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ABSTRACT Objective: VEGF-D is a potential biomarker for lymphangioleiomyomatosis (LAM); however, its diagnostic performance has yet to be systematically studied. Methods: We searched PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library to identify primary studies on VEGF-D in relation to the diagnosis of LAM. The quality of the studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Summary estimates of diagnostic accuracy were pooled using a bivariate random effects model. Subgroup and sensitivity analyses were performed to explore possible heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was applied to rate the quality of evidence and indicate the strength of recommendations. Results: Ten studies involving 945 patients were of high risk in quality, as assessed using the QUADAS-2. The pooled diagnostic parameters were indicated as follows: sensitivity = 0.82 (95% CI, 0.71-0.90); specificity = 0.98 (95% CI, 0.94-0.99); and diagnostic OR = 197 (95% CI, 66-587). The AUC of summary ROC analysis was 0.98. The subgroup and sensitivity analyses revealed that the overall performance was not substantially affected by the composition of the control group, prespecified cutoff value, the country of origin, or different cutoff values (p > 0.05 for all). A strong recommendation for serum VEGF-D determination to aid in the diagnosis of LAM was made according to the GRADE. Conclusions: VEGF-D seems to have great potential implications for the diagnosis of LAM in clinical practice due to its excellent specificity and suboptimal sensitivity.
RESUMO Objetivo: O VEGF-D é um potencial biomarcador para linfangioleiomiomatose (LAM); entretanto, seu desempenho diagnóstico ainda não foi sistematicamente estudado. Métodos: Foram realizadas buscas nos bancos de dados PubMed, EMBASE, Scopus, Web of Science e Cochrane Library para identificar estudos primários sobre o VEGF-D com relação ao diagnóstico de LAM. A qualidade dos estudos foi avaliada por meio da ferramenta Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). As estimativas sumárias de acurácia diagnóstica foram combinadas utilizando um modelo bivariado de efeitos aleatórios. Análises de subgrupo e de sensibilidade foram realizadas para explorar possíveis heterogeneidades. O sistema Grading of Recommendations Assessment, Development, and Evaluation (GRADE) foi aplicado para avaliar a qualidade das evidências e indicar a força das recomendações. Resultados: Dez estudos envolvendo 945 pacientes eram de alto risco em qualidade, segundo a ferramenta QUADAS-2. Os parâmetros diagnósticos combinados foram indicados da seguinte forma: sensibilidade = 0,82 (IC95%: 0,71-0,90); especificidade = 0,98 (IC95%: 0,94-0,99); e OR diagnóstica = 197 (IC95%: 66-587). A ASC da análise summary ROC foi de 0,98. As análises de subgrupo e de sensibilidade revelaram que o desempenho global não foi substancialmente afetado pela composição do grupo controle, valor de corte pré-especificado, país de origem ou diferentes valores de corte (p > 0,05 para todos). Uma forte recomendação para a dosagem de VEGF-D sérico para auxiliar no diagnóstico de LAM foi feita de acordo com o sistema GRADE. Conclusões: O VEGF-D parece ter grandes implicações potenciais para o diagnóstico de LAM na prática clínica em virtude da excelente especificidade e sensibilidade subótima.
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Humans , Lymphangioleiomyomatosis/diagnosis , Biomarkers , ROC Curve , Sensitivity and Specificity , Vascular Endothelial Growth Factor DABSTRACT
Objective To investigate the expression of hypoxia-inducible factor-1 alpha (HIF-1 α),vascular endothelial growth factor-A (VEGF-A) and vascular endothelial growth factor-D (VEGF-D)in hypoxic environment as well as the relationship between HIF-lα and VEGF-D.Methods Human esophageal cancer cell line EC9706 was cultured under hypoxia environment for 6,12 and 24 h,the cell radiosensitivity was evaluated by survival curve.HIF-1 α siRNA was constructed and transfected into human EC9706 cells.Protein expressions of HIF-1 α,VEGF-A and VEGF-D were analyzed by Western blot before and after RNA interference.Results EC9706 cells under hypoxia showed radioresistance with a SF2 of 0.62 higher than that of normoxic cells of 0.43.Moreover,the protein expressions of HIF-1α,VEGF-A and VEGF-D were all increased (F =205.24,227.88,130.55,P ＜0.05) due to hypoxia treatment.On the contrary,after HIF-1α siRNA transfer,the protein expressions of HIF-1α,VEGF-A and VEGF-D in EC9706 cells were not influenced by hypoxia treatment.Conclusions EC9706 cells in hypoxic environment was radioresistance,and the upexpressions of HIF1α,VEGF-A and VEGF-D may be involved.
