肿瘤血管生成拟态

肿瘤的生长和转移有赖于血管形成。血管生成拟态与经典的血管生成概念不同,是指在没有内皮细胞参与的情况下,由某些肿瘤细胞直接形成具有微循环功能的类血管结构的过程。血管生成拟态能够为肿瘤的生长提供更加良好的血供,并且与侵袭性肿瘤的转移和不良预后密切相关。血管生成拟态的发生机制可能与侵袭性肿瘤细胞类胚胎样表型的逆转有关。     

肿瘤血管生成拟态

肿瘤的生长和转移有赖于血管形成。血管生成拟态与经典的血管生成概念不同，是指在没有内皮细胞参与的情况下，由某些肿瘤细胞直接形成具有微循环功能的类血管结构的过程。血管生成拟态能够为肿瘤的生长提供更加良好的血供，并且与侵袭性肿瘤的转移和不良预后密切相关。血管生成拟态的发生机制可能与侵袭性肿瘤细胞类胚胎样表型的逆转有关。     

涎腺腺样囊性癌COX-2表达与肿瘤血管生成的研究

目的：探讨环氧化酶-2（Cycloxygenase-2,COX-2）表达与涎腺腺样囊性癌（salivary adenoid cystic carcino-ma,SACC）血管生成的关系。方法：免疫组化法检测SACC中COX-2、诱导型一氧化氮合酶（inducible nitric oxide synthase,iNOS）、血管内皮生长因子（vascular endothelial growth factor,VEGF）表达,并测定肿瘤微血管密度（microvessel density,MVD）。结果：SACC中COX-2表达与VEGF、iNOS表达密切相关（P〈0.05,P〈0.01）。SACC中COX-2表达阳性组和阴性组MVD有显著差异（P〈0.01）.结论：SACC中COX-2表达和肿瘤血管生成有关,iNOS和VEGF可能参与COX-2对肿瘤血管生成的促进作用。     

口腔鳞癌COX-2表达和肿瘤血管生成的研究

目的 探讨环氧化酶-2(COX-2)表达和口腔鳞癌血管生成的关系.方法 免疫组化检测口腔鳞癌COX-2、诱导型一氧化氮合酶(iNOS)、血管内皮生长因子(VEGF)表达,并测定肿瘤微血管密度(MVD).结果 口腔鳞癌COX-2表达与VEGF、iNOS表达密切相关(P＜0.05).口腔鳞癌COX-2表达阳性组和阴性组MVD有显著差异(P＜0.01)结论 口腔鳞癌COX-2表达和肿瘤血管生成有关,iNOS 和VEGF可能参与COX-2对肿瘤血管生成的促进作用.     

肿瘤血管形成方式及其分子机制

血管形成是肿瘤生长和转移的基础.肿瘤血管形成方式包括出芽式血管生成、套叠式血管生成、成血管细胞募集、血管选定、镶嵌体血管和血管生成拟态等.本文就肿瘤血管形成方式及其分子机制作一综述.     

肿瘤血管生成直接抑制剂研究进展

血管抑素、内皮抑素、CM-101、TNP-470等血管生成直接抑制剂,直接作用于内皮细胞,抑制肿瘤血管生成,从而发挥抑制肿瘤生长及其浸润和转移的作用。作者对这些肿瘤血管生成抑制的作用机制及抑癌作用进行了综述。     

COX-2和唇癌血管生成相关性研究

目的：探讨环氧化酶-2（COX-2）表达与唇癌血管生成的关系。方法：免疫组化检测唇癌COX-2、诱导型一氧化氮合酶（iNOS）、血管内皮生长因子（VEGF）的表达,并测定肿瘤微血管密度（MVD）。结果：唇癌COX-2表达与VEGF、iNOS表达密切相关（P〈0．05）,唇癌COX-2表达阳性组和阴性组的MVD有显著差异（P〈0．01）。结论：COX-2表达和唇癌血管生成密切相关,iNOS和VEGF可能参与COX-2对肿瘤血管生成的促进作用。     

黏液表皮样癌中血小板反应蛋白-1与血管生成

肿瘤的发生、发展和转移依赖于肿瘤的血管生成,而血小板反应蛋白-1在肿瘤的血管生成方面有着重要的作用.因此,了解血小板反应蛋白-1在不同恶性肿瘤中的表达与血管生成之间的关系,了解其在不同恶性程度的涎腺黏液表皮样癌中的表达与微血管密度之间的关系,对进一步阐释涎腺黏液表皮样癌的发病机制有着重要的意义.笔者下面就血小板反应蛋白-1的结构与功能,血小板反应蛋白-1在肿瘤组织中表达与抑制肿瘤血管生成作一综述.     

