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EphA2-mediated mesenchymal–amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts

Abstract

Tumor progression is deeply influenced by epigenetic changes induced by tumor stroma. Cancer-associated fibroblasts (CAFs) have been reported to promote epithelial–mesenchymal transition in 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 cells actively recruit EPCs, known to affect tumor progression through 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 transition in 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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Acknowledgments

This work was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), by Istituto Toscano Tumori and Regione Toscana (TUMAR). We thank Dr. Sergio Serni for prostate surgical specimens and Eugenio Torre for histological analyses.

Conflict of interest

The authors declare no conflict of interest.

Author information

Correspondence to Paola Chiarugi.

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Giannoni, E., Taddei, M.L., Parri, M. et al. EphA2-mediated mesenchymal–amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts. J Mol Med 91, 103–115 (2013) doi:10.1007/s00109-012-0941-9

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Keywords

  • Cancer-associated fibroblasts
  • Endothelial progenitor cells
  • Ephrins
  • Mesenchymal-to-amoeboid transition
  • Vasculogenesis