血管生成拟态与子宫颈癌的研究进展

血管生成拟态(VM)作为肿瘤中一种新的不依赖于血管内皮细胞的血液供应模式近年来备受关注.诸如缺氧、上皮间质转化(EMT)、肿瘤干细胞(CSCs)的存在等许多因素在VM的形成过程及肿瘤包括子宫颈癌的进展中发挥重要作用.研究VM及其影响因素在宫颈癌进展的作用机制为其复发、转移的治疗提供新思路.     

血管生成拟态在恶性肿瘤的研究进展

血管生成拟态(VM)一种存在于恶性肿瘤的血液供应模式,乳腺恶性肿瘤VM的形成机制十分复杂.肿瘤细胞的可塑性和多种分子的调节在VM形成机制中起重要作用,同时缺氧微环境及微小RNA(miRNA)与VM的发生和发展具有相关性.缺氧微环境及miRNA与乳腺恶性肿瘤VM关系尤为密切,将有望成为乳腺癌临床研究中重要的诊断及判断预后的指标.     

肿瘤血管生成拟态在结肠癌中的研究进展

血管生成拟态（vasculogenic mimicry,VM）是近年来发现的一种与经典的肿瘤血管生成途径完全不同、不依赖机体内皮细胞的全新肿瘤微循环模式,与肿瘤生长、侵袭、转移及患者预后密切相关。VM可能是一个潜在的肿瘤治疗新靶点,但其形成的分子机制尚未完全清楚。本文就近年来VM在结肠癌中发现、可能分子机制及其对治疗的影响作一综述,探讨当前研究中存在的问题,展望未来的发展方向。     

恶性黑色素瘤血管生成拟态的形态学观察

目的:通过人体石蜡包埋组织切片、动物实验及电镜观察研究血管生成拟态(vasculogenic mimicry VM)的形态结构及其分布特点.方法:收集具有VM的恶性黑色素瘤组织进行PAS和CD31重复染色,观察VM的形态结构及其在肿瘤组织中的分布特点,构建恶性黑色素瘤B16动物模型,将活性炭注入小鼠循环系统内观察VM的结构,同时使用电镜技术观察VM的超微结构.结果:PAS阳性而CD31阴性的VM在肿瘤组织中呈片状分布,与内皮依赖性血管和马赛克血管共同维持肿瘤组织血液供应,动物实验和电镜观察结果也进一步证实了VM的存在.结论:以活性炭作为示踪剂研究B16动物移植瘤组织内VM,表明VM与机体血循环相连通,是肿瘤组织内的功能性微循环.作为一种新的肿瘤血液供应模式,VM存在于某些恶性肿瘤组织中,肿瘤细胞可以通过VM获得充足的血液供应.     

胶质瘤血管生成拟态的研究进展

血管生成拟态（vasculogenic mimicry,VM）是血管依赖性实体肿瘤中一种无内皮细胞的“血管样”结构,是肿瘤在高度侵袭过程中的一种特殊的供血模式。VM广泛存在于多种人体恶性肿瘤中,与肿瘤的进展、转移、侵袭和复发密切相关。本文将就胶质瘤血管生成拟态的发生机制、信号通路途径以及分子调控机制等作一综述,并探讨目前研究中面临的问题,旨在为胶质瘤的基因治疗的新切入点提供理论依据。     

黑色素瘤组织内三种血液供应模式时间关系的初步探讨

目的：探讨血管生成拟态（VM）、马赛克血管和内皮依赖性血管三种血液供应模式在肿瘤生长过程中的时间延续性变化。方法：将B16黑色素瘤组织块接种到C57纯系小鼠鼠鼷部．待肿瘤大小约0．5mm左右时．连续处死小鼠，将瘤组织块制作成切片．在切片上进行三种血液供应模式的计数．初步判定三种血液供应模式的时间关系趋势，同时利用双重免疫组化染色和电镜技术进行形态学观察.结果：随着肿瘤体积的不断增大．VM数目不断减少．而内皮依赖性血管数目呈现出不断增加趋势，马赛克血管的数目多少无明显变化．肿瘤体识的大小与内皮依赖性血管数目呈高度正相关（γ=0．718，P=-0．009）而与VM成高度负相关（γ=0．77，P=0．003）免疫组化双染和电镜观察的结果显示马赛克血管的管壁同时由内皮细胞和肿瘤细胞构成.结论：VM是黑色素瘤生长的早期血液供应的主要形式后来VM逐渐被内皮细胞依赖性血管替代，马赛克血管可能是VM和内皮依赖性血管之间的一种过渡形式.     

肿瘤血管生成拟态

血管生成拟态(VM)是近几年来在许多肿瘤中发现的一种全新的肿瘤内血管生成模式,即高度侵袭性肿瘤细胞通过自身变形和基质重塑产生血管样通道而达到自身血液供应的方式.现就其形态特点、分子机制、研究意义等作一综述.     

