Purpose: Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, seeding, growth, and angiogenesis, as well as suppression of anti-tumor immunity. Migration of inflammatory monocytes to sites of inflammation or tumor metastasis is mediated primarily via the action of the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis through receptor or ligand blockade represents an attractive therapeutic target for the treatment of metastatic disease.
Methods: Losartan, an angiotensin II type 1 receptor (AT1R) antagonist, has been previously reported to suppress tumor growth through mechanisms associated with tumor angiogenesis and inhibition of TGF-β signaling. However, our studies also suggest an important contribution to the anti-tumor effects of losartan from monocyte migration inhibition. Therefore, we conducted studies in murine breast (4T1) and colon (CT26) carcinoma experimental pulmonary metastasis models, to determine the degree to which losartan's anti-metastatic effect was predominantly dependent on disruption of CCL2-CCR2 mediated monocyte recruitment to tumor metastases.
Results: We found that daily treatment with losartan prolonged survival, and significantly reduced metastatic burden, percentages of CD11b+/Ly6C+ lung monocytes, and tumor microvessel density in mice with 4T1 and CT26 pulmonary metastases. However, compared to pure CCR2 antagonists, our studies show that losartan does not act as a direct competitive antagonist to CCR2. Rather, in vitro assays and studies in CCR2 -\- mice indicated that losartan's anti-metastatic effect was primarily mediated via suppression of monocyte recruitment through indirect interruption of the CCL2-CCR2 axis. Importantly, losartan proved more effective at reducing monocyte recruitment and slowing CT26 pulmonary metastatic tumor growth compared to a specific CCR2 antagonist.
Conclusions: We conclude therefore that losartan exerts significant anti-metastatic activity in aggressive murine metastasis models, and that losartan's major anti-metastatic effect is mediated by blockade of CCL2-CCR2 dependent monocyte recruitment. Thus, by virtue of its myeloid cell activity, losartan, in combination with conventional cancer therapeutics, has potential for use as an anti-metastatic agent in animals and humans at high risk for tumor metastasis.
Citation Format: Daniel P. Regan, Amanda M. Guth, Ryan J. Hansen, Daniel L. Gustafson, Steven W. Dow. Angiotensin II type 1 receptor antagonism suppresses tumor metastasis through inhibition of CCL2-CCR2 mediated monocyte recruitment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A161.
- ©2016 American Association for Cancer Research.