Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis

Metastasis is a complex process which contributes to the dissemination of cancer cells to other organs and forms new tumor sites. The proliferation of tumor cells is a necessary step for the initiation and progression of cancers and is associated with the formation of new vessels. In the latter stages of metastasis, cancer cells may spread into the extracellular matrix and may form metastatic nodules. Despite efforts to prevent this, effective therapies are limited in the treatment of some malignancies. Among the different tumor properties which could be usefully employed as a cancer target, metastasis may be one suitable target. The renin- angiotensin system is a physiological pathway that contributes to the proliferation of tumor cells, angiogenesis and the inflammatory response in tumor tissue. Angiotensin II (ANGII), a key peptide of this pathway, induces cell proliferation through the activation of two cellular pathways (mitogen-activated protein kinase (MAPK)-STAT3 and phosphoinositide 3-kinase (PI3K) –AKT pathway). AT1-R increases angiogenesis via the elevation of angiogenic factors expression (vascular endothelial growth factor (VEGF) and matrix metallopeptidases (MMPs)). The local activation of the RAS pathway increases the expression of ICAM, VCAM and MMPs genes that are involved in the late steps of the metastasis process. There is some evidence that RAS components are expressed in metastatic tumors and RASIs (renin-angiotensin system inhibitors) could be used to reduce cancer metastasis by affecting the mechanisms involved in several different cancers. Therefore, we have summarized the effects of RASIs, observed in pre-clinical and clinical studies of cancer cell metastasis.