肿瘤血管生成拟态

血管生成拟态(VM）是近几年来在许多肿瘤中发现的一种全新的肿瘤内血管生成模式，即高度侵袭性肿瘤细胞通过自身变形和基质重塑产生血管样通道而达到自身血液供应的方式，现就其形态特点、分子机制、研究意义等作一综述。     

肿瘤微循环研究进展

肿瘤微循环研究进展魏子白，吴云林上海第二医科大学附属瑞金医院消化科（上海２０００２５）恶性肿瘤的生长和转移必须以合宜的血液供应为前提，肿瘤的血液供应是通过与宿主正常血管混合以形成新的肿瘤微循环得以实现，因此肿瘤微循环有许多与正常组织微循环不同的特性，...     

血管生成拟态在骨肉瘤中的研究进展

血管生成拟态(vasculogenic mimicry,VM)是指高度恶性肿瘤细胞模拟血管内皮细胞形成的一种具有输送血液的管道结构,是近年发现的一种全新的肿瘤微循环模式.     

Vasculogenic mimicry: current status and future prospects

In 1999, Maniotis reported that blood vessels of highly aggressive uveal melanomas are formed by tumor cells instead of endothelial cells. He termed this novel concept in tumor vascularization vasculogenic mimicry (VM). Since then, VM has been seen in several malignant tumor types such as breast cancer, liver cancer, glioma, ovarian cancer, melanoma, prostate cancer, and bidirectional differentiated malignant tumors. Laser scanning confocal angiography, electron microscopy, and three-dimensional cell culture have confirmed the existence of VM. The molecular mechanisms that underlie VM are not fully clear, but metalloproteinases via their cleavage of laminin, VE-cadherin by promoting adherence of the VM channel wall to tumor cells, tumor cell dedifferentiation, and tumor microenvironment have been shown to play a role in VM. Zhang and co-workers have proposed a three-stage phenomenon among VM channels, mosaic blood vessels, and endothelium-dependent blood vessels, wherein all three patterns participate in tumor blood supply. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. VM-targeting strategies include suppressing tyrosine kinase activity and using a knockout EphA2 gene, downregulating VE-cadherin, using antibodies against human MMPs and the laminin 5gamma2 chain, and using anti-PI3K therapy. We review here the current status of research on VM; discuss molecular mechanisms of VM, factors affecting VM formation, and its clinical significance; and explore the development of novel tumor-targeted treatments that are based on the biochemical and molecular events that regulate VM.     

Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications

Tumor cell vasculogenic mimicry (VM) describes the functional plasticity of aggressive cancer cells forming de novo vascular networks, thereby providing a perfusion pathway for rapidly growing tumors, transporting fluid from leaky vessels, and/or connecting with endothelial-lined vasculature. The underlying induction of VM seems to be related to hypoxia, which may also promote the plastic, transendothelial phenotype of tumor cells capable of VM. Since its introduction in 1999 as a novel paradigm for melanoma tumor perfusion, many studies have contributed new insights into the underlying molecular pathways supporting VM in a variety of tumors, including melanoma, glioblastoma, carcinomas, and sarcomas. In particular, critical VM-modulating genes are associated with vascular (VE-cadherin, EphA2, VEGF receptor 1), embryonic and/or stem cell (Nodal, Notch4), and hypoxia-related (hypoxia-inducible factor, Twist1) signaling pathways. Each of these pathways warrants serious scrutiny as potential therapeutic, vascular targets, and diagnostic indicators of plasticity, drug resistance, and the aggressive metastatic phenotype.     

Endothelium originated from colorectal cancer stem cells constitute cancer blood vessels

Tumor growth depends on the formation of blood vessels that provide the supply of nutrients and oxygen. Previous data have shown that glioblastoma stem cells are able to give rise to vascular cells to constitute the functional vessels in tumor tissues. However, which kinds of vascular cells are generated from glioblastoma stem cells is largely debated. In addition, there is little evidence showing that the stem cells from other kinds of tumors can produce vascular cells to constitute the functional blood vessels in tumor tissues. Here we show that cancer stem cells of human colorectal carcinomas (CoCSC) can give rise to vascular endothelial cells and compose the vasculatures in cancer tissues. The human‐cell‐specific nuclear antigen NuMA⁺ vascular endothelial cells were detected in the blood vessels in xenografts derived from CoCSC. NuMA⁺ endothelial cells incorporated into functional blood vessels. Our data indicate that the cancer stem cells derived from human colorectal carcinomas have the capacity to generate functional blood vessels and provide a new mechanism for tumor vasculogenesis in carcinoma.     

