary and metastatic axillary (ALN) and inguinal lymph node (ILN) tumors over 5-6 tumor doublings. Excised tumors were examined for (i) MVD assessed by immunostaining with anti-CD31 antibody, (ii) VEGF expression assessed by immunostaining with anti-VEGF antibody, and (iii) histopathologic extent of metastatic lymph node invasion. MVD and VEGF scores rose asymptotically with increasing tumor weight in both primary and metastatic tumors. The MVD saturation level was significantly greater for primary tumors (MVD = 22) than for ALNs or ILNs (MVD = 14). Maximal VEGF score was not statistically different between the three kinds of tumors, however the rate of rise in VEGF expression was different. Near-maximal VEGF expression occurred early in tumor growth, preceding microvessel development. Both MVD and VEGF expression in lymph nodes were proportional to the pathology score characterizing increasing metastatic invasion. LNMs limited to the subcapsular sinus had the lowest MVD, indicating an ability to survive without significant vasculature. These findings underscore the differences in angiogenesis between primary tumors and LNMs and have implications for therapy of metastatic cancer.     

乳腺肿瘤癌变过程中血管生成与VEGF表达相关性研究

Objective  

The aim of the study was to detect the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in breast benign tissues and malignant tumors to clarify the relationship between VEGF expression, angiogenesis and breast carcinoma occurrence.     

Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer

Macrophage migration inhibitory factor (MIF) is known to be an important contributor to tumor progression. Overexpression of MIF has been reported in different types of tumors. However, the correlation between MIF expression and tumor pathologic features in patients with breast cancer has not been elucidated. In this study, we examined the expression of MIF, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in human tissues with or without tumor. In addition, we investigated the expression of MIF in MDA-MB-231, MCF-7 (breast cancer cell lines) and MCF-10A (epithelial cell line) cells, and its effect on VEGF and IL-8. We found that MIF was overexpressed in breast cancer tissues compared with normal ones. The level of MIF showed the positive correlation between the expression of IL-8 and tumor microvessel density (MVD). The patients with positive MIF expression in tumor tissues showed a significantly worse disease-free survival compared with negative ones. Increased MIF serum levels were also found to correlate with higher levels of IL-8 in the sera of the patients with breast cancer. In vitro experiments successfully detected MIF in breast cell lines. However, the expression level of it by normal epithelial cells was much less than that of cancer cells. Exogenous MIF did not cause endothelial tube formation and migration but induced a dose dependent increase in VEGF and IL-8 secretion in breast cancer cell lines. In summary, our studies show that human breast cancer tissue expresses MIF. Its in vitro effect on VEGF and IL-8 indicates that MIF may contribute to tumor in angiogenesis and thus play an important role in the pathogenesis of breast cancer.     

Vascular endothelial growth factor (VEGF) in human breast cancer: Correlation with disease-free survival

Studies have shown that microvessel density influences breast-cancer prognosis. Since tumor angiogenesis is considered to be substantially affected by the excretion of vascular endothelial growth factor (VEGF) from tumor cells, we examined whether VEGF concentration is different in malignant and in non-malignant breast tissue. It was also of interest to discover whether intratumoral VEGF concentration influences disease-free survival (DFS) of breast-cancer patients. Analysis is based on 120 tissue specimens taken from breast fibromas (n = 23), normal epithelial breast tissue adjacent to fibromas (n = 8) and invasive breast cancer (n = 89). VEGF concentration was quantified by using an immunoassay. Microvessel density was determined by immunostaining for factor-VIII-related antigen. Median VEGF concentration is given in pg/mg protein (25%-quantile—75%-quantile) and it was 0 (0–1.8) in normal breast tissue, 9.8 (0.52–43.0) in fibromas and 130.4 (50.8–362.2) in invasive carcinomas. A univariate Cox model revealed that node status, tumor size, estrogen-receptor concentration, histological grading and microvessel density were prognostic factors for disease-free survival in breast cancer. We found a significant correlation between VEGF concentration and microvessel count, but VEGF concentration did not significantly influence disease-free survival. Although VEGF protein was found at a significantly higher concentration in malignant than in non-malignant tissue, determination of intratumoral VEGF protein by an enzyme immunoassay was not prognostically relevant in our patient population. Int. J. Cancer 74:455–458, 1997. © 1997 Wiley-Liss, Inc.     

