Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

The corticotropin-releasing factor (CRF) receptor CRFR2 is expressed widely in peripheral tissues and in the vasculature, although its functional roles in those tissues have only recently begun to be elucidated. Previously we found that genetic deletion of CRFR2 resulted in profound postnatal hyperv...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (10), p.3939-3944
Main Authors: Hao, Zhengrong, Huang, Yan, Cleman, Jake, Jovin, Ion S, Vale, Wylie W, Bale, Tracy L, Giordano, Frank J
Format: Article
Language:English
Subjects:
Adenoviruses
Animals
Biological Sciences
Cancer
Carcinoma, Lewis Lung - blood supply
Carcinoma, Lewis Lung - genetics
Carcinoma, Lewis Lung - pathology
Cell cycle
Cell growth
Cell Proliferation
Cells
Endothelial cells
Gene Expression Regulation, Neoplastic
Ligands
Lungs
Male
Mast cells
Mice
Mice, Inbred C57BL
Neovascularization, Pathologic - pathology
Peptides
Receptors
Receptors, Corticotropin-Releasing Hormone - genetics
Receptors, Corticotropin-Releasing Hormone - metabolism
Rodents
Tumor burden
Tumors
Ultrasonography
Urocortins - metabolism
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Summary:The corticotropin-releasing factor (CRF) receptor CRFR2 is expressed widely in peripheral tissues and in the vasculature, although its functional roles in those tissues have only recently begun to be elucidated. Previously we found that genetic deletion of CRFR2 resulted in profound postnatal hypervascularization in mice, characterized by both an increase in total vessel number and a dramatic increase in vessel diameter. These data strongly suggested that ligands for CRFR2 act to limit tissue vascularity, perhaps as a counterbalance to factors that promote neovascularization. Urocortin 2 (Ucn2) is a specific ligand for the CRFR2. We hypothesized that activation of CRFR2 by Ucn2 might thus suppress tumor vascularization and consequently limit tumor growth. Here, we show that viral-mediated expression of Ucn2 strikingly inhibits the growth and vascularization of Lewis Lung Carcinoma Cell (LLCC) tumors in vivo. Further, we found that this effect on tumor growth inhibition was independent of whether exposure to Ucn2 occurred before or after establishment of measurable tumors. In vitro, Ucn2 directly inhibited the proliferation of LLCC, suggesting that the tumor-suppressing effects of CRFR2 activation involve a dual mechanism of both a direct inhibition of tumor cell cycling and the suppression of tumor vascularization. These results establish that Ucn2 inhibits tumor growth, suggesting a potential therapeutic role for CRFR2 ligands in clinical malignancies.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0712366105