EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts.
2013
Tumor progressionis deeply influenced by epigenetic changes induced by tumor stroma. Cancer-associated fibroblasts (CAFs) have been reported to promote
epithelial–mesenchymal transitionin
cancer cells, thereby enhancing their aggressiveness and stem-like properties. As CAFs are able to recruit
endothelial progenitor cells(EPCs) to tumor site, we aim to investigate their interplay for prostate carcinoma progression. Both prostate CAFs and
cancer cellsactively recruit EPCs, known to affect
tumor progressionthrough increased
vasculogenesis. EPCs synergize with CAFs to further promote epigenetic plasticity of
cancer cells, through a
mesenchymal-to-amoeboid transition. Indeed, after fibroblasts have engaged
epithelial–mesenchymal transitionin
cancer cells, a further shift towards amoeboid motility is promoted by EPCs through contact-mediated triggering of the bidirectional ephrinA1/EphA2 signaling. The activation of ephrinA1 reverse pathway enhances EPC-induced neo-vascularization, thus promoting tumor growth, while EphA2 forward signaling elicits
mesenchymal–amoeboid transition in
cancer cells, favoring their adhesion to endothelium, transendothelial migration, and lung metastatic colonization. We therefore underscore that the metastatic advantage given by tumor microenvironment embraces different motility strategies and propose EphA2-targeted tools as useful adjuvants in anti-metastatic treatments.
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