血管生成抑制剂与恶性肿瘤

血管生成抑制剂与恶性肿瘤李龙江综述温玉明审校大量研究证明肿瘤生长必须依赖血管生成。肿瘤的一些产物能够促进血管生成。抑制血管生成的某些步骤或整个过程，进而控制肿瘤生成，对肿瘤治疗和防止肿瘤远处转移有重要意义。Ｆｏｌｋｍａｎ［１］首先提出用对抗血管生成的...     

DNA结合抑制蛋白-1与肿瘤发生的研究进展

DNA结合抑制蛋白(Id)-1被分离出来已近20年,其编码基因作为一种癌基因参与了诸多肿瘤的发生.本文就Id-1的致癌作用、Id-1在肿瘤浸润和转移中的作用、Id-1在肿瘤血管生成中的作用、Id-1在癌细胞化疗药物耐药性中的作用等研究进展作一综述.     

miR-221/222在肿瘤中的研究进展

微小RNA（miR）-221和miR-222为位于X染色体上具有相同种子序列的miRNA。研究表明其在多种肿瘤中起促癌或抑癌作用,参与信号激活、细胞增殖、分化、凋亡、血管生成以及侵袭迁移等生物进程。本文就miR-221/222在肿瘤中的作用进行综述,并对其在口腔鳞状细胞癌中的研究进展做一介绍。     

Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in oral squamous cell carcinoma: its correlation with angiogenesis and disease progression

BACKGROUND: Angiogenesis is a crucial step in the successful growth, invasion, and metastasis of a tumor. It has been popularly accepted that vascular endothelial growth factor (VEGF) is the most potent angiogenic factor in tumor angiogenesis. As another possible star molecule responsible for tumor angiogenesis, the role of nitric oxide (NO) in tumor biology has gained much attention in recent years. The aim of this study was to investigate whether the expression of endothelial nitric oxide synthase (eNOS) and VEGF in oral squamous cell carcinoma (OSCC) is associated with angiogenesis. The present study also made a preliminary exploration of the possible cross-talking existing between eNOS and VEGF during tumor angiogenesis. METHODS: In this study, expression of eNOS and VEGF were studied immunohistochemically in tissue sections from 40 patients with OSCC and 20 normal controls. To exclude eNOS antibody cross-reactivity with inducible or neuronal nitric oxide (iNOS or nNOS), eNOS expression was confirmed by using an eNOS mRNA in situ hybridization kit. The intratumoral microvessels were highlighted by immunostaining with anti-factor VIII-related antigen monoclonal antibody and counted as well-established methods. Then, chi-square test or Student's t-test was performed to study the correlations between the expression of eNOS and VEGF, microvessel density (MVD), and various clinicopathologic factors. RESULTS: Both eNOS and VEGF expression significantly increased in OSCC tissues, with a positive rate of 47.5% and 50%, respectively. The average MVD in OSCC tissues was 23.45 per high-power field (HPF), showing an obvious association with lymph node metastasis and clinical stages of patients with OSCC. Either eNOS or VEGF positivity was correlated with vessel involvement and OSCC progression. The mean MVD was significantly higher in eNOS- or VEGF-positive tumors than in eNOS- or VEGF-negative tumors. An obvious, correlation was also seen between eNOS and VEGF expression in OSCC tissues in this study. CONCLUSIONS: Overexpression of eNOS and VEGF might make an important contribution to the tumor angiogenesis in OSCC. NO generation by eNOS might be implicated in the VEGF-associated angiogenic process. Further investigation of the possible cross-talking between eNOS and VEGF with respect to tumor angiogenesis is necessary.     

Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer

It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.     

Abnormalities of tumor endothelial cells and cancer progression

Tumor growth and metastasis are dependent on angiogenesis, which is the formation of new blood vessels. The newly formed blood vessels around the tumor supply oxygen and nutrients to the tumor, supporting its progression. Moreover, these blood vessels also serve as channels through which tumor cells metastasize to distant organs. The balance between angiogenic stimulators and inhibitors regulates angiogenesis in the tumor microenvironment. Tumor blood vessels, especially the endothelial cells lining tumor blood vessels (tumor endothelial cells [TECs]), are important targets in cancer therapy. As newly formed tumor blood vessels originate from pre-existing normal vessels, tumor blood vessels and TECs have traditionally been considered to be the same as normal ones.However, tumor blood vessels have a distinctively abnormal phenotype, including morphological alterations. Recently, it has been revealed that TECs constitute a heterogeneous population, exhibiting characteristics that are largely induced by tumor microenvironmental factors. Furthermore, TECs induce cancer progression through metastasis. In this review, we describe recent studies on TEC abnormalities related to cancer progression and consider their therapeutic implications.     

Intra-tumor injection of an angiogenesis inhibitor, TNP-470, in rabbits bearing VX2 carcinoma of the tongue

A semi-synthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor. In this study, we evaluated the anti-tumor efficacy of TNP-470 on rabbits bearing VX2 carcinoma of the tongue, by comparison of topical, intra-tumor (i.t.) injection with systemic, intra-venous (i.v.) administration. The i.t. injection of the angiogenesis inhibitor produced much stronger anti-tumor effects, and almost complete tumor regression was achieved at doses of 10 mg/kg or 20 mg/kg. TNP-470 injected intra-tumorally significantly reduced expression of proliferating cell nuclear antigen (PCNA) and microvessel density in the VX2 carcinoma of the tongue. TNP-470 also halted the tumor-associated neovascularization in the rabbit cornea assay. These data suggest that i.t. injection of TNP-470 effectively inhibits tumor angiogenesis and disrupts microvasculature development, which may suppress tumor growth. In conclusion, the i.t. injection of TNP-470 provided remarkable anti-tumor effects on the VX2 carcinoma of the tongue and is expected to have promising therapeutic uses for oral cancer.     

Microvessel density and expression of vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived endothelial growth factor in oral squamous cell carcinomas

Angiogenesis, the growth of capillary vessels, plays an important role in the metabolic functions of malignant tissues. Tumor growth and malignant transformation are considered to be dominated by uncontrolled angiogenesis. To understand the mechanism of increased vascularity associated with malignant tissues, we immunohistochemically evaluated microvessel density (MVD) and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived endothelial growth factor (PDGF) in oral cancers. Microvessel density did not differ significantly between normal oral mucosa and epithelial dysplasia, but was significantly increased in tumor tissues. Expression of angiogenic factors was not found in normal oral mucosa, but increased in association with increasing vascularity in OSCC tissue. In tumor tissue, angiogenic factor expression correlated with MVD. MVD in OSCC was related to T stage, tumor differentiation, and stage of invasion. VEGF expression also correlated with tumor differentiation and the stage of invasion. These findings suggest that VEGF might play an important role in tumor angiogenesis of OSCC.     

Control of angiogenic activity in carcinogen-initiated and neoplastic hamster pouch keratinocytes and their hybrid cells

