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

Ager EI, Chong WW, Wen SW, Christophi C - Cancer Cell Int. (2010)

Bottom Line: This increase in VEGF secretion by MoCRs was confirmed in vitro.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. eager@unimelb.edu.au.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Representative images of the kidney (upper panels) and lung (lower panel) for treated and control mice. No histological differences could be discerned.
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Figure 7: Representative images of the kidney (upper panels) and lung (lower panel) for treated and control mice. No histological differences could be discerned.

Mentions: Lung and kidney tissues were collected to ensure that these organs, both of which are important in the systemic RAS and which have important local RAS, were unaltered by treatment (Figure 7). This analysis was important as, to the best of the authors knowledge, CGP42112A has not yet been tested in vivo for the length of time studied here. No notable changes in either the lungs or kidneys between treated and control groups were found nor was there any evidence of altered behaviour or general condition between control and treatment groups.


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

Ager EI, Chong WW, Wen SW, Christophi C - Cancer Cell Int. (2010)

Representative images of the kidney (upper panels) and lung (lower panel) for treated and control mice. No histological differences could be discerned.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902462&req=5

Figure 7: Representative images of the kidney (upper panels) and lung (lower panel) for treated and control mice. No histological differences could be discerned.
Mentions: Lung and kidney tissues were collected to ensure that these organs, both of which are important in the systemic RAS and which have important local RAS, were unaltered by treatment (Figure 7). This analysis was important as, to the best of the authors knowledge, CGP42112A has not yet been tested in vivo for the length of time studied here. No notable changes in either the lungs or kidneys between treated and control groups were found nor was there any evidence of altered behaviour or general condition between control and treatment groups.

Bottom Line: This increase in VEGF secretion by MoCRs was confirmed in vitro.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. eager@unimelb.edu.au.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus