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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

Percent PI-positive MoCR cells. The percent of PI-positive (apoptotic) cells after 24 and 120 hours was assessed using FACs at the same time as CFSE analysis. Although the concentrations of CGP-421112A had their most significant effects at different times and under different background conditions, in general, CGP42112A treatment increased apoptosis. Significant P values are shown with an * and solid line, while those of interest with P values between 0.1 and 0.05 are indicated with a dotted line and no *. Data are presented as mean ± S.E.M.
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Figure 2: Percent PI-positive MoCR cells. The percent of PI-positive (apoptotic) cells after 24 and 120 hours was assessed using FACs at the same time as CFSE analysis. Although the concentrations of CGP-421112A had their most significant effects at different times and under different background conditions, in general, CGP42112A treatment increased apoptosis. Significant P values are shown with an * and solid line, while those of interest with P values between 0.1 and 0.05 are indicated with a dotted line and no *. Data are presented as mean ± S.E.M.

Mentions: 1 μM CGP42112A treatment for 24 hours significantly increased the percent of apoptotic MoCR cells when cultured in a background of 2% FBS compared to control (P = 0.0097, t-test; Figure 2A). Similar increases in apoptosis, although failing to reach significance, were seen at 48 and 72 hours. In the 0.1% FBS background, apoptosis was increased by both 0.1 and 1 μM CGP42112A, reaching significance for the 0.1 μM treatment (P = 0.0361). After 120 hours of treatment (Figure 2B), this increase in apoptosis remained evident and was significant in the 2% FBS background (P = 0.0323), while in the 0.1% FBS background the data was inconclusive but suggestive of a similar trend (P = 0.0595).


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

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

Percent PI-positive MoCR cells. The percent of PI-positive (apoptotic) cells after 24 and 120 hours was assessed using FACs at the same time as CFSE analysis. Although the concentrations of CGP-421112A had their most significant effects at different times and under different background conditions, in general, CGP42112A treatment increased apoptosis. Significant P values are shown with an * and solid line, while those of interest with P values between 0.1 and 0.05 are indicated with a dotted line and no *. Data are presented as mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Percent PI-positive MoCR cells. The percent of PI-positive (apoptotic) cells after 24 and 120 hours was assessed using FACs at the same time as CFSE analysis. Although the concentrations of CGP-421112A had their most significant effects at different times and under different background conditions, in general, CGP42112A treatment increased apoptosis. Significant P values are shown with an * and solid line, while those of interest with P values between 0.1 and 0.05 are indicated with a dotted line and no *. Data are presented as mean ± S.E.M.
Mentions: 1 μM CGP42112A treatment for 24 hours significantly increased the percent of apoptotic MoCR cells when cultured in a background of 2% FBS compared to control (P = 0.0097, t-test; Figure 2A). Similar increases in apoptosis, although failing to reach significance, were seen at 48 and 72 hours. In the 0.1% FBS background, apoptosis was increased by both 0.1 and 1 μM CGP42112A, reaching significance for the 0.1 μM treatment (P = 0.0361). After 120 hours of treatment (Figure 2B), this increase in apoptosis remained evident and was significant in the 2% FBS background (P = 0.0323), while in the 0.1% FBS background the data was inconclusive but suggestive of a similar trend (P = 0.0595).

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