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Altered efficacy of AT1R-targeted treatment after spontaneous cancer cell-AT1R upregulation.

Ager EI, Wen SW, Chan J, Chong WW, Neo JH, Christophi C - BMC Cancer (2011)

Bottom Line: The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells.While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.

View Article: PubMed Central - HTML - PubMed

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

ABSTRACT

Background: Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We aimed to establish if combined targeting of the 'classical' and 'alternative' arms of the RAS could result in synergistic inhibition of colorectal cancer (CRC) liver metastases.

Methods: Immediately following induction of CRC liver metastases through intrasplenic injection of murine CRC cells, treatment with irbesartan (AT1R blocker; 50 mg/kg/day s.c.), captopril (ACE inhibitor; 750 mg/kg/day i.p.), CGP42112A (AT2R agonist; 0.6 μg/kg/hr i.p.), and/or ANG-(1-7) (24 μg/kg/hr i.p.) began and continued for 21 days. Liver to body weight ratio and/or stereology were used as a measure of tumour burden. Immunohistochemistry was used to determine AT1R and VEGF expression as well as proliferation (Ki67), apoptosis (active caspase 3) and angiogenesis (CD34).

Results: Combined RAS therapies failed to improve upon single arm therapies. However, while irbesartan previously inhibited tumour growth in this model, in the current experiments irbesartan failed to affect tumour burden. Subsequent analysis showed a cancer-cell specific upregulation of the angiotensin II type I receptor (AT1R) in irbesartan-insensitive compared to irbesartan-sensitive tumours. The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells. While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.

Conclusions: Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.

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Related in: MedlinePlus

The number of apoptotic cells per tumour area (measured at 200x magnification). n = 5 or 6 for each group except for AT1RLOW tumours which, because of the reduced tumour load, had additional samples (n of 10). Between 10 and 30 images were taken from each mouse across 1 to 5 tumours (dependent on tumour load). Representative images are shown to the right. Significant P values between 0.01 and 0.05 are shown with an *, those less than 0.01 are shown with **. Data are presented as mean ± S.E.M.
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Figure 5: The number of apoptotic cells per tumour area (measured at 200x magnification). n = 5 or 6 for each group except for AT1RLOW tumours which, because of the reduced tumour load, had additional samples (n of 10). Between 10 and 30 images were taken from each mouse across 1 to 5 tumours (dependent on tumour load). Representative images are shown to the right. Significant P values between 0.01 and 0.05 are shown with an *, those less than 0.01 are shown with **. Data are presented as mean ± S.E.M.

Mentions: Irbesartan treatment significantly increased the number of apoptotic cells in both AT1RHI tumours (P = 0.0291, t-test) and AT1RLOW tumours (P = 0.0144) (Figure 5). Although this increase was not as great in the AT1RHI tumours compared to that seen in the AT1RLOW tumours. Both treated and non-treated AT1RHI tumours showed higher levels of apoptosis than their corresponding AT1RLOW tumours (P ≤ 0.000, t-test).


Altered efficacy of AT1R-targeted treatment after spontaneous cancer cell-AT1R upregulation.

Ager EI, Wen SW, Chan J, Chong WW, Neo JH, Christophi C - BMC Cancer (2011)

The number of apoptotic cells per tumour area (measured at 200x magnification). n = 5 or 6 for each group except for AT1RLOW tumours which, because of the reduced tumour load, had additional samples (n of 10). Between 10 and 30 images were taken from each mouse across 1 to 5 tumours (dependent on tumour load). Representative images are shown to the right. Significant P values between 0.01 and 0.05 are shown with an *, those less than 0.01 are shown with **. Data are presented as mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3141779&req=5

Figure 5: The number of apoptotic cells per tumour area (measured at 200x magnification). n = 5 or 6 for each group except for AT1RLOW tumours which, because of the reduced tumour load, had additional samples (n of 10). Between 10 and 30 images were taken from each mouse across 1 to 5 tumours (dependent on tumour load). Representative images are shown to the right. Significant P values between 0.01 and 0.05 are shown with an *, those less than 0.01 are shown with **. Data are presented as mean ± S.E.M.
Mentions: Irbesartan treatment significantly increased the number of apoptotic cells in both AT1RHI tumours (P = 0.0291, t-test) and AT1RLOW tumours (P = 0.0144) (Figure 5). Although this increase was not as great in the AT1RHI tumours compared to that seen in the AT1RLOW tumours. Both treated and non-treated AT1RHI tumours showed higher levels of apoptosis than their corresponding AT1RLOW tumours (P ≤ 0.000, t-test).

Bottom Line: The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells.While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.

View Article: PubMed Central - HTML - PubMed

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

ABSTRACT

Background: Targeting of the renin angiotensin system (RAS) reduces tumour growth in experimental models of cancer. We aimed to establish if combined targeting of the 'classical' and 'alternative' arms of the RAS could result in synergistic inhibition of colorectal cancer (CRC) liver metastases.

Methods: Immediately following induction of CRC liver metastases through intrasplenic injection of murine CRC cells, treatment with irbesartan (AT1R blocker; 50 mg/kg/day s.c.), captopril (ACE inhibitor; 750 mg/kg/day i.p.), CGP42112A (AT2R agonist; 0.6 μg/kg/hr i.p.), and/or ANG-(1-7) (24 μg/kg/hr i.p.) began and continued for 21 days. Liver to body weight ratio and/or stereology were used as a measure of tumour burden. Immunohistochemistry was used to determine AT1R and VEGF expression as well as proliferation (Ki67), apoptosis (active caspase 3) and angiogenesis (CD34).

Results: Combined RAS therapies failed to improve upon single arm therapies. However, while irbesartan previously inhibited tumour growth in this model, in the current experiments irbesartan failed to affect tumour burden. Subsequent analysis showed a cancer-cell specific upregulation of the angiotensin II type I receptor (AT1R) in irbesartan-insensitive compared to irbesartan-sensitive tumours. The upregulation of AT1R was associated with an increase in proliferation and VEGF expression by cancer cells. While animals bearing irbesartan-sensitive tumours showed a marked decrease in the number of proliferating cells in the liver and VEGF-expressing infiltrating cells in the tumour following AT1R treatment, these were unchanged by treatment in animals bearing irbesartan-insensitive (high AT1R expressing) tumours.

Conclusions: Although the results do not support increased efficacy of combined treatment, they provide intriguing evidence of the importance of RAS expression in determining patient response and tumour growth potential and suggest that components of the RAS could be used as biomarkers to aid in patient selection.

Show MeSH
Related in: MedlinePlus