title: Altered efficacy of AT1R-targeted treatment after spontaneous cancer cell-AT1R upregulation.
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.
authors.affiliation: The Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia. eager@unimelb.edu.au
authors.forename: Eleanor I
authors.initials: EI
authors.lastname: Ager
authors.forename: Shu Wen
authors.initials: SW
authors.lastname: Wen
authors.forename: Joyna
authors.initials: J
authors.lastname: Chan
authors.forename: Way W
authors.initials: WW
authors.lastname: Chong
authors.forename: Jaclyn H
authors.initials: JH
authors.lastname: Neo
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D000803:Angiotensin I / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D000077405:Irbesartan; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C060894:CGP 42112A; D000803:Angiotensin I; D002216:Captopril; C118790:angiotensin I (1-7); D000077405:Irbesartan