Endothelin-1 induced Mxi-2/Ago2 complex formation resulting in P53 downregulation promoting breast cancer development

Melanie von Brandenstein, Julia Straube, Heike Loeser, Luca Ozretic, Jochen W.U. Fries
2013 Life Sciences  
Pathological angiogenesis and lymphangiogenesis are a hallmark of cancer and both serve as the major routes for cancer cell dissemination and metastasis. The tumor-vasculogenic process is the result of the interaction between endothelial and tumor cells and requires the coordinated actions of growth factors with both angiogenic and lymphangiogenic properties. Unrevealing the potential mediators able to modulate this complex process would provide the basis for the development of molecularly
more » ... ted therapeutics directed against both tumor and tumor-associated endothelial cells. The multifunctional peptide endothelin-1 (ET-1) and its receptors have been correlated with invasiveness and metastasis and have been shown to be markedly increased in the vasculature of several kinds of tumors and associated with tumor grade and poor prognosis. ET-1 acts in both blood and lymphatic endothelial as well as in tumor cells through its G-protein coupled receptors, ETA and ETB, to promote angiogenesis and lymphangiogenesis. The mechanism by which ET-1 promotes these processes is beginning gradually defined. During tumor progression ET-1 exerts crucial roles in the vasculogenic switch promoting, via ETBR, endothelial cell proliferation, migration, protease production and morphogenesis, and, via both receptors, vascular endothelial growth factor (VEGF) release. Moreover, ET-1 stimulates highly aggressive tumor cells to form vessel-like networks that do not involve endothelial cells. The ET-1-induced vasculogenic effects, progress through the induction of the transcriptional hypoxia-inducible factor (HIF)-1α and HIF-2α, and through a complex interplay with VEGF family members. Furthermore, expression of ET-1 and its receptors is controlled by VEGF and hypoxia in both endothelial and tumor cells, suggesting that a positive interegulation between ET-1/HIF-1α, VEGF and hypoxia is able to amplify the neovasculogenic response. The better mechanistic understanding of these complex interactions is gradually paving the way toward the rationale exploitation of the ET-1/ET receptor signaling pathway as a therapeutically attractive target for neoplastic disease characterized by active neovascularisation.
doi:10.1016/j.lfs.2013.12.041 fatcat:xyxex6zqwna5nbtrpfzwovwf3q