Vasculogenesis and angiogenesis in nonseminomatous testicular germ cell tumors

Testicular germ cell tumors (TGCTs) comprise the vast majority of all testicular malignancies and are the most common type of cancer among young male adults. The nonseminomatous variant of TGCTs is characterized by the presence of embryonic and extraembryonic tissues together with a population of pluripotent cancer stem cells, the so-called embryonal carcinoma. One of the main causes of the resistance of these tumors to therapy is their ability to invade adjacent tissues and metastasize into distant sites of the body. Both of these tumor processes are highly favored by the neovascularization of the malignant tissue. New vessels can be generated by means of angiogenesis or vasculogenesis, and both have been observed to occur during tumor vascularization. Nevertheless, the precise contribution of each process to the neoplastic vascular bed of TGCTs remains unknown. In addition, another process known as tumor-derived vasculogenesis, in which malignant cells give rise to endothelial cells, has also been reported to occur in a number of tumor types, including experimental TGCTs. The participation and cross talk of these 3 processes in tumor vascularization is of particular interest, given the embryonic origin of teratocarcinomas. Thus, in the present review, we discuss the importance of all 3 vascularization processes in the growth, invasion, and metastasis of testicular teratocarcinomas and summarize the current state of knowledge of the TGCT microenvironment and its relationship with vascularization. Finally, we discuss the importance of vascularization as a therapeutic target for this type of malignancy.     

Angiopoietin-Related/Angiopoietin-Like Proteins Regulate Angiogenesis

A general understanding of the molecular mechanisms underlying angiogenesis is emerging from the analysis of targeted mutations in vasculature-related genes. These analyses reveal that angiopoietin signaling through the TIE2 receptor is involved in regulating angiogenesis. Recently, we and several other groups have independently identified several molecules containing a coiled-coil domain and a fibrinogen-like domain, both of which are structurally conserved in angiopoietins. Because these molecules do not bind to the angiopoietin-specific receptor,TIE2, they have been named angiopoietin-related proteins (ARPs) or angiopoietin-like proteins (Angptls). ARPs/Angptls, which are all currently orphan ligands, also have potent activity for regulating angiogenesis as proangiogenic or antiangiogenic factors, suggesting that their receptors may be expressed on endothelial cells. In addition, ARPs/Angptls show pleiotropic effects not only on vascular cells but also on cells of other lineages, such as skin and chondrocyte cells. More recent studies have proposed that ARPs/Angptls are involved in various pathologies, such as tumor angiogenesis and metabolic diseases. To summarize the current findings relating to these proteins, we focus in this review on the functions of ARPs/Angptls as new angiogenic modulating factors in the vascular system and discuss the pleiotropic functions of ARPs/Angptls in nonvascular cell lineages.     

Systemic sclerosis stimulates angiogenesis in the chick embryo chorioallantoic membrane

Skin biopsies from patients with systemic sclerosis (SSc) were investigated for their angiogenic activity by using the chick embryo chorioallantoic membrane (CAM) assay. Ten samples of SSc and 10 of normal skin from age- and sex-matched subjects were grafted onto the CAM, and the angiogenic response in pathological and control implants was assessed on histological sections by a planimetric point-count method 4 days after grafting. The vascular counts in the area underlying the SSc were significantly higher than those of normal skin and a dense mononuclear cell infiltrate was detectable around the blood vessels in pathological specimens. These results suggest that SSc may promote angiogenesis, perhaps leading to the release of several angiogenic factors. Moreover, the role played in the angiogenic response by the inflammatory cells forming the cellular infiltrate is suggested by this study.     

Pin1抑制剂胡桃醌对乳腺癌细胞株MCF7Adr增殖、迁移及血管新生能力的影响

目的研究Pin1抑制剂胡桃醌对乳腺癌细胞株MCF7Adr增殖、迁移及血管新生能力的影响。方法培养乳腺癌细胞株MCF7Adr,分别用不含药物的DMEM(对照组)、Pin1抑制剂胡桃醌处理(处理组),采用流式细胞法检测细胞周期、划痕实验检测细胞的迁移能力、Western-blot检测Cyclin E的蛋白含量、酶联免疫吸附法检测细胞上清液中血管内皮生长因子(VEGF)的水平。结果处理组的G2/M期比例高于对照组(t=21.848,P<0.01),G0/G1比例、S期比例低于对照组(t=6.234,6.658,均P<0.05),Cyclin E蛋白含量、(A0-A24)/A0值低于对照组(t=17.586,26.679,均P<0.01),处理组细胞的上清液中VEGFA、VEGFB、VEGFC水平低于对照组(t=15.237,13.894,16.382,均P<0.01)。结论 Pin1抑制剂胡桃醌能有效抑制乳腺癌细胞株MCF7Adr的增殖、迁移和血管新生能力,Pin1抑制剂可作为乳腺癌治疗的备选药物。     

VHL-deficient vasculogenesis in hemangioblastoma

Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel–Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo.     

