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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

PCNA staining of CRC cells growing in the liver (A) shows that CGP42112A treatment inhibited MoCR proliferation in vivo. Immunostaining for active caspase 3 also confirmed a treatment-induced increase in cancer cell apoptosis (B) in the same in vivo model. MoCR metastases were induced in the liver of CBA mice and allowed to grow for 21 days before fixing in PFA and immunohistochemcial analyses. 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 5: PCNA staining of CRC cells growing in the liver (A) shows that CGP42112A treatment inhibited MoCR proliferation in vivo. Immunostaining for active caspase 3 also confirmed a treatment-induced increase in cancer cell apoptosis (B) in the same in vivo model. MoCR metastases were induced in the liver of CBA mice and allowed to grow for 21 days before fixing in PFA and immunohistochemcial analyses. 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: Immunohistochemical staining for PCNA on tumour bearing liver specimens was performed to determine if CGP42112A could inhibit proliferation of cancer cells in vivo. CGP42112A (P = 0.029, Games-Howell) treatment caused a reduction in proliferation of tumour cells (Figure 5A). Immunohistochemical staining for active Caspase-3 was used to distinguish apoptotic cancer cells for quantitative analysis. CGP42112A treatment resulted in a significant increase (P = 0.018, Bonferroni t-test) in apoptosis of tumour cells growing in the liver compared to controls (Figure 5B).


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

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

PCNA staining of CRC cells growing in the liver (A) shows that CGP42112A treatment inhibited MoCR proliferation in vivo. Immunostaining for active caspase 3 also confirmed a treatment-induced increase in cancer cell apoptosis (B) in the same in vivo model. MoCR metastases were induced in the liver of CBA mice and allowed to grow for 21 days before fixing in PFA and immunohistochemcial analyses. 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 5: PCNA staining of CRC cells growing in the liver (A) shows that CGP42112A treatment inhibited MoCR proliferation in vivo. Immunostaining for active caspase 3 also confirmed a treatment-induced increase in cancer cell apoptosis (B) in the same in vivo model. MoCR metastases were induced in the liver of CBA mice and allowed to grow for 21 days before fixing in PFA and immunohistochemcial analyses. 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: Immunohistochemical staining for PCNA on tumour bearing liver specimens was performed to determine if CGP42112A could inhibit proliferation of cancer cells in vivo. CGP42112A (P = 0.029, Games-Howell) treatment caused a reduction in proliferation of tumour cells (Figure 5A). Immunohistochemical staining for active Caspase-3 was used to distinguish apoptotic cancer cells for quantitative analysis. CGP42112A treatment resulted in a significant increase (P = 0.018, Bonferroni t-test) in apoptosis of tumour cells growing in the liver compared to controls (Figure 5B).

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