Twenty years after：the beautiful hypothesis andthe ugly facts

The limited clinical beneifts from current antiangiogenic therapy for cancer patients have triggered some critical thoughts and insightful investigations aiming to further elucidate the relationship between vessels and cancer. Tumors need blood perfusion but there are mounting evidences that angiogenesis alone does not explain it in all the neoplasms. In this editorial, for a special issue on tumor and vessels published in theChinese Journal of Cancer, we brielfy introduce the history of the evidences that solid tumors can sometimes obtain blood perfusion by alter?native approaches other than sprouting angiogenesis, i.e., vessel co?option and vasculogenic mimicry. This editorial provides also the links to several most recently published discoveries and hypotheses on tumor interaction with blood vessels.     

Mechanisms ofvascularization inmurine models ofprimary andmetastatic tumor growth

Directed capillary ingrowth has long been considered synonymous with tumor vascularization. However, the vascu?lature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting; instead, malignant tumors can acquire blood vessels via alternative vascularization mechanisms, such as intussusceptive microvascular growth, vessel co?option, and glomeruloid angiogenesis. Importantly, in response to anti?angiogenic therapies, malig?nant tumors can switch from one vascularization mechanism to another. In this article, we brielfy review the biological features of these mechanisms and discuss on their signiifcance in medical oncology.     

Distribution of VEGF mRNA in breast cancer with nonradioactive in situ hybridization at electron microscopic levels

Angiogenesis is essential for tumor growth andimportant in tumor metastasis and prognosis. Vascularendothelial growth factor (VEGF) stimulates endothelial proliferation in vitro and angiogenesis in vivo. VEGF expression has been correlated with high vascularity in tumors, including carcinoma of the breast. In situ hybridization analysis provides a meanqualitatively study the heterogeneity of primary tumors and metastasis based on the types of genes transcribed. To study the expression of …     

Implications of vessel co-option in sorafenib-resistant hepatocellular carcinoma

The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well under-stood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma (HCC) where alternate therapies are lacking. We recently published a paper entitled “Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma” in theJournal of the National Cancer Institute, providing a potential explanation for this limited beneift. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vas-culature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment.     

EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND BASIC FIBROBLAST GROWTH FACTOR IN HUMAN NON-SMALL CELL LUNG CANCER AND THEIR CLINICAL SIGNIFICANCE

Solid tumors contain tumor cells and vascular systems[1]. The growth and metastasis of solid tumors beyond 1-2mm in diameter depends on neovascularization. So the study of neovascularization helps to explain the biologic behavior of tumor. Angiogenesis is a complicated process mediated by a variety of angiogenic factors, which include vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(bFGF). VEGF is an endothelial cell-specific mitogen with a pivotal role and may a…     

Detection of VEGF levels in ascites and peritoneal fluid

Angiogenesis is an absolute requirement for the neoplastic growth of solid tumors. It is also essential for tumor invasion and metastasis, facilitating the shedding of tumor cells into surrounding blood vessels. Tumor cells have been shown to secrete a variety of angiogenic factors and thereby induce the local formation of new blood capillaries. Among these factors contributing to angiogenesis, vascular endothelial growth factor (VEGF, also called vascular permeability factor, VPF), a bifun…     

Relationship between Lymphatic Vessel Density and Lymph Node Metastasis of Invasive Micropapillary Carcinoma of the Breast

OBJECTIVE To investigate the relationship between lymphatic vessel density and lymph node metastasis of invasive micropapillary carcinoma (IMPC) of the breast. METHODS The immunohistochemical study for vascular endothelial growth factor-c (VEGF-C), VEGF Receptor-3 (VEGFR-3) and lymphatic vessel density of 51 cases of IMPC were performed, and lymph node metastases were examined by microscopic analysis of these cases. RESULTS In IMPC, VEGF-C was expressed in the cytoplasm and/or on the membrane of the tumor cells, and the expression of VEGF-C showed a positive correlation with lymph node metastasis (P<0.01). Lymphatic vessel density was determined by the number of micro-lymphatic vessels with VEGFR-3 positive staining. Lymphatic vessel density was positively correlated with VEGF-C expression (P<0.01) and lymph node metastasis (P<0.01). The percentage of IMPC in the tumor was not associated with the incidence of lymph node metastasis. The metastatic foci in lymph nodes were either pure or predominant micropapillary carcinoma. CONCLUSION The results suggested that VEGF-C overexpression stimulated tumor lymphangiogenesis, and the increased lymphatic vessel density may be the key factor that influenced lymph node metastasis of IMPC.     

