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Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases

BACKGROUND: Blockade 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...

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Autores principales: Ager, Eleanor I, Chong, Way W, Wen, Shu-wen, Christophi, Christopher
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902462/
https://www.ncbi.nlm.nih.gov/pubmed/20584290
http://dx.doi.org/10.1186/1475-2867-10-19
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author Ager, Eleanor I
Chong, Way W
Wen, Shu-wen
Christophi, Christopher
author_facet Ager, Eleanor I
Chong, Way W
Wen, Shu-wen
Christophi, Christopher
author_sort Ager, Eleanor I
collection PubMed
description BACKGROUND: Blockade 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. RESULTS: In 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. CONCLUSIONS: These 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.
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spelling pubmed-29024622010-07-13 Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases Ager, Eleanor I Chong, Way W Wen, Shu-wen Christophi, Christopher Cancer Cell Int Primary research BACKGROUND: Blockade 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. RESULTS: In 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. CONCLUSIONS: These 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. BioMed Central 2010-06-28 /pmc/articles/PMC2902462/ /pubmed/20584290 http://dx.doi.org/10.1186/1475-2867-10-19 Text en Copyright ©2010 Ager et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Primary research
Ager, Eleanor I
Chong, Way W
Wen, Shu-wen
Christophi, Christopher
Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title_full Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title_fullStr Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title_full_unstemmed Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title_short Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases
title_sort targeting the angiotensin ii type 2 receptor (at2r) in colorectal liver metastases
topic Primary research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902462/
https://www.ncbi.nlm.nih.gov/pubmed/20584290
http://dx.doi.org/10.1186/1475-2867-10-19
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