脑动脉粥样硬化与肝细胞生长因子-转化生长因子-β1平衡关联性研究进展

脑动脉粥样硬化以颅内动脉管壁增厚、僵硬、狭窄及闭塞为主要病理发展过程,以缺血性脑血管病为主要临床表现,近年来其呈现高发病率、高致残率,给患者、家庭及社会医疗资源带来巨大负担;脑动脉粥样硬化所致颅内血管分支减少也成为血管性痴呆主要致病因素。肝细胞生长因子(HGF)作为一种来源于间质细胞的分泌型肝素亲和糖蛋白,具有促进细胞增殖、迁移、分化、形态发生、抗凋亡等多种生物活性功能,目前其促血管新生机制成为研究热点。转化生长因子-β1(TGF-β1)是一种调节多种细胞生长和分化的信号分子,前期研究表明TGF-β1与HGF相互作用间存在互逆平衡关系,该平衡对维持机体正常内环境稳态发挥重要作用。本文就脑动脉粥样硬化与HGF-TGF-β1平衡关联性相关研究进行综述,总结HGF-TGF-β1平衡的维持对颅内动脉粥样硬化发生发展的影响,分析给予外源性HGF以达到促血管新生从而治疗缺血性脑血管病的临床可行性。     

Medication-related osteonecrosis of the jaw: A literature review

BackgroundAntiresorptive agents such as bisphosphonates and denosumab, as well as angiogenesis inhibitors, may induce medication-related osteonecrosis of the jaw (MRONJ). However, the exact mechanisms of MRONJ are unclear and definitive treatment strategies have not yet been developed. Moreover, the aging population requiring antiresorptive agents and angiogenesis inhibitors has been increasing worldwide. Therefore, the aim of this literature review was to introduce the latest information on MRONJ. The epidemiology, triggering factors, risk factors, drug holiday, pathoetiology and treatment strategies for each drug-induced ONJ were investigated by conducting a PubMed search.HighlightThe prevalence and incidence of ONJ were very low. Some mechanisms of ONJ have been identified, although they were not definitive. Novel treatment strategies have been proposed in basic and clinical research. Several factors, including age and the administration duration of bisphosphonates, are risks for the development of bisphosphonate-related ONJ (BRONJ). Dental implant therapy and peri-implantitis could become risk factors of BRONJ, regardless of the onset timing of bisphosphonates. No reliable information about ONJ induced by denosumab and angiogenesis inhibitors was found.ConclusionCaution should be taken when dental treatment including implant therapy is performed in patients receiving bisphosphonates, denosumab, and angiogenesis inhibitors. There is limited scientific evidence regarding the relationship between MRONJ and older age. Further ONJ-related research on the aging population is required to manage the treatment of such diseases in older people in the future.     

Isthmin 对博来霉素诱导肺纤维化小鼠胶原沉积及血管生成的影响

目的探讨Isthmin（ISM）对肺纤维模型小鼠肺部胶原沉积、血管新生的影响,为肺纤维化的防治提供理论依据。方法将昆明小鼠随机分成：对照组、模型组、ISM组3组,每组16只。博来霉素（BLM）气管内滴人制作小鼠肺纤维化模型,对照组（气管内注射0．9％NS＋尾静脉注入0．9％NS）、模型组（气管内注射BLM＋尾静脉注入0．9％NS）、ISM组（气管内注射BLM＋尾静脉注入Isthmin蛋白）。分别于第7天、14天、21天、28天取实验小鼠肺组织,病理切片苏木精-伊红染色（HE）染色观察肺结构变化,Masson染色了解肺部胶原沉积情况,CD31免疫组化观察对血管内皮细胞数目的影响。结果给予ISM蛋白可减轻小鼠肺结构破坏,减少肺部胶原沉积,血管内皮细胞数目增加。肺组织胶原纤维Masson染色经平均光密度比较,模型组与对照组第7、14、21和28天差异具有统计学意义（P〈0．01）;Isthmin组与模型组比较,第21天和28天差异具有统计学意义（P〈0．01）;肺组织CD31蛋白平均光密度比较,模型组与对照组第14天、21天和28天差异显著（P〈0．05）、第7天差异具有统计学意义（P〈0．01）,Isthmin组与模型组比较,第21天和28天差异具有统计学意义（P〈0．05）。结论ISM蛋白可减轻肺纤维化程度,但不是通过抑制血管形成实现的。