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Over the past few decades, VEGF‐targeted antiangiogenic therapy for cancers has gained increasing attention. Nevertheless, there are still several limitations such as the potential resistance mechanisms arising in cancer cells against these therapies and their potential adverse effects. These limitations highlight the need for novel anti‐angiogenesis molecules and better understanding of the mechanisms of tumor angiogenesis. In the present study, we investigated the antiangiogenic properties of a novel 14‐mer antiangiogenic peptide (14‐MAP) derived from N‐terminal 14 kDa buffalo prolactin and characterized its mode of action. 14‐MAP at the picomolar concentration inhibited VEGF‐ and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology, BK)‐stimulated endothelial nitric oxide (eNO) production, cell migration, and proliferation in endothelial cells and vessel development in the chick embryo. Although this peptide inhibited both VEGF‐ and BK‐dependent angiogenic processes, its action was more pronounced in the latter. Moreover, the interference of 14‐MAP with the eNO synthase (eNOS)‐cyclic GMP pathway was also identified. A combination of a low dose of Avastin, a widely used drug targeting VEGF‐dependent angiogenesis, and 14‐MAP significantly reduced tumor size in an in vivo model of human colon cancer. Taken together, our results suggest that 14‐MAP, a BK‐ and eNOS‐dependent antiangiogenic peptide, might be useful for overcoming the limitation of VEGF‐targeted antiangiogenic therapy in cancer patients. However, further studies will be required to further characterize its mode of action and therapeutic potential.

OTX2 promotes tumour growth in Group 3 medulloblastoma. Here, the authors show that OTX2 regulates PAX3 to induce neural de-differentiation and promote tumourigenesis in Group 3 medulloblastoma.

Thalidomide, a powerful teratogen, re-emerged as a wonder drug for its teratogenic, anti-angiogenic and anti-tumor properties. Being FDA approved for Multiple Myeloma along with the analogs lenalidomide and pomalidomide is currently being tested in more than 2000 clinical trials for a range of conditions including solid tumors and inflammatory disorders. Fibroblast growth factor receptors (FGFRs) play key roles in embryonic development and cancer. There are indications that thalidomide might be linked to FGFR biology, however no experimental evidence is available till now. To understand the effects of thalidomide and its analogs, lenalidomide and pomalidomide, we utilized in silico predictive tools, kinome profiling, transcriptome and phophoproteome tools to study the modulation of FGFR signalling in endothelium. Genecodis and Enrichr with the differentially expressed genes were used to obtain the Gene Ontology, Transcription factor, Pathway and miRNA enrichments. The association of the drug with FGFR signalling was investigated at various levels. Protein-chemical network tool, STITCH and Pocketome predicted strong association of thalidomide with FGFR2. At gene expression level, FGFR1 and FGFR2 were found to be affected under the three drug treatments in in vitro and in vivo models. Kinomescan results suggest the binding of thalidomide with high affinity to a mutant FGFR3 (G697C) and FGFR2. To validate this, we checked the activity of FGFR2 kinase under the three drug treatments and found that they affected the kinase activity in a dose-dependent manner with pomalidomide having lowest IC50 value. Blind docking using Autodock revealed the possible binding sites and interestingly all the three analogs were predicted to bind to Lys517 of FGFR2. Lys517 is one of the ATP binding sites, suggesting that possibly analogs interfere with the ATP binding. Taken together, FGFRs could be potential targets of thalidomide and its analogs and the modulation of FGFRs by thalidomide partially explain the teratogenic and anti-tumor properties of the drug. Thus through different platforms, the mechanisms of drugs could be understood in a better way. This in turn will aid in modifying the drug structures resulting in the development of new analogs with more efficacy and reduced undesired effects.

Existing animal models for screening tumor angiogenic process have various setbacks that necessitate further investigations. In this study, we developed an ex-ovo egg yolk angiogenesis model to screen the angiogenic potency of tumor cells (HeLa and SiHa cell lines). The egg yolk angiogenesis assay was applied to study the nitric oxide (NO) influence on switching from sprouting angiogenesis (SA) to intussusceptive angiogenesis (IA) under tumor microenvironment. Morphological analysis and SA-like or IA-like markers expression were determined during the development of chicken chorioallantoic membrane (CAM) from day 5 to 13. Expression of Notch1, Notch2, EphrinB2, and Tie2 were considered as SA-like while TEM8, CALD1, CXCR4 and HOMX1 were followed as IA-like markers. The HeLa and SiHa cell lines embedded CAM showed an increase in micro and macro blood vessels and vascular size, junction and length which are the pivotal morphological parameters of angiogenesis. Further, the study revealed that HeLa is more aggressive than SiHa in inducing tumor angiogenesis. To determine the NO signaling implication in tumor milieu, NO donor (Spermine NONOate (SPNO)), NOS inhibitor (L-nitro-L-arginine-methyl ester (L-NAME) and VEGF inhibitor (Avastin) were administrated to chick embryo vascular bed with and without HeLa cells. The results demonstrated that HeLa cells promote IA through NO signaling, VEGF and eNOS and it was documented by angiogenic morphological parameters and SA-like or IA-like markers expression. Therefore, our study claims that ex-ovo egg yolk angiogenesis model could be used to study tumor angiogenesis and NO plays a key role in switching of IA under tumor microenvironment., (Copyright © 2018 Elsevier Inc. All rights reserved.)