The expression of transforming growth factor-beta1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma.

BACKGROUND: Transforming growth factors beta (TGFs beta) are involved in a variety of important cellular functions, including cell growth and differentiation, adhesion, migration, extracellular matrix formation, and immune function. Moreover, it has been reported that TGFs beta are correlated with angiogenesis. However, the role of TGF-beta as an angiogenic factor in gastric carcinoma is still unclear. METHODS: TGF-beta1 expression was determined in 101 patients with gastric carcinoma by immunohistochemical procedures, and this expression was compared in the current study with both the expression of vascular endothelial growth factor (VEGF), which is thought to be the most potent angiogenic factor, and microvessel density, to evaluate the effect of TGF-beta1 on the angiogenesis of gastric carcinoma tissues. RESULTS: TGF-beta1 expression was detected in 23 tumors (22.8%). TGF-beta1 expression was more frequent in differentiated than in undifferentiated gastric carcinoma. Furthermore, TGF-beta1 expression was significantly correlated with the depth of invasion and the stage of disease. There was a close correlation between TGF-beta1 expression and VEGF expression. There was no correlation between TGF-beta1 expression and microvessel density, whereas VEGF expression was significantly correlated with microvessel density. With regard to prognosis, the 5-year survival rate was 55.9% for patients with TGF-beta1 positive tumors and 67.0% in patients with TGF-beta1 negative tumors. Accordingly, the prognosis for patients with TGF-beta1 negative tumors was significantly better than that for patients with TGF-beta1 positive tumors. Multivariate analysis indicated that lymph node metastasis, tumor size, and TGF-beta1 expression were independent prognostic factors. CONCLUSIONS: These results suggest that TGF-beta1 might be associated with tumor progression by indirectly stimulating angiogenesis through the up-regulation of VEGF expression in gastric carcinoma.     

Angiostatin expression in ovarian cancer

Angiostatin is a potent inhibitor of neovascularization, tumor growth and metastasis. We examined the expression of angiostatin and vascular endothelial growth factor (VEGF) through immunohistochemical analysis, along with microvessel density, in primary tumors obtained from 55 ovarian carcinoma patients. Angiostatin expression was not related to either stage of disease or histology. However, VEGF expression and microvessel density were related to stage of disease. Angiostatin expression did not correlate with VEGF expression. Microvessel density correlated with VEGF, but not angiostatin expression. Univariate analysis revealed that lack of angiostatin expression, VEGF expression, microvessel density and advanced stage of disease were significant risk factors for reduced survival. Multivariate analysis revealed that lack of angiostatin expression and advanced stage of disease were significant risk factors for reduced survival. Survival time was longer in patients with angiostatin-positive and VEGF-negative tumors than in patients with angiostatin-negative and VEGF-positive tumors. The presence of angiostatin expression and absence of VEGF expression are favorable prognostic factors with regard to survival in ovarian carcinoma patients.     

Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival

Background: Angiogenesis, the process whereby endothelial cells divide and migrate to form new blood capillaries, has been assessed in tumours by measuring microvessel density. High microvessel density is a significant adverse prognostic factor in breast cancer. The angiogenic factor, basic fibroblast growth factor (bFGF), has been associated with tumourigenesis and metastasis in several human cancers. There are few quantitative studies of bFGF expression in normal tissues compared to cancer.Patients and methods: We have measured bFGF levels in 149 human primary breast carcinomas and assessed the findings in relation to microvessel density, oestrogen receptor (ER) and epidermal growth factor receptor (EGFR).Basic FGF levels were measured by ELISA. Western blotting and immunohistochemistry were carreid out to confirm the presence of bFGF.Results: Levels of bFGF were more than 10-fold higher in tumour cytosols compared to reduction mammoplasty tissue and 3-fold compared to non neoplastic cytosols from the same breast as the tumour (P < 0.0001). Immunohistochemistry showed bFGF protein was localised exclusively in the stroma whereas no bFGF staining was observed in the epithelial cells. High bFGF levels were significantly related to high ER (P = 0.01). Similarly, high bFGF levels were significantly related to low grade (P = 0.046) and to small tumour size (P = 0.04). No significant relationship was observed between bFGF and microvessel count, EGFR or age. In univariate analysis and in a Cox proportional hazard model bFGF did not reach significance for overall or relapse free survival.Conclusions: Our results show that although bFGF is elevated in breast carcinomas compared to normal breast tissue it is not related to microvessel density and it is not an independent predictor of survival in breast cancer patients. Basic FGF may be one of multiple factors that synergise with other growth factors such as VEGF to enhance angiogenesis.     

Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density

Summary Angiopoietin (Ang) is a ligand for the endothelium-specific tyrosine kinase receptor Tie-2, while a shift in the Ang-1:Ang-2 expression ratio in favor of Ang-2 was found to be associated with tumor angiogenesis. In the present study, we analyzed the immunohistochemical expression of Ang-2 in a series of 198 breast cancers, in which VEGF expression and microvessel density (MVD) were previously determined. Ang-2 expression was negative in 24 (12%), positive in 50 (25%) and strongly positive in 124 (63%) of 198 cases. A significant correlation was found between Ang-2 and VEGF expressions (p=0.0004) and between Ang-2 expression and MVD (p=0.0006), while a high MVD was found in 10 (77%) of 13 tumors with a strongly positive VEGF and positive Ang-2 expression and in 40 (71%) of 56 tumors with a strongly positive VEGF and strongly positive Ang-2 expression. Although there was no difference in the disease free survival (DFS) stratified according to Ang-2 expression alone, the 69 patients with a strongly positive VEGF and a strongly positive or positive Ang-2 expression had a significantly (p=0.0316) worse DFS than those with other combinations of VEGF and Ang-2 expressions. A multivariate analysis indicated lymph node metastasis and MVD to be independently significant prognostic factors for DFS, while the combination of VEGF and Ang-2 expressions was not a significant factor for DFS. In conclusion, the Ang-2 expression was found to be closely correlated with VEGF expression and MVD in breast cancer, while a high MVD was frequently found in tumors with a high expression of both VEGF and Ang-2. The survival analysis demonstrated a high MVD, which was induced by a high expression of both VEGF and Ang-2, to therefore have a strong prognostic significance in breast cancer.     

Association of resistance-related protein expression with poor vascularization and low levels of oxygen in human rectal cancer

Rectal carcinomas of previously untreated patients were analyzed for oxygen status using a computerized polarographic needle electrode histograph. Microvessel density and expression of c-jun, vascular endothelial growth factor (VEGF) and several resistance-related proteins (glutathione S-transferase-π, GST; thymidylate synthase, TS; metallothioneine, MT) were determined using immunohistochemistry. To examine whether a relationship exists between intratumoral vessel density and tumor oxygenation, microvessel counts were determined in a 400× field using factor-VIII-related antigen and were correlated with the corresponding pO₂ values. Linear regression analysis revealed a significant relationship between vessel density and oxygenation status of the tumors. Expression of c-jun, VEGF and resistance-related proteins was correlated with microvessel counts and pO₂ values. Significantly lower vessel counts were found in GST- and MT-positive tumors and in tumors with overexpression of c-jun and VEGF than in negative tumors. In addition, significantly lower pO₂ values were found in c-jun- and VEGF-positive tumors as well as a tendency for pO₂ values to be lower in tumors where MT, GST and TS were expressed. These data show that expression of c-jun, VEGF, and resistance-related proteins is linked with poor vascularization and low oxygenation status in rectal cancer. © 1996 Wiley-Liss, Inc.     

