A happy medium download

To further investigate these vascular functions, Hong Chen, Wang Min and colleagues generated mice with floxed epsin 1 and null epsin 2 alleles; double deficiency for these genes specifically in endothelial cells was achieved by driving the expression of the Cre recombinase from the vascular-endothelial cadherin VEcad ; also known as Cdh5 promoter.

These mice were more resistant to the growth of subcutaneous allografts of melanoma and lung cancer cells, and orthotopic allografts of glioblastoma, as wellas to spontaneous tumours such ascarcinogen-induced colorectal cancer and large T antigen-driven prostate cancer, compared with wild-type mice. Whereas normal organ vasculature was relatively unaffected by epsin deficiency, the tumour vessels were enlarged, disorganized and leaky, probably resulting in impaired oxygen and nutrient supply to the tumours.

So, what is the molecular explanation for these effects? Given the endocytic roles of epsins, the authors investigated whether epsins might normally promote the internalization and degradation of VEGFR2 and thus the downregulation of VEGF signalling. However, in endothelial cells that lacked epsin 1 and epsin 2, VEGFR2 endocytosis was defective; this led to enhanced proliferative and migratory responses to VEGF stimulation in vitro , and to increased angiogenesis in response to ectopic VEGF expression in vivo.

Overall, this work suggests a model in which a 'medium' level of VEGF signalling is required to support tumour growth, and that a lack of epsin 1 and epsin 2 leaves vessels hypersensitive to VEGF stimulation and the resulting dysfunctional and tumour-suppressive angiogenesis. In support of this, injecting a VEGFR2 inhibitor into tumour-bearing mice was tumour promoting in mice that were deficient for epsin 1 and epsin 2 but was tumour suppressive in wild-type mice.

It will be interesting to see whether targeting epsins, with the aim of disrupting the tumour vasculature, will be a promising therapeutic strategy.

Key challenges include assessing the safety of systemic rather than endothelial-specific epsin targeting, whether it will be effective for controlling established tumours and determining when the pro-angiogenic effects will be tumour-promoting rather than tumour-suppressive. Pasula, S. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. Download references. You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Burgess, D. A happy medium?.

Nat Rev Cancer 13, 5 Download citation. Published : 13 December Issue Date : January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Cellular and Molecular Life Sciences Plot Summary. Murry Mr. Murry Mrs. Whatsit Mrs.

Who Mrs. LitCharts Teacher Editions. Teach your students to analyze literature like LitCharts does. Detailed explanations, analysis, and citation info for every important quote on LitCharts. The original text plus a side-by-side modern translation of every Shakespeare play. Sign Up. Already have an account? Sign in. From the creators of SparkNotes, something better.

Literature Poetry Lit Terms Shakescleare. Download this LitChart! Teachers and parents! Struggling with distance learning? Themes All Themes. Symbols All Symbols. Theme Wheel. Everything you need for every book you read. The way the content is organized and presented is seamlessly smooth, innovative, and comprehensive. Before going to the dark planet, Camazotz, the Mrs. W's take the children to see the Happy Medium , who lives on a planet on Orion's belt and who can show them in her crystal ball things that are happening all over the universe.

The Medium shows them the evil that is happening, but also the good that is being done to fight the evil, so that the children can achieve a happy medium in their outlook going in to fight the Black Thing.

For each quote, you can also see the other characters and themes related to it each theme is indicated by its own dot and icon, like this one:. Chapter 5 Quotes.