Changes in the renin angiotensin system during the development of colorectal cancer liver metastases.
BACKGROUND
Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease.


METHODS
Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software.


RESULTS
Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen.


CONCLUSIONS
These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade.
Neo
Jaclyn H
JH
Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. j.neo@pgrad.unimelb.edu.au
Ager
Eleanor I
EI
Angus
Peter W
PW
Zhu
Jin
J
Herath
Chandana B
CB
Christophi
Christopher
C
D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis; D012083:Renin / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin