Abstract:
:The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. Whereas previous investigations have focused mostly on ET action in malignant cells, we chose a model allowing separate assessment of the effects of ETs and their receptors ET(A)R and ET(B)R in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ET(B)R deficiency, we showed significant reduction of growth and metastasis of MAT B III rat mammary adenocarcinoma cells overexpressing ET(A)R and ET-1 but negative for ET(B)R. Lack of stromal ET(B)R expression did not influence angiogenesis. However, it was correlated with diminished infiltration by tumor-associated macrophages and with reduced production of tumor necrosis factor-alpha, both known as powerful promoters of tumor progression. These effects were almost completely abolished in transgenic sl/sl rats, wherein ET(B)R function is restored by expression of an intact ET(B)R transgene. This shows that tumor growth and metastasis are critically dependent on ET(B)R function in cells of the microenvironment and suggests that successful ETR antagonist therapy should also target the stromal component of ET signaling
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Binder C,Hagemann T,Sperling S,Schulz M,Pukrop T,Grimshaw MJ,Ehrenreich Hdoi
10.1158/1535-7163.MCT-09-0032subject
Has Abstractpub_date
2009-08-01 00:00:00pages
2452-60issue
8eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-09-0032journal_volume
8pub_type
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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