The endometrium has its own renin-angiotensin system (RAS). It is subject to control by estrogens and shows cyclical expression. The dominant pathway within tissue renin-angiotensin systems (RASs) is proangiogenic and proliferative.

Hypothesis: The endometrial RAS promotes the growth and spread of endometrial cancer.

Aim:  To study the expression and control of the RAS in an endometrial epithelial cancer cell line (ECC-1).

Methods: ECC-1 cells were cultured in phenol red-free DMEM/F-12, supplemented with 10% fetal bovine serum. Cells were treated with one of the following for 24 or 48h:

1)    vehicle

2)    0.3mM 8 Bromo-cAMP

3)    Ang II (50 nM)

4)    Losartan (1μM)

5)    rhprorenin (50 ng/mL)

6)    handle region peptide (HRP, 1 μM; a decapeptide which inhibits prorenin interacting with the prorenin receptor)

Expression of renin (REN), prorenin receptor (ATP6AP2), angiotensin converting enzyme (ACE), ACE2, angiotensinogen (AGT), the type 1 and type 2 Ang II receptors (AGTR1 and AGTR2), the Mas receptor (MasR) and vascular endothelial growth factor (VEGF) at 24 and 48 h was measured using qPCR with Alien as an internal standard.

Results: AGTR2, ACE2 and MasR were not detected. All other genes were expressed. cAMP increased expression of REN, ACE and VEGF mRNAs (all P<0.001, compared to vehicle).

Treatment with Ang II for 24h stimulated ACE (P<0.001) and VEGF expression (P=0.038), while treatment with the AT₁R blocking drug, losartan, suppressed VEGF expression (P=0.002). These effects were not sustained for 48h. Prorenin treatment stimulated AGT expression (P<0.015). Incubation with HRP suppressed ATP6AP2 (P<0.026) and VEGF expression (P<0.001).

Conclusion: Stimulation of the prorenin receptor/prorenin/ACE/AT₁R pathway in an endometrial cancer cell line is associated with upregulation of VEGF expression and inhibition of this pathway inhibits VEGF. Thus drugs that interfere with this pathway are potential anticancer agents through their actions on a key angiogenic pathway.