Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells

Abstract

Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.

The effects of modifying RhoA and Rac1 activities on heterotypic contact inhibition of locomotion

“…In metastatic prostate (PC-3) cells RhoA activation due to the engagement of ephrin-A ligands and EphrinA receptors activates RhoA leading to actomyosin contraction and lamella withdrawal, i.e. homotypic CIL [36]. Fibroblast ephrin-B ligands interact with PC-3 EphrinB receptors, triggering sustained activation of Cdc42 and filipodia extension, thereby stimulating PC-