Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs. It promotes both EC network formation and enhances directed migration toward basic fibroblast growth factor. Activation of αvβ3 and bone marrow tyrosine kinase on chromosome X (BMX) is required for migration stimulated by direct binding but not for migration stimulated by soluble factors. RGD-peptide treatment of mice with established intracerebral GBM xenografts significantly reduced the percentage of Sox2-positive tumor cells and CSCs in close proximity to ECs, decreased integrin αvβ3 and BMX activation and p130CAS phosphorylation in the ECs, and reduced the vessel surface area. These results reveal a previously unrecognized aspect of the regulation of angiogenesis in GBM that can impact therapeutic anti-angiogenic targeting

Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity

BACKGROUND: Neuropilin-1 (NRP1) is a non-tyrosine kinase receptor for vascular endothelial growth factor (VEGF) recently implicated in tumour functions.METHODS: In this study we used a specific antagonist of VEGF binding to the NRP1 b1 domain, EG3287, to investigate the functional roles of NRP1 in human carcinoma cell lines, non-small-cell lung A549, kidney ACHN, and prostate DU145 cells expressing NRP1, and the underlying mechanisms involved.RESULTS: EG3287 potently displaced the specific binding of VEGF to NRP1 in carcinoma cell lines and significantly inhibited the migration of A549 and ACHN cells. Neuropilin-1 downregulation by siRNA also decreased cell migration. EG3287 reduced the adhesion of A549 and ACHN cells to extracellular matrix (ECM), and enhanced the anti-adhesive effects of a beta 1-integrin function-blocking antibody. EG3287 increased the cytotoxic effects of the chemotherapeutic agents 5-FU, paclitaxel, or cisplatin on A549 and DU145 cells, through inhibition of integrin-dependent cell interaction with the ECM.CONCLUSIONS: These findings indicate that NRP1 is important for tumour cell migration and adhesion, and that NRP1 antagonism enhances chemosensitivity, at least in part, by interfering with integrin-dependent survival pathways. A major implication of this study is that therapeutic strategies targeting NRP1 in tumour cells may be particularly useful in combination with other drugs for combating tumour survival, growth, and metastatic spread independently of an antiangiogenic effect of blocking NRP1. British Journal of Cancer (2010) 102, 541-552. doi:10.1038/sj.bjc.6605539 www.bjcancer.com Published online 19 January 2010 (C) 2010 Cancer Research U

The role of the VEGF-C/VEGFR-3 axis in cancer progression

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression

The CXC-Chemokine CXCL4 Interacts with Integrins Implicated in Angiogenesis

The human CXC-chemokine CXCL4 is a potent inhibitor of tumor-induced angiogenesis. Considering that CXCL4 is sequestered in platelet α-granules and released following platelet activation in the vicinity of vessel wall injury, we tested the hypothesis that CXCL4 might function as a ligand for integrins. Integrins are a family of adhesion receptors that play a crucial role in angiogenesis by regulating early angiogenic processes, such as endothelial cell adhesion and migration. Here, we show that CXCL4 interacts with αvβ3 on the surface of αvβ3-CHO. More importantly, human umbilical vein endothelial cells adhere to immobilized CXCL4 through αvβ3 integrin, and also through other integrins, such as αvβ5 and α5β1. We further demonstrate that CXCL4-integrin interaction is of functional significance in vitro, since immobilized CXCL4 supported endothelial cell spreading and migration in an integrin-dependent manner. Soluble CXCL4, in turn, inhibits integrin-dependent endothelial cell adhesion and migration. As a whole, our study identifies integrins as novel receptors for CXCL4 that may contribute to its antiangiogenic effect

Personally-oriented models of development of musically gifted children

Introduction. Nowadays, the development of national competitiveness depends on many factors, but the quality of human capital is first of all. One of priority tasks of education system in Russian Federation is search and support of gifted children and teenagers: creation of conditions for their productive education, full upbringing and optimum development of their abilities providing further maximum self-realisation of a person. Today, however, the implementation of these requirements is real only in megalopolises, large regional centers, but not in small cities, which have no sufficient resources and environment conditions, cultivating potential of every gifted child, especially in the case of art talent. The shortage of highly skilled teachers and cultural industry, weak involvement into cultural life (inability to attend concerts, theatrical performances, exhibitions, etc.), very limited access to participation in creative competitions, olympiads, competitions – all this negatively affects motivation engage in art activity and can lead to serious personal crises and waste of talent.The aim of the article was to reveal the content of models of work with musically gifted children, who have certain problems that block their creative development.Methodology and research methods. The research was based on personally-oriented and system-based approaches to education of gifted children. The authors considered the ideas of Russian and foreign researchers about the need for pedagogical support of gifted children, who have problems in general and cultural development. The methods of theoretical analysis of scientific and scientific-methodological resources, comparative analysis of the results of practical activity, generalisation, oral and written survey and modeling were employed.Results and scientific novelty. The most common challenges of the development of gifted children, who live in towns, are revealed: lack of motivation for creativity and further development; a low level of general culture; tense atmosphere in family, which is expressed most often in the inattentive relation of parents to interests and abilities of a child. The specialists of Ural Musical College and children’s art schools of the city of Ekaterinburg and Sverdlovsk region developed and approved the models of social and pedagogical support of gifted children to eliminate the causes of their failures in education. According to the classification of problems in the development of gifted children, three types of personally-oriented models are offered: 1) motivation to creative activity, 2) cultural self-enrichment, 3) conditions for creative development of the child in family. The realisation of each model should be based on close cooperation of staff members of specialised centres (e.g. in musical college) for work with musically gifted children, teachers of children’s music schools, teachers of educational institutions of towns, children and their parents. The most effective activities, contributing to the solution of the formulated tasks of each model, are identified: concert-performing, cultural-educational and analytical (fixation and reflection of the results of creative development).Practical significance. The experimental testing of models proved the efficiency and possibility of complete and partial use of their components in Russian schools in order to manage the process of development of musically gifted pupils