Vasculogenic mimicry is associated with poor survival in patients with mesothelial sarcomas and alveolar rhabdomyosarcomas

Increased vasculogenesis must occur for tumors to develop and be maintained. Normally, vascular networks are composed of tube structures lined with endothelial cells. However, the vascular networks that form around some highly aggressive cancers possess a distinct tubular structure, resulting from a process called vasculogenic mimicry (VM) that does not have endothelial cells. In these tubes, the tumor cells function as endothelial cells. VM has been found in several different types of cancers such as melanoma, breast cancer, prostate cancer, and ovarian cancer. We hypothesized that it also plays a role in the development and metastasis of sarcomas, which are typically aggressive tumors. We used immunohistochemical analyses and electron microscopy to identify VM channels in 81 synovial sarcomas (SSs), 37 mesothelial sarcomas (MSs), 69 alveolar rhabdomyosarcomas (ARs), and 190 melanomas, which were used as a comparison group. The presence of red blood cells in the vessels was also used as a criterion for VM. Because VM is generally believed to be associated with aggressive cancers, we tested whether the presence of VM channel correlated with patient survival. We detected VM channels in 11 of 81 SSs (13.6%), 10 of 37 MSs (27.0%), 13 of 69 ARs (18.8%), and 10 of 190 melanomas (5.3%). The VM channels were not distributed uniformly in the tumor tissues but appeared in patches. In addition, VM channels were most frequently observed in the boundary regions between the tumor and adjacent normal tissues. The tumor cells around the VM tubes frequently stained positive for collagen IV and CD31 and were also PAS-positive. In contrast, tumors that lack VM channels generally also lack these markers. Our studies of the correlation of VM with patient survival also showed that VM correlated with shorter survival in patients with MS (P=0.03), AR (P=0.03), and melanoma (P=0.04), but not with SS (P=0.76). Our studies demonstrated that VM channels are a clinically important phenotype in sarcomas and melanomas. Our findings also suggested that a subpopulation of tumor cells possess features of both endothelial cells that line the vessels and mesenchymal cells that secrete the extracellular matrix required for the vascular infrastructure.     

Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry

Ovarian cancer is a silent killer, and shows early extensive tumor invasion and peritoneal metastasis. The microcirculation of most tumors includes cooperation of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis and vasculogenic mimicry (VM). VM is critical for a tumor blood supply and is asscociated with aggressive features and metastasis. Our studies highlight the plasticity of aggressive human ovarian carcinoma cells and call into question the underlying significance of their ability to form VM in vitro induced by VEGF-a. These studies also show their clinicalpathological features of the cancers with human Paraffin-embedded tumor tissue samples. Results show that the process: VEGF-a-->EphA2-->MMPs-->VM is the main pathway for VM formation and VEGF-a appears to play an important role in the formation of VM based on our in vitro assays and clinical immunohistochemical analyses. VM-targeting strategies for ovarian cancer include anti-VEGF-a treatment, knocking down the EphA2 gene and using antibodies against human MMPs if the tumor is VM positive. This strategy may be of significant value in laying the foundation for a more explicit anti-tumor angiogenesis therapy.     

Morphologic research of microcirculation patterns in human and animal melanoma

Objective The pattern and distribution of microcirculation of malignant melanoma were studied in human malignant melanoma tumor samples and in an animal model by staining of paraffin-embedded sections and transelectron microscopy. Methods Blood supply models for melanoma were studied with immunohistochemical and periodic acid-Schiff (PAS) double-staining technique. New sections were made from 190 paraffin-embedded melanoma samples, and immunohistochemical staining of the platelet-endothelial cell adhesive molecule (CD31 antigen) and PAS staining were conducted to confirm different microcirculation patterns of melanoma Furthermore, malignant melanoma cells B16 and LiBr were injected into the groin of C57 mice and into the abdominal cavity of SCID mice, respectively. Tumors with vasculogenic mimicry (VM) were stained with PAS and CD31 to study the morphology and distribution of VM in mice melanoma. A diluted suspension of activated carbon was injected into the circulation of mice previously inoculated in the groin with B16 melanoma cells. Tumor tissue with VM was observed under electron microscopy. Results There were three kinds of microcirculation pattern in human and animal melanoma. The walls of VM were positive for PAS staining and negative for CD31 staining in the tumor tissues. The distribution of VM and mosaic vessels was not uniform and appeared in patches. VM along with endothelium-dependent vessels and mosaic vessels sustained the blood supply for the tumors. The results from electron microscopy validated the presence of three patterns. Conclusions The results obtained using activated carbon as a tracer showed that VM and mosaic vessels connect with the host blood circulation. VM and mosaic vessels exist in malignant melanoma. Tumor cells can obtain oxygen and nutriment through VM and mosaic vessels besides endothelium-dependent vessels.     

基质金属蛋白酶和肿瘤血管生成拟态的相关研究

血管生成拟态（vasculogenic mimicry,VM）是一种新的肿瘤细胞血液供应的方式。现有研究表明,基质金属蛋白酶（matrix metalloproteinase,MMPs）具有促进 VM 管道形成的作用。本文将对 MMPs 与血管生成拟态（vasculogenic mimicry,VM）的关系及其相关分子机制进行归纳,进一步探索两者之间的关系,从而为研究 VM 管道形成提供新的思路。