EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts.
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.
Department of Biochemical Sciences, University of Florence, viale Morgagni 50, 50134 Florence, Italy.
Elisa
E
Giannoni
Maria Letizia
ML
Taddei
Matteo
M
Parri
Francesca
F
Bianchini
Michela
M
Santosuosso
Renata
R
Grifantini
Gabriella
G
Fibbi
Benedetta
B
Mazzanti
Lido
L
Calorini
Paola
P
Chiarugi
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018450:Disease Progression; D036382:Ephrin-A1 / Q000235:genetics / Q000378:metabolism; D036383:Ephrin-A2 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007231:Infant, Newborn; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration; D059016:Tumor Microenvironment
D036382:Ephrin-A1; D036383:Ephrin-A2