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Objective To detect the expression of vascular endothelial growth factor(VEGF)-C and VEGF-D in normal gastric tissue and gastric carcinoma tissue,and further investigate the relationship between VEGF-C,VEGF-D and lymph vessel density (LVD),lymph node metastasis.Methods The expression of VEGF-C and VEGF-D in gastric carcinoma tissues were examined by using SP immunohistochemical method in 30 normal gastric tissue and 75 gastric carcinoma tissue respectively.The lymph vessel were marked by LYVE-1 and calculated LVD.Results The rate of positive expression of VEGF-C and VEGF-D in gastric carcinoma tissue was significantly higher than that in normal gastric tissue,there was significant difference [73.3 ％ (55/75) vs.33.3 ％ (10/30),66.7 ％ (50/75) vs.30.0 ％ (9/30),P ＜0.01].The level of LVD in gastric carcinoma tissue with lymph node metastasis (40 cases) was significantly higher than that in without lymph node metastasis (35 cases)[(8.85 ± 1.24)/HP vs.(4.75 ± 1.04)/HP](P =0.000).The level of LVD increased when the expression level of VEGF-C and VEGF-D gradually went up.Conclusions The level of LVD increases in gastric carcinoma tissue.VEGF-C and VEGF-D are two significant factors for LVD and lymph node metastasis.
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Objective To investigate the expressions of vascular endothelial growth factor (VEGF)-C,-D and VEGF receptor-3 (VEGFR-3/Flt-4) in pN0 early gastric cancer (ECG) and their relationship with lymph node micrometastasis.Methods From January 2005 to January 2010,the paraffin-embedded specimens of 61 pN0 ECG were collected.The expressions of VEGF-C,VEGF-D and VEGFR-3 in 61 pN0 early gastric cancer tissue,25 adjacent tissue and CAM5.2 expression in 868 hematoxylin-eosin staining negative lymph nodes were detected by immunohistochemical assay.The rate of lymph node micrometastasis of 61 pN0 ECG was evaluated.According to the data type,t test,x2 test or Fisher exact probability were performed for the relationship analysis between the expressions of VEGF-C,VEGF-D and VEGFR-3 in pN0 stage ECG and lymph node micrometastasis.Results The high expressions of VEGF-C,VEGF-D and VEGFR-3 in the 61 pN0 ECG were 34.4％ (21/61),34.4％ (21/61) and 44.3％ (27/61) respectively,which were higher than those of adjacent tissues [12.0％ (3/25),8.0％ (2/25) and 16.0％ (4/25) respectively] (x2=4.433,6.321 and 6.144 respectively,all P＜0.05).There were 10 cases (16.4％) of pN0 ECG with lymph node micrometastasis.In pN0 ECG,the low expressions of VEGF-C and VEGFR-3 in negative Flt-4 vascular invasion (FVI) were common than positive FVI (x2 =15.828,6.879 and 9.244,all P＜0.05).The high expressions of VEGF-C and VEGFR-3 were related to the depth of tumor invasion (x2 =5.561 and 5.678,both P＜0.05),the density of VEGFR 3 positive vascular (FVD) (t=2.987and 5.652,both P＜0.01) and lymph node micrometastasis (x2 =6.705 and 6.192,both P＜0.05),but not related to the degree of differentiation (P＞0.05).However,the high expression of VEGF-D was not related to depth of tumor invasion,FVD and lymph node micrometastasis (all P＞0.05),but related to the degree of differentiation (x2 =8.472,P =0.004).The high expressions of VEGF-C,VEGF-D and VEGFR-3 were not related to gender,age,tumor location,macroscopic type and tumor size (all P＞0.05).Conclusions The high expressions of VEGF-C,VEGFR-3 were related to lymph node micrometastasis in pN0 ECG.Although the high expression of VEGF-D was not related to lymph node micrometastasis,it could indirectly affect lymph node micrometastasis through VEGF-C-VEGFR-3 axis in pN0 ECG.
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Tumor metastasis to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers and serves as a major prognostic indicator for disease progression.Recent studies have revealed that tumor lymphangiogenesisis correlated with lymph node metastasis in experimental cancer models and in several types of human Cancers.Metastatic tumor cells may continue to promote lymphatic vessel growth even after their metastasis to sentinel lymph nodes,likely promoting further cancer spread.Vascular endothelial growth factor-C(VEGF-C)and VEGF-D are the first specific lymphangiogenesis factor identified,and a large number of clinical studies have shown a correlation between tumor expression of VEGF-C or VEGF-D and lymph node metastasis.Additional tumor lymphangiogenesis factors have been recently identifled,including VEGF-A.Importantly,blockade of the VEGFR-3 pathway by specific antibodies,by soluble receptor constructs,and by small molecule kinase iubibitors efficiently inhibits experimental tumor lymphangiogenesis and metastasis and might also represent a novel therapeutic avenue for the treatment of human cancers.
