Vasculogenic mimicry:a novel target for glioma therapy

Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry(VM), or the formation of non-endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas.

Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy

"Vasculogenic mimicry(VM)",is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent,stem cell-like phenotype,and form a pattern of vasculogenic-like networks in threedimensional culture.As an angiogenesis-independent pathway,VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients.Moreover,VM is resistant to angiogenesis inhibitors.Here,we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy.

Vasculogenic mimicry in non-small cell lung cancer and its relationship with tumor stage

Objective： The purpose of the study was to study the mechanism of vasculogenic mimicry （VM） and its relationship with tumor stage in non-small cell lung cancer （NSCLC）. Methods： Forty-two patients with NSCLC were collected, 19 belonged to the early stage （stages Ⅰ ＋Ⅱ） while 23 were late stage （stages Ⅲ ＋ Ⅳ）. Moreover, 20 patients got surgical treat ment and 22 got chemotherapy. We studied the relationship of VM with stage, chemotherapeutic effect, HIF-la, microves sel density （MVD） and clinicopathologic features. Results： VM in patients of early stages were significantly more than late stages （68.4% vs 26.1%, P = 0.006）, and the positive rate of VM was proportional to HIF-la （P = 0.034）. But no correlation was found between VM and chemotherapeutic effect （14.3% vs 26.7%, P = 1.00） or MVD （P 〉 0.05）. Furthermore, we found VM also showed a negative correlation with distant metastases and lymph nodes metastases （P 〈 0.05） while no correlation was found with other clinicopathologic. Conclusion： VM was generated during the early stage in NSCLC and correlated with lymph nodes metastases. As the disease progressed, VM may be replaced by vascular endothelial cells, so the late-stage patients especially people with distant metastases had fewer VM. As the main factor produced by hypoxia, HIF-la may make a difference in VM formation. Thus we inferred VM might be a new target for targeted therapy, and could provide help for clinical staging and treatment.

肿瘤细胞微环境对胶质瘤血管生成拟态形成的影响

目的探讨肿瘤细胞微环境改变对胶质瘤血管生成拟态(VM)形成的影响。方法通过制造化学缺氧环境、添加U251上清和用U251细胞预处理Matrigel等3种方法诱导胶质瘤细胞SHG44形成VM,并检测上述几种培养基上清中的血管内皮生长因子(VEGF)、转化生长因子-β(TGF-β)、成纤维细胞生长因子(b FGF)、血小板源生长因子(PDGF)及肿瘤坏死因子-α(TNF-α)的表达与对照组SHG44细胞的差异,同时比较组间基质金属蛋白酶(MMP)活性水平。结果几种方法均能诱导SHG44细胞形成VM结构,其中缺氧组VM形成能力最强,添加U251上清组次之,U251细胞预处理Matrigel组最弱,且几个处理组上清中的VEGF、TGF-β和PDGF浓度与各组VM形成能力相关,MMP-2活性也与VM形成能力相关。结论胶质瘤VM形成很可能是微环境改变后多种因素作用的结果,其中VEGF、TGF-β、PDGF、MMP-2与VM形成关系具有相关性。

血管生成拟态和马赛克血管与肾癌的靶向治疗

肾癌是泌尿系统最常见的恶性肿瘤之一,年发病率为17.9/10万,有逐年增加趋势。转移性和高危肾细胞癌预后差,且对化疗和/或放疗均不敏感。虽然细胞因子(干扰素和白介素-2)治疗被广泛应用,但因其反应率低和生存期短,故而疗效欠佳。针对抗血管生成途径,运用靶向药物行术前辅助或术后辅助治疗肾细胞癌显著提高了患者的无复发存活率。本文主要综述从基础到临床,尤其是有关血管生成拟态和马赛克血管在肾癌治疗中的一些重要进展。虽然抗血管生成的靶向治疗已确立了治疗转移性肾癌的新标准,但是仍需要新的药物或联用来提高疗效,减少药物相关的毒性。

Twenty years after:the beautiful hypothesis and the ugly facts

The limited clinical benefits 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 the Chinese Journal of Cancer,we briefly introduce the history of the evidences that solid tumors can sometimes obtain blood perfusion by alternative 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.

阻断转化生长因子-β信号通路对胶质瘤血管生成拟态的抑制作用

目的探讨阻断转化生长因子-β（TGF-β）信号通路对胶质瘤血管生成拟态㈣的影响及其可能机制。方法三维培养人脑胶质瘤细胞系U251、SHG44，观察U251培养上清、TGF-β因子对SHG44细胞形成VM的影响；比较0μg／mL（PBS组）、15μg／mL（Abl5组）．30μg／mL（Ab30组）TGF-β中和抗体对U251、SHG44细胞形成VM的影响；酶联免疫吸附法（ELISA）检测空白组、PBS组、Abl5组，Ab30组U251培养上清中血管内皮生长因子（VEGF）及血小板衍生生长因子（PDGF）的表达以及空白组、TGF-β组、PBS组、Ab15组，Ab30组SHG44细胞上清VEGF、PDGF的表达。结果三维培养时，U251细胞排列形成VM，SHG44细胞并不形成VM，而仅仅相互聚集成大小不等的细胞集落；U251培养上清可以诱导SHG44细胞形成VM，且在培养24-48h最为明显，TGF-β因子不能诱导SHG44细胞形成VM：PBS组、Abl5组、Ab30组U251细胞环状结构数量依次降低，差异有统计学意义（P〈0．05）。与U251上清共培养的SHG44细胞在加入TGF-β中和抗体后，3组细胞形成环状结构数量也依次降低，差异有统计学意义（P〈0．05）；与空白组和PBS组比较，Abl5组、Ab30组U251细胞上清中VEGF、PDGF浓度下降，差异有统计学意义（P〈0．05），与空白组和TGF-β组相比，PBS组、Ab15组、Ab30组SHG44细胞上清中两种因子浓度均增高，差异有统计学意义（P〈0．05）。结论抑制TGF-β信号通路可以使胶质瘤VM形成能力下降，这可能与VEGF及PDGF表达减少有关。