EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

Abstract

EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 in tumor progression is still debated. In melanoma, EphA2 has been reported to affect cell migration and invasiveness allowing cells to move by a proteolysis-independent strategy, commonly referred as amoeboid motility. With the aim to understand the role of EphA2 in prostate cancer metastatic spreading, we stably silenced EphA2 expression in a model of aggressive metastatic prostate carcinoma. Our results show that EphA2 drives the metastatic program of prostate carcinoma, although its involvement greatly differs among metastatic steps. Indeed, EphA2 expression (i) greatly affects prostate carcinoma cell motility style, guiding an amoeboid movement based on Rho-mediated cell rounding and independent from metalloprotases, (ii) is ineffective on transendothelial migration, adhesion onto extracellular matrix proteins, and on resistance to anoikis, (iii) regulates clonogenic potential of prostate carcinoma, thereby increasing anchorage-independent growth and self-renewal, prostasphere formation, tumor onset, dissemination to bone, and growth of metastatic colonies. Our finding indicate that EphA2-overexpressing prostate carcinoma cells gain an invasive benefit from their amoeboid motility style to escape from primary tumors and then, enhancing their clonogenic potential successfully target bone and grow metastases, thereby acknowledging EphA2 as a target for antimetastatic therapy of aggressive prostate cancers. Mol Cancer Res; 9(2); 149-60. Ó2011 AACR.

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

“…While the canonical pathway has been considered to be a form of tumorsuppressive signaling, some recent reports have identified its critical role in single-cell invasion and the shift to the mesenchymal-to-amoeboid transition. 67,68) Additionally, the EphA2 G391R mutation has been detected in lung squamous cell carcinoma. 69) This mutation not only induces EphA2 tyrosine activation but also promotes cell invasion, focal adhesion, and cell survival.…”

Anoikis: an emerging hallmark in health and diseases

“…One of the main inducers of MAT is the EphA2 receptor, which stimulates RhoA and matrix metalloproteinase (MMP)-independent cell invasion [110,111]. In analogy with the acquisition of anoikis resistance induced by EMT, EphA2, which is over-expressed in many types of cancer [112], also confers resistance to anoikis through the action of the guanine nucleotide exchange factor Ephexin4, PI3K and Akt [113].…”

EphA2 protein expression in metastatic renal cell carcinoma treated with VEGF-inhibitors is predictive of patient survival

“…Corresponding to these observations, EphA2 expression levels of tumor cells could depend on their state between a more epithelial and a more mesenchymal phenotype. But whereas EphA2 signaling can influence the invasiveness and metastatic dissemination through various mechanisms [21][22][23][36][37][38][39][40][41] , our observations suggest that in metastases EphA2 signaling differs in function from primary tumors, rendering targeted therapy much more complex.…”

“…These invasive properties and increased motility abilities result consequently in a pro-metastatic phenotype [14,[20][21][22] . According to the complex and varying signaling functions of EphA2 in tumorigenesis, different modulation systems for Eph signaling were reported, e.g.…”