Analysis of p53 and vascular endothelial growth factor and its receptor Flk-1 expression in human gallbladder carcinoma for determination of tumor vascularity

Objective： More and more studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. There is some evidence that p53 mutations cause overexpression of vascular endothelial growth factor （VEGF）, a major inducer of angiogenesis. In addition, there is now growing evidence that several malignancies express receptors for VEGF, especially receptor-2 （Flk-1/KDR）, raising the possibility that the VEGF/VEGF receptor axis may serve as an autocrine pathway in some tumors. We examined the expression of p53 and VEGF and its receptor FlK-1, together with microvessel count （MVC） to investigate the role of VEGF as an angiogenic marker, the presence of VEGF/Flk-1 axis, and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma. Methods： Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, Flk-1 and factor VIII-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage, differentiation grade, MVC, and lymph nodes metastasis. Results： VEGF, Flk-1 expression and positive p53 protein accumulation and BEGF expression was found in 63.3%, 67.3% and 61.2% of tumors, respectively. The expression of Flk-1 was markedly correlated with VEGF （P〈0.05）. The percentage of the patients with both positive VEGF and Flk-1 expressions was 49.0% （24/49）, and their MVC value was markedly higher than that of the others. P53 and VEGF staining status were identical in 55.1% of tumors. The Nevin staging of p53-or VEGF-positive tumors was significantly later than negative tumors. The MVC in p53-or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups. Conclusion： The findings suggest the VEGF/F1 k- 1 axis and p53-VEGF pathway tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression, plus Flk-1 and VEGF expression might be useful for predicting the tumor vacularity and biologic behaviors of gallbladder cancer.     

Combination therapy in cancer：effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor (VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation is far from clear. The most widespread explanation is enhanced delivery of therapeutics due to vascular remodeling, lower interstitial pres-sure, and increased blood lfow. While the antiangiogenic effects on vascular morphology have been fairly consistent in both preclinical and clinical settings, the improvement of tumor vessel function is debated. This review focuses on the effect of anti-VEGF therapy on tumor microenvironment morphology and functions, and its therapeutic beneifts when combined with other therapies. The uptake and spatial distribution of chemotherapeutic agents into the tumor after anti-VEGF are examined.     

Development of the Relationship between Angiogenesis and Tumor Dormancy

Tumor dormancy, a complex and still poorly understood phenomenon, has been defined by the long-term persistence of occult can- cer cells during tumor progression. Recurrence and metastasis may occur just because of an activation of a small portion of the tumor cells. In our view, sustained angiogenesis is considered essential in triggering invasive tumor growth. Here we analyze the correlation between angiogenesis and tumor dormancy, the establishment of tumor dormancy models, the imaging strategies and the new biomarkers for dececting microscopic tumors before or during the angiogenic switch. It imperative to understand the role of an- giogenesis in tumor dormancy, as this will accelerate the development of anti-angiogenesis techniques to induce dormancy and/or eradicate dormant disease.     

Nitric oxide synthase and vascular endothelial growth factor expression in hepatocellular carcinoma and the correlation with angiogenesis

It is now well established that tumor growth and metastasis are angiogenesis dependent[1]. Since Weidner reported microvessel density (MVD) was useful in prognosis of patients with breast cancer[2], the prognostic value of MVD have been certified in several tumors including primary liver cancer[3]. The increasing activity of Nitric oxide synthase (NOS) correlated with tumor angiogenesis[4]. We examined HCC tissue sections immunohistochemically for expression of iNOS, eNOS, VEGF, and …     

环氧化酶-2对鼻咽癌血管生成及预后的影响

Objective： The purpose of this study was to evaluate cyclooxygenase-2 （COX-2） expression in nasopharyngeal carcinoma （NPC） and its correlation with clinicopathologic features, angiogenesis, and prognosis. Methods： The expressions of COX-2 and vascular endothelial growth factor （VEGF） and microvascular density （MVD） were determined with immunohistochemical methods in eighty-six NPC patients followed up over 5 years. Results： Sixty-three tumors （73.3%） were classified as COX-2 positive. COX-2 expression was positively related to VEGF expression （r=0.438, P〈0.01） and correlated with the tumor pathological grade, extent of primary lesion, lymph node metastasis, distant metastasis and shorter survival. Conclusion： Our results suggest that COX-2, being highly expressed and strongly correlated with angiogenesis in nasopharyngeal carcinoma, is apt to be used as a predictor of prognosis, including local recurrence and distant metastasis.     

