miR-195 inhibits tumor growth and angiogenesis through modulating IRS1 in breast cancer

Angiogenesis has been found as an attractive target for drug therapy as it is necessary for tumor growth. Accumulating evidences show that microRNAs (miRNAs), which are a group of highly conserved, single-stranded, short non-coding RNAs, play important roles through directly targeting angiogenic factors and protein kinases. The purpose of this study is to investigate the role of miR-195 in breast cancer development and angiogenesis through targeting IRS1. We show that miR-195 is inversely related with Insulin receptor substrate 1 (IRS1) in both breast cancer cells and breast cancer tissues. Induction of miR-195 could suppress IRS1 protein expression through binding to its 3′UTR regions either by transfection with miR-195 oligo or by infection with lentivirus encoding miR-195 gene. Moreover, re-expression of IRS1 reverses miR-195-mediated repression of tumor cell growth and miR-195 inhibits tumor angiogenesis through suppressing IRS1-VEGF axis. These data suggest that miR-195 mimics are potential therapeutic agents for breast cancer diagnose.     

OP-1 injection increases VEGF expression but not angiogenesis in a rabbit model of distraction osteogenesis

We have previously shown that a single injection of rhBMP-7 (OP-1) applied to the regenerate early during distraction accelerates bone consolidation in a rabbit model of distraction osteogenesis. In the present study, we hypothesised that the injection of OP-1 improves bone consolidation by increasing blood flow to the distracted site. Blood flow into the regenerate of a rabbit model was measured and vascular endothelial growth factor (VEGF) expression was tested using semi-quantitative PCR. Immunohistochemistry was used for assessing the temporal and spatial expression of platelet endothelial cell adhesion molecule (PECAM), VEGF and its receptors following OP-1 injection. We observed a higher expression of VEGF and its receptors in the regenerate with OP-1 treatment. However, there was no difference in the increase in bone blood flow nor PECAM expression between the treated and control groups of animals. Interestingly, the increased expression of VEGF and its receptors was associated with chondrocyte and fibroblast-like cells, but not with endothelial cells. These results suggest that accelerated ossification by OP-1 may depend on a non-vascular mechanism, possibly involving a non-angiogenic function of VEGF signalling.     

Anti-angiogenic treatment in breast cancer: Facts,successes, failures and future perspectives

Angiogenesis is one of the hallmarks of cancer and a crucial requisite in the development of tumors. Interrupting this process by blocking the vascular endothelial growth factor (VEGF) with the monoclonal antibody bevacizumab has been considered a possible breakthrough in the treatment of various types of cancer, especially for advanced disease. However in breast cancer, studies have shown ambivalent results causing debate about the value of this drug. In this article, we review the evidence for anti-angiogenic treatment options for breast cancer, as well as discuss the possible factors limiting the effectiveness of anti-angiogenic agents and offer a recommendation regarding the future research on these therapies for the treatment of breast cancer.     

Epidermal growth factor-like domain 7 promotes cell invasion and angiogenesis in pancreatic carcinoma

Epidermal growth factor-like domain 7 (EGFL7), also known as vascular endothelial stain, was firstly identified as a modulator of smooth muscle cell migration. Though the expression of EGFL7 was reported to be up-regulated during tumorigenesis, the clinical and biological functions of EGFL7 in pancreatic carcinoma (PC) were still not fully elucidated. In this study, we found that the serum EGFL7 level in PC tissues was statistically higher than that in normal subjects (p < 0.001), and its level in non-resectable patients was also higher than that in resectable ones (p = 0.013). Among these resectable PC patients, the postoperative EGFL7 expression was significantly down-regulated when tumors were resected (p = 0.018). Using the immunohistochemistry method, our results demonstrated that the positive expression of EGFL7 was significantly associated with the TNM stage (p = 0.024), lymph node metastasis (p = 0.003) and local invasion (p = 0.022), and the EGFL7 expression closely correlated to the micro-vessel density (MVD) in PC tissues by Spearman analysis (r = 0.941, p = 0.000). In vitro, EGFL7 was silenced by the small interference RNA in PC cells, and our data indicated that down-regulation of EGFL7 did not influence the cycle progression, proliferation, colony formation and apoptosis of PC cells (p > 0.05), whereas inhibition of EGFL7 expression could decrease PaCa-2 cell invasion (p < 0.05). More interestingly, by tubular formation, Chick embryo chorioallantoic membrane (CAM) and ELISA assays, our results revealed that silencing EGFL7 expression represented a strong inhibiting effect on tubular formation of micro-vessels through down-regulating the protein levels of VEGF and Ang-2 (p < 0.05). Our results raised the possibility of using EGFL7 as a potential prognostic biomarker and therapy target of PC, and down-regulation of EGFL7 might be considered to be a potentially important molecular treatment strategy for patients with PC.     

Targeting angiogenesis in ovarian cancer

Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resistance leading to disease recurrence. This prompted interest in the development of therapies targeting critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms initiated by the vascular endothelial growth factor, the platelet-derived growth factor, the fibroblast growth factor, angiopoietins, and others. These pathways are not only important to the modulation of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival. In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating such agents alone and in combination with chemotherapy are ongoing. Early clinical results position antiangiogenic therapy at the forefront of change to the standard treatment of difficult to treat ovarian cancer.     

子宫浆液性癌的分子学特征及靶向治疗研究进展

子宫浆液性癌（uterine serous carcinoma,USC）是一种特殊类型的子宫内膜癌。有别于常见的子宫内膜样腺癌,USC较为少见,且恶性程度高,侵袭转移风险高,临床上预后较差。随着子宫内膜癌分子学研究的不断深入,分子学特征被应用于子宫内膜癌的病理分型诊断、治疗和预后评价中。研究发现USC中存在多种基因的突变,这些相关基因的突变对该病的诊断和预后具有重要的指导意义。同时,特异性的分子学改变为USC的靶向治疗提供了潜在的治疗靶点。目前,多种靶向治疗手段包括人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）抑制剂、免疫检查点抑制剂、抗血管生成治疗、磷脂酰肌醇3激酶（phosphoinositide 3-kinases,PI3K）通路抑制剂和多腺苷二磷酸核糖聚合酶[poly(ADP-ribose) polymerase,PARP]抑制剂等被应用于USC的临床治疗研究中,针对性的靶向治疗有望成为USC治疗的新突破。