Targeting the angiotensin II type 2 receptor AT2R in colorectal liver metastasesReport as inadecuate




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Cancer Cell International

, 10:19

First Online: 28 June 2010Received: 25 November 2009Accepted: 28 June 2010

Abstract

BackgroundBlockade of the angiotensin ANG II type 1 receptor AT1R inhibits tumour growth in several cancers, including colorectal cancer CRC liver metastases. While AT1R blockade has been extensively studied, the potential of targeting the antagonistically acting AT2R in cancer has not been investigated. This study examined the effect of AT2R activation with the agonist CGP42112A in a mouse model of CRC liver metastases.

ResultsIn vitro, mouse CRC cell MoCR proliferation was inhibited by treatment with CGP42112A in a dose dependent manner while apoptosis was increased. Immunofluorescent staining for key signalling and secondary messengers, PLA2 and iNOS, were also increased by CGP42112A treatment in vitro. Immunohistochemical staining for proliferation PCNA and the apoptosis active caspase 3 markers confirmed a CGP42112A-associated inhibition of proliferation and induction of apoptosis of mouse CRC cells MoCR in vivo. However, angiogenesis and vascular endothelial growth factor VEGF appeared to be increased by CGP42112A treatment in vivo. This increase in VEGF secretion by MoCRs was confirmed in vitro. Despite this apparent pro-angiogenic effect, a syngenic orthotopic mouse model of CRC liver metastases showed a reduction in liver to body weight ratio, an indication of tumour burden, following CGP42112A treatment compared to untreated controls.

ConclusionsThese results suggest that AT2R activation might provide a novel target to inhibit tumour growth. Its potential to stimulate angiogenesis could be compensated by combination with anti-angiogenic agents.

AbbreviationsANG IIangiotensin II

ANG-1-7angiotensin-1-7

ACEangiotensin converting enzyme

AT1Rangiotensin II type 1 receptor

AT2Rangiotensin II type 2 receptor

CRCcolorectal cancer

MasRmitochondrial assembly receptor

NOnitric oxide

iNOSinducible nitric oxide synthase

PLA2phospholypase A2

RASrenin angiotensin system

VEGFvascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2867-10-19 contains supplementary material, which is available to authorized users.

An erratum to this article is available at http:-dx.doi.org-10.1186-1475-2867-10-37.

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Author: Eleanor I Ager - Way W Chong - Shu-wen Wen - Christopher Christophi

Source: https://link.springer.com/







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