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.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

  2. 2.

    Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150

  3. 3.

    Cirri P, Chiarugi P (2011) Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res 1:482–497

  4. 4.

    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

  5. 5.

    Cirri P, Chiarugi P (2011) Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev 31:195–208

  6. 6.

    Giannoni E, Parri M, Chiarugi P (2012) EMT and oxidative stress: a bidirectional interplay affecting tumor malignancy. Antioxid Redox Signal 16:1248–1263

  7. 7.

    Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428

  8. 8.

    Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

  9. 9.

    Friedl P (2004) Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 16:14–23

  10. 10.

    Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Res 70:6945–6956

  11. 11.

    Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374

  12. 12.

    Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749

  13. 13.

    Friedl P, Wolf K (2010) Plasticity of cell migration: a multiscale tuning model. J Cell Biol 188:11–19

  14. 14.

    Parri M, Taddei ML, Bianchini F, Calorini L, Chiarugi P (2009) EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res 69:2072–2081

  15. 15.

    Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Brocker EB, Friedl P (2003) Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160:267–277

  16. 16.

    Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19:6043–6052

  17. 17.

    Parri M, Buricchi F, Taddei ML, Giannoni E, Raugei G, Ramponi G, Chiarugi P (2005) EphrinA1 repulsive response is regulated by an EphA2 tyrosine phosphatase. J Biol Chem 280:34008–34018

  18. 18.

    Taddei ML, Parri M, Angelucci A, Onnis B, Bianchini F, Giannoni E, Raugei G, Calorini L, Rucci N, Teti A et al (2009) Kinase-dependent and -independent roles of EphA2 in the regulation of prostate cancer invasion and metastasis. Am J Pathol 174:1492–1503

  19. 19.

    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

  20. 20.

    Serrati S, Margheri F, Pucci M, Cantelmo AR, Cammarota R, Dotor J, Borras-Cuesta F, Fibbi G, Albini A, Del RM (2009) TGFbeta1 antagonistic peptides inhibit TGFbeta1-dependent angiogenesis. Biochem Pharmacol 77:813–825

  21. 21.

    Angelucci A, Gravina GL, Rucci N, Festuccia C, Muzi P, Vicentini C, Teti A, Bologna M (2004) Evaluation of metastatic potential in prostate carcinoma: an in vivo model. Int J Oncol 25:1713–1720

  22. 22.

    Margheri F, Chilla A, Laurenzana A, Serrati S, Mazzanti B, Saccardi R, Santosuosso M, Danza G, Sturli F, Rosati L et al (2011) Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae. Blood 118:3743–3755

  23. 23.

    Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA (2008) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109:1801–1809

  24. 24.

    Friedl P, Maaser K, Klein CE, Niggemann B, Krohne G, Zanker KS (1997) Migration of highly aggressive MV3 melanoma cells in 3-dimensional collagen lattices results in local matrix reorganization and shedding of alpha2 and beta1 integrins and CD44. Cancer Res 57:2061–2070

  25. 25.

    Giannoni E, Bianchini F, Calorini L, Chiarugi P (2011) Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 14:2361–2371

  26. 26.

    Cat B, Stuhlmann D, Steinbrenner H, Alili L, Holtkotter O, Sies H, Brenneisen P (2006) Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species. J Cell Sci 119:2727–2738

  27. 27.

    Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10:165–180

  28. 28.

    Taddei ML, Parri M, Angelucci A, Bianchini F, Marconi C, Giannoni E, Raugei G, Bologna M, Calorini L, Chiarugi P (2011) EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cells. Mol Cancer Res 9:149–160

  29. 29.

    Parri M, Chiarugi P (2010) Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal 8:23

  30. 30.

    Brabek J, Mierke CT, Rosel D, Vesely P, Fabry B (2010) The role of the tissue microenvironment in the regulation of cancer cell motility and invasion. Cell Commun Signal 8:22

  31. 31.

    Dobrzanski P, Hunter K, Jones-Bolin S, Chang H, Robinson C, Pritchard S, Zhao H, Ruggeri B (2004) Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res 64:910–919

  32. 32.

    Cercone MA, Schroeder W, Schomberg S, Carpenter TC (2009) EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia. Am J Physiol Lung Cell Mol Physiol 297:L856–L863

  33. 33.

    Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, Jain RK (2010) Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci USA 107:21677–21682

  34. 34.

    Kinch MS, Carles-Kinch K (2003) Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer. Clin Exp Metastasis 20:59–68

  35. 35.

    Wykosky J, Debinski W (2008) The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol Cancer Res 6:1795–1806

  36. 36.

    Erez N, Truitt M, Olson P, Arron ST, Hanahan D (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17:135–147

  37. 37.

    Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C et al (2010) Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med 2:211–230

  38. 38.

    Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15:416–428

Download references


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.

Electronic supplementary materials

Below is the link to the electronic supplementary material.


(JPEG 761 kb)

(MOV 2947 kb)

(MOV 665 kb)

(MOV 1196 kb)

(MOV 845 kb)

(MOV 949 kb)


High resolution image (TIFF 6881 kb)


(DOC 30 kb)


(MOV 2947 kb)


(MOV 665 kb)


(MOV 1196 kb)


(MOV 845 kb)


(MOV 949 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation


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