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Objective To explore the expression of endothelial growth factor-D (VEGF-D) and uroki-nase-type plasminogen activator(uPA) in rectal carcinoma and to reveal their correlation to the tumor invasion and metastasis.Methods The expression of VEGF-D and uPA in 30 cases with rectal carcinoma and normal tissue was detected by immunohistochemistry and Western blot.Results The expression of VEGF-D and uPA was de-tected both in tumor tissue and normal tissue, but significantly higher in tumor tissue (P < 0.01), they expressed mostly in endochylema.The expression of VEGF-D or uPA was significantly higher in Dukes' stage C + D than that in Dukes' stage A + B(P <0.01), was also higher in tissues with lymph node metastasis or distant metasta-sis than those without metastasis(P <0.05 ,P <0.01).They were found to be lower in cancer tissue along with the differentiation degree increase(P < 0.05) .Condnsions The overexpression of VEGF-D and uPA in rectal carcinoma may play an important part in the tumorigenesis and progression of rectal carcinoma.
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Objective To investigate the expression of VEGF-D and MMP-2 and explore their relationship with tumor invasion and local metastasis in pancreatic carcinoma.Methods The expression of VEGF-D and MMP-2 in 30 patients with pancreatic carcinomas and 6 cases with normal pancreatic tissues were detected by SABC immunohistochemical method.Results The positive rates of VEGF-D and MMP-2 proteins were 60%(18/30)and 66.7%(20/30)respectively,no expression of VEGF-D and MMP-2 was detected in normal pancreatie tissues.The expression of VEGF-D was significantly correlated with lymph node metastasis(P＜0.05),and the expression of MMP-2 was significantly correlated with lymph node metastasis and tumor local invasion(P＜0.05).The expression of VEGF-D protein Was positively correlated with MMP-2 protein(rs=0.54,P＜0.01).Conclusions There is a significantly positive correlation between high expression of VEGF-D and MMP-2 proteins in pancreatic carcinoma,and they may contribute to the invasive properties of pancreatic cancer.
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Objective To investigate the expressions of vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor-D (VEGF-D) and their relationship with lymph node metastasis in gastric cancer. Methods Eighty patients with gastric cancer had been admitted to our department from January 2005 to December 2005, including 48 with local lymph node metastasis and 32 without local lymph node metastasis. Ten specimens of normal gastric mucosa from patients with gastric ulcer were used as control. The expression of VEGF-C and VEGF-D in serum and tissues were detected. Results The senun levels of VEGF-C and VEGF-D in patients with gastric cancer were significantly higher than those in the control group (χ2= 8.39, P < 0.05). The positive rate of the VEGF-C expression in the sermn of patients with gastric cancer was influenced by the lymph node metastasis (χ2 = 7.01, P < 0.05). The positive rates of the expressions of VEGF-C and VEGF-D in the gastric cancer tissue were 53% (42/80) and 63% (50/80), which were significantly higher than those in the normal gastric mucosa (χ2 =6.44, 6.58, P <0.05). The positive rate of the VEGF-C expression in the tissue of patients with gastric cancer was influenced by the lymph node metastasis (χ2=11.25, P <0.05). Conclusions The expression of VEGF-C is closely related to lymph node metastasis of gastric cancer. The serum levels of VEGF-C can be used as biologic markers in detecting lymph node metastasis of gastric cancer preoperatively.
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Objective: To study the expressions of vascular endothelial growth factor D (VEGF-D) and its receptor fms-like tyrosine kinase-4 (Flt-4) and to determine whether the presence of VEGF-D and Flt-4 was associated with the clinicopathologic characteristics and prognosis of pancreatic cancer. Methods: The expressions of VEGF-D and Flt-4 proteins were examined by immunohistochemical staining in 48 pancreatic cancer tissues, 32 adjacent pancreatic tissues, and 13 normal pancreatic tissue samples. Differences in distribution of VEGF-D or Flt4 were analyzed using the χ2 test. Kaplan-Meier survival analysis was used to estimate survival time and log-rank test was used to compare differences in survival time between the patients with or without VEGF-D or Flt-4 expression. Results: Immunohistochemical analysis revealed that the positive staining rates of VEGF-D and Flt-4 in pancreatic cancer tissues were significantly lower than that in para-cancerous tissues (P < 0.05), but significantly higher than that in normal pancreatic tissues (P < 0.05). Pancreatic cancer tissues with lymph node metastasis had higher expression of VEGF-D and Flt-4 compared with those without lymph node metastasis (P < 0.01). The median survival time and 1-, 2-, 3-year survival rate of VEGF-D-or Flt-4-positive patients were significantly decreased compared with VEGF-D- or Flt-4-negative patients (P < 0.05). Conclusion: VEGF-D and Flt-4 may contribute to lymph node metastasis and may serve as a prognostic factor for pancreatic cancer patients.
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Lymph node metastasis is an important prognostic factor in gastric cancer. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that activates VEGF receptor (VEGFR)-3, a receptor expressed in the lymphatic endothelium. We investigated the clinical value of VEGF-D expression and VEGFR-3 positive vessel density in gastric carcinoma with regard to lymphangiogenesis. Immunohistochemical staining was used to determine the expression of VEGF-D and VEGFR- 3 in specimens from 104 cases of resected gastric cancer. VEGF-D expression was observed in 62.5% of the gastric cancers and in 9.6% of the non-neoplastic gastric tissue. The VEGFR-3-positive vessel density was significantly greater in the VEGFD positive group than the negative group. VEGF-D expression was significantly associated with lymph node metastasis, increased serum CEA levels, and the nonsignet ring cell type. The VEGFR-3-positive vessel density was correlated with tumor size, lymphatic invasion, and lymph node metastasis. The VEGF-D expression and high VEGFR-3-positive vessel density were significant poor prognostic factors for relapse-free survival. These results suggest that VEGF-D and VEGFR-3-positive vessel density are potential molecular markers that predict lymphatic involvement in gastric carcinoma.
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Adult , Aged , Female , Humans , Male , Middle Aged , Immunohistochemistry , Lymphatic Metastasis , Prognosis , Stomach Neoplasms/blood supply , Vascular Endothelial Growth Factor D/analysis , Vascular Endothelial Growth Factor Receptor-3/analysisABSTRACT
Objective To evaluate the role of vascular endothelial growth factor-D(VEGF-D)in lymphangiogenesis of breast cancer,and investigate its relationship with some clinicopathological parameters and prognosis. Methods VEGF-D expression was detected in 85 cases with primary breast carcinoma by immunohistochemistry,and VEGF-D mRNA was detected by RT-PCR.Podoplanin monoclonal antibody was used to mark lymphatic endothelial cell and lymphatic vessel density(LVD) was counted.The relationship among the aboved parameters,clinicopathological parameters and prognosis was analysed. Results It was revealed by immunohistochemistry that VEGF-D expression was ranked by 5 levels: negative,n=5(5.88%);"+",n=17(20%);"++",n=34(40%);"+++",n=22(25.88%),and "++++",n=7(8.24%).VEGF-D expression was associated with tumor lymph node metastasis and TNM clinical stage(P
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Objective To investigate the correlation between the expressions of vascular endothelial growth factor C (VEGF C) and vascular endothelial growth factor D (VEGF D) and the lymph node metastasis of groin and retroperitoneum in human epithelial ovarian carcinoma. Methods The expressions of VEGF C and VEGF D in benign, borderline, and malignant epithelial ovarian tumors were detected by immunohistochemistry and light microscopy. Results The expressions of VEGF C and VEGF D were found in benign, borderline, and malignant epithelial ovarian tumors. The expressions of VEGF C and VEGF D in ovarian carcinomas were significantly higher than those in benign and borderline ovarian tumors. The expression levels of VEGF C and VEGF D were correlated with peritoneal metastasis, lymph node metastasis of groin and retroperitoneum, and clinical stage, but not with distant metastasis, histology type, histological grade, and age. Conclusion Up regulation of VEGF C and VEGF D in epithelial ovarian carcinoma is advantageous to lymph node metastasis. This process may probably be correlated with lymphangiogenesis in tumors.
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Objective To introduce the current studies of the role of vascular endothelial growth factor-C(VEGF-C) and VEGF-D in lymphangiogenesis and lymph node metastasis of gastrointestinal neoplasma.Methods The related literatures in recent 5 years were reviewed.Results The growth factors VEGF-C and VEGF-D enhance lymphangiogenic metastasis of gastrointestinal neoplasma with the property of angiogenesis and lymphangiogenesis.In gastric adenocarcinoma,VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion,lymph node metastasis,venous invasion and reduced 5-year survival rates.The role of VEGF-C in esophageal squamous cancer and colorectal cancer and VEGF-D in colorectal cancer is not certain,with conflicting reports in the published literatures.Conclusion The VEGF-C,VEGF-D/VEGFR-3 signal pathway may become the ideal target for inhibition of tumor proliferation and metastases,antilymphangiogenesis therapy may be a novel potential strategy in tumor biological therapy.
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Objective To explore the expressions of endothelial growth factor-D (VEGF-D) and urokinase-type plasminogen activator (uPA) in colon carcinoma and to reveal their correlation with the tumor invasion and metastasis. Methods The expressions of VEGF-D and uPA were detected by immunohistochemistry and Western blotting in 30 specimens of colon carcinoma and 30 specimens of normal neighbouring colon tissue 5 cm away from the lesions. Results The expressions of VEGF-D and uPA mostly located in endochylema, less in nucleus, of both tumor tissue and normal tissue, and they were significantly higher in tumor tissue than normal tissue (P