This study was undertaken to test the hypothesis that deregulated expression of the angiogenic phenotype by tumor cells is due to loss or inactivation of an angiogenesis suppressor gene(s). We used the technique of somatic cell hybridization to test the ability of untreated or chemical carcinogen-initiated hamster pouch keratinocytes, when fused to squamous epithelial neoplasms, to suppress tumor angiogenic activity by assaying hybrid-conditioned media (CM) in the avascular cornea of rat eyes. A non-angiogenic keratinocyte line, CL-2, derived from cultures of untreated epithelium and 3 lines of carcinogen-initiated keratinocytes, PN3, 5, and 7, of varying angiogenic potential were fused, using polyethylene glycol, to 3 tumorigenic, potently angiogenic, drug-resistant, hamster pouch carcinomas cell lines: HCPC-1, AW16E1-1, and AW16 E1-2. Serum-free 48-h CM from hybrid clones was prepared and assayed for angiogenic activity in rat corneas. CM from 5 hybrid clones derived from normal x neoplastic keratinocytes failed to induce an angiogenic response in 28 of 29 (97%) corneas tested. In contrast, CM from 4 hybrid clones derived from fusions between carcinogen-initiated and tumor cells were potently angiogenic in 24 of 25 (96%) corneas tested. Two angiogenesis suppressed hybrids clones were propagated in culture for an extended period of time, to permit chromosome segregation, and were found to re-express the angiogenic phenotype. These result indicate that angiogenesis is a recessive trait in normal hamster keratinocytes which is regulated in trans in these hybrid cells. It would also appear that loss or inactivation of angiogenesis suppressor function occurs early in the neoplastic process.     

Control of angiogenic activity in carcinogen-initiated and neoplastic hamster pouch keratinocytes and their hybrid cells

This study was undertaken to test the hypothesis that deregulated expression of the angiogenic phenotype by tumor cells is due to loss or inactivation of an angiogenesis suppressor gene(s). We used the technique of somatic cell hybridization to test the ability of untreated or chemical carcinogen-initiated hamster pouch keratinocytes, when fused to squamous epithelial neoplasms, to suppress tumor angiogenic activity by assaying hybrid-conditioned media (CM) in the avascular cornea of rat eyes. A non-angiogenic keratinocyte line, CL-2, derived from cultures of untreated epithelium and 3 lines of carcinogen-initiated keratinocytes, PN3, 5, and 7, of varying angiogenic potential were fused, using polyethylene glycol, to 3 tumorigenic, potently angiogenic, drug-resistant, hamster Serum-free 48-h CM from hybrid clones was prepared and assayed for angiogenic activity in rat corneas. CM from 5 hybrid clones derived from normal × neoplastic keratinocytes failed to induce an angiogenic response in 28 of 29 (97%) corneas tested. In contrast, CM from 4 hybrid clones derived from fusions between carcinogen-initiated and tumor cells were potently angiogenic in 24 of 25 (96%) corneas tested. Two angiogenesis suppressed hybrids clones were propagated in culture for an extended period of time, to permit chromosome segregation, and were found to re-express the angiogenic phenotype. These result indicate that angiogenesis is a recessive trait in normal hamster keratinocytes which is regulated in trans in these hybrid cells. It would also appear that loss or inactivation of angiogenesis suppressor function occurs early in the neoplastic process.     

Regional difference in intratumoral lymphangiogenesis of oral squamous cell carcinomas evaluated by immunohistochemistry using D2-40 and podoplanin antibody: an analysis in comparison with angiogenesis

BACKGROUND: Whether tumor cells induce lymphangiogenesis intratumorally or permeate pre-existing lymphatic vessels in the peritumoral area still remains unclear. In this study, we investigated in detail the intratumoral lymphangiogenesis of oral squamous cell carcinomas (SCC) in comparison with tumor angiogenesis. METHODS: Immunohistochemistry with D2-40, podoplanin antibody, and CD34 antibody were used to evaluate the lymphatic vessel density (LVD) and blood microvessel density (MVD). Vascular endothelial growth factor (VEGF) and VEGF-C expressions of oral SCC were also assessed by immunohistochemistry. RESULTS: LVD significantly increased in the superficial area of tumor tissue compared with normal mucosa, whereas it decreased in the deep area of intratumoral tissue near the invasion front, in sharp contrast to MVD, which significantly increased throughout tumor tissue. Consistent with the decreased intratumoral LVD and increased intratumoral MVD, VEGF-C expression of tumor cells was down-regulated in the deep area of tumor tissue, while VEGF expression of tumor cells was up-regulated throughout the tumor tissue. CONCLUSIONS: Lymphangiogenesis in oral SCC varies depending on the region within the tumor tissue. It is not induced in the genuine tumor stroma near the invasion front, probably due to the down-regulation of VEGF-C expression of tumor cells, which is different from VEGF-mediated induction of intratumoral angiogenesis.