Publication Date:
2008-04-18
Description:
The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamzah, Juliana -- Jugold, Manfred -- Kiessling, Fabian -- Rigby, Paul -- Manzur, Mitali -- Marti, Hugo H -- Rabie, Tamer -- Kaden, Sylvia -- Grone, Hermann-Josef -- Hammerling, Gunter J -- Arnold, Bernd -- Ganss, Ruth -- England -- Nature. 2008 May 15;453(7193):410-4. doi: 10.1038/nature06868. Epub 2008 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, Western Australia 6000, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18418378" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Capillary Permeability
;
Cell Hypoxia/physiology
;
Female
;
Male
;
Mice
;
Neovascularization, Pathologic/*prevention & control
;
Oxygen/metabolism
;
Pancreatic Neoplasms/*blood supply/genetics/*immunology/metabolism
;
RGS Proteins/*deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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