Expression of vascular endothelial growth factor in renal cell carcinoma and the relation to angiogenesis and p53 protein expression

BACKGROUND AND OBJECTIVES: Vascular endothelial growth factor (VEGF) seems to play an important role in tumor angiogenesis. The tumor-suppressor gene p53 has been thought to regulate VEGF expression. We investigated the effect of VEGF expression on renal cell carcinoma (RCC) and the correlation between the expression of VEGF and tumor angiogenesis and p53 protein expression. METHODS: Sixty-two RCCs were examined by immunohistochemical studies with anti-VEGF, anti-p53, and anti-CD34 antibodies. RESULTS: Forty tumors (80.6%) were classified as VEGF positive, and 28 tumors (45.2%) were positive for p53 protein. The microvessel density was 75.3 +/- 33.5. A significant correlation was found between VEGF expression and both the nuclear grade (P < 0.05) and the TNM stage (P < 0.05). The tumors with VEGF expression had a significantly higher microvessel density than those without VEGF expression (P < 0.01). There was no statistically significant correlation between p53 protein and VEGF expression. No statistically significant differences in survival were found to be associated with microvessel density, VEGF expression or p53 protein expression. By using multivariate survival analyses, nuclear grade (P < 0.05) and TNM stage (P < 0.05) were the only independent prognostic factors. CONCLUSIONS: Our data do not show a direct regulation of VEGF expression by p53. We suggest that VEGF expression plays a role in the promotion of angiogenesis in RCC.     

血管内皮生长因子在大肠癌中的表达及预后价值

目的：研究血管内皮生长因子（ＶＥＧＦ）在朋肠癌中的表达及其与临床病理特征的关系。方法：采用免疫组织化学方法检测８０例大肠癌手术标本肿瘤组织内的血管内皮生长因子（ＶＥＧＦ）和微血管计数（ＭＶＤ）。结果：ＶＥＧＦ表达阳性率为６１．２％,ＶＥＧＦＤ表达阳性的肿瘤组织其ＭＶＤ明显高于阴性者（Ｐ＜０．０５）。ＶＥＧＦ表达与肿瘤的浸润性生长、浆膜浸润、淋巴结转移和肝转移有明显相关性（Ｐ＜０．０５）。此外,ＶＥ     

Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer

Vascular endothelial growth factor (VEGF) has emerged as one of the most important angiogenic growth factors from experimental in vitro and in vivo studies. In the present study, we investigated the relationship between VEGF expression and microvessel density (MVD) and defined their prognostic relevance on a series of 242 patients with node-negative breast cancer, using immunohistochemical methods. In parallel, estrogen and progesterone receptors were quantitatively assessed using the dextran-charcoal technique and cell proliferation was evaluated as S-phase cell fraction according to (3)H-thymidine-labeling index (TLI). The percentage of VEGF-expressing cells varied from 0-95% in the different tumors and was unrelated to menopausal status, tumor size or steroid receptor status. Conversely, a significant inverse relation was observed with patient age or tumor cell proliferation, albeit with very poor correlation coefficients. A significant relation was observed between VEGF expression and MVD (r(s) = 0.55, p < 0.001). Clinical outcome analyzed as a function of high and low VEGF expression showed slight differences in terms of both disease-free survival (DFS) and overall survival (OS) that never reached statistical significance. Moreover, the trend was paradoxically in favor of patients with highly VEGF-expressing tumors. Finally, DFS and OS curves, when analyzed as a function of VEGF expression or MVD, were superimposable. In conclusion, our study did not highlight a prognostic relevance of VEGF expression in patients with node-negative breast cancer, as already observed for MVD.     

Correlational study of vascular endothelial growth factor expression and microvessel density in primary malignant gastric lymphoma

Vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in primary malignant gastric lymphoma were studied, and their correlation as well as its clinical significance was analyzed. Thirty-five patients diagnosed with primary malignant gastric lymphoma were enrolled in this study. VEGF expression in the tumor tissues was detected by immunohistochemistry. Microvessel density in tumors was counted with Weidner's method and compared with MVD in normal tissues 5 cm away from tumor site. Collected data were analyzed statistically. Our results showed that VEGF expression and MVD in tumor tissues were higher than those in normal tissues, and the difference between these two groups was significant (P < 0.01). As VEGF expression was elevated, MVD was also increased in tumor tissues. Statistical analysis revealed that VEGF expression was positively correlated with MVD (r = 0.392, P < 0.05). VEGF was highly expressed in primary malignant gastric lymphoma and positively correlated with MVD. These results strongly suggest that anti-angiogenesis therapy investigated in gastric lymphoma is a prospective clinical trial.