Significance of inspecting serum VEGF during therapy of tumor

Neovascularization has been shown to be essential for the growth of solid tumor. Several angiogenic factors have been identified, such as transforming growth factors, fibroblast growth factor, platelet-derived endothelial cell factor and vascular endothelial growth factor (VEGF). Because of its ability to increase the permeability of microvasculature to circulating macromolecules and to stimulate tumor angiogenesis. VEGF is considered to play important role in neovascularization and distant…     

Correlation of VEGF and COX-2 Expression with VM in Malignant Melanomas

OBJECTIVE To investigate the relationship between vascular epithelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in melanomas and the expressive difference of VEGF and COX-2 between melanomas with and without vasculogenic mimicry(VM).METHODS Sixty cases of malignant melanomas emoeaaea In paraffin were studied. The tumors were divided into a high-grade malignant group and a low-grade malignant group based on their tumor type, atypia and survival time of the patient. Then tissue microarrays were produced from these paraffin-embedded tumor tissues which were stained for VEGF, COX-2 and PAS. The difference in expression between VEGF and COX-2 in the malignant melanomas was compared using a grid-count. In addition, the tumors were also divided into mimicry and non-mimicry groups based on their PAS staining. Then the differences between the PAS positive and negative areas of the 2 groups were compared.RESULTS In malignant melanomas with VM, VEGF and COX-2 expression was less in tumors in which VM was absent, but VEGF, COX-2 expression in high-grade malignant melanomas was higher than that in low-grade grade malignant melanomas. Expression of VEGF was correlated with COX-2 expression.CONCLUSION VM exists in some high-grade malignant melanomas. The differences and relations between VEGF and COX-2 showed that some high-grade malignant melanomas possess a unique molecular-mechanism of tumor metastasis and blood supply.     

The VEGF signaling pathway in cancer: the road ahead

The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.     

Significance of VEGF and NF-κB Expression in Thyroid Carcinoma

Vascular endothelial growth factor (VEGF), a dimeric 42-kd pro- tein, is a multifunctional cytokine that plays a key role in both physiological and pathological angiogenesis.[1] Angiogenesis is known to be a prerequisite for tumor growth and metastasis.VE…     

肝细胞癌介入栓塞前后血管内皮生长因子和内皮抑素的变化与预后的关系

Objective To study the relationship between the change in serum levels of vascular endothelial growth factor(VEGF) and endostatin (ES) after trascatheter arterial chemoembolization (TACE) and the prognosis of patients with liver carcinoma. Methods Serum VEGF and endostatin levels were measured by enzyme-linked immunoassay in 120 patients with hepatocellular carcinoma before and a week after TACE.Results Among patients with large (diameter ≥5 cm) tumors , the serum levels of ES and VEGF before and after TACE are 43.35 ( ±9.80),48.35 ( ± 10.89), 310.23 (±64.31) ,and 369.10 ( ±60. 11) ng/ml respectively. Among patients with portal vein tumor thrombus, the corresponding figures are 54.28 (±8.78 ),50.28 (±7.51), 331.26 (±63.38) and 400.29 (±60.98) ng/ml. The levels of VEGF and ES were significantly related to the presence of portal vein tumor thrombus, the clinicopathological grade and size of the tumor(P ＜0.05 ). Patients with a higher grade tumor were more likely to have elevated levels of VEGF and ES.So are patients with more advanced stage tumors. In addition, higher levels of VEGF and ES in serum are associated with worse survival. Conclusion Elevated serum VEGF and endostatin levels in patients with hepatocellular carcinoma are closely correlated with the grade and size of the tumor, and the presence of portal vein tumor thrombus. Serum VEGF and ES level may be used for predicting the biological behavior, invasion, metastasis and prognosis of hepatocellular carcinoma.     

裸鼠肺癌移植瘤中NRP-1的表达及其意义

Objective:To establish angiogenesis model of xenografts of lung cancer cell in nude mouse and investigate the expression of the neuropilin-1 (NRP-1) protein in tumors and its role in progression and angiogenesis of lung cancer.Methods:Human lung adenocarcinoma cells A549 were analyzed for the expression of vascular endothelial growth factor165(VEGF165)mRNA using RT-PCR in vitro.TWo groups of nude mice were subcutaneously inoculated with A549 at different tumor-loading time.Two groups of xenografts were jdentified by hematoxylin and eosin (HE) staining.their microvessel density (MVD) were analyzed meanwhile.Two groups were analyzed for the expression of NRP-1 protein and their mean absorbency by using immunohistochemistry and automatic image analysis system respectively.Results:A549 expressed VEGF165 mRNA,and xenografts of A549 in nude mice were successfully established and confirmed by HE staining.The atypia of cancer cells and angiogenesis were occurred in two groups.Two groups of MVD were 13.06±1158.23.61±3.11(vessels/mm2)(P＜0.01).NRP-1 protein was expressed in cytoplasm of vascular endothelium cells and partial tumor cells.Two groups of mean absorbency of NRP-1 were 0.1095±O.0228,0.1784±0.0151 (P＜0.01).Conclusion:The angioqenesis models of xenografts in nude mice with lung cancer cell A549 expressing VEGF165 mRNA at different tumor-loading times were established successfully.The expression of NRP-1 protein and MVD were increased with the tumor progression.Our results demonstrate that NRP-1 protein in lung cancer is related to angiogenesis.