Abstract
S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.
Highlights
Angiogenesis is a crucial multi-step process in tumor growth, disease progression, and metastasis, where an orderly activation of genes controlling proliferation, invasion, migration and survival of endothelial cells (EC) participate, forming the angiogenic cascade [1,2].In the last decades, the active research in this field led to the development of regulatory approvals through the blockade of pathways related to vascular endothelial growth factor (VEGF), providing an effective therapeutic demonstration of the proof of concept in certain types of cancer [3,4,5]
S100A4 was tested in the dose range of 0.3–3 mM, exhibiting a small but significant migration activity at 3 mM
To address the question of whether S100A4 could serve as a therapeutic target in vivo, we evaluated the effect of S100A4 overexpression in a non-expressing human melanoma cell line (M21)
Summary
Angiogenesis is a crucial multi-step process in tumor growth, disease progression, and metastasis, where an orderly activation of genes controlling proliferation, invasion, migration and survival of endothelial cells (EC) participate, forming the angiogenic cascade [1,2].In the last decades, the active research in this field led to the development of regulatory approvals through the blockade of pathways related to VEGF, providing an effective therapeutic demonstration of the proof of concept in certain types of cancer [3,4,5]. According to clinical data these therapies have not produced enduring efficacy in tumor reduction or long-term survival, due to an emergent resistance to the antiangiogenic therapy [6,7]. This limitation opens a new challenge for the knowledge and identification of other main factors involved in tumor angiogenesis to develop agents targeting multiple proangiogenic pathways [8,9]. Its members interact with specific target proteins involved in a variety of cellular processes, such as cell cycle regulation, cell growth, differentiation, motility and invasion, showing a strong association with some types of cancer [10,11]. Extracellular roles for S100 members (S100B, S100A2, S100A8, S100A9, S100A12, S100P) and for S100A4 have been reported and are closely associated with tumor invasion and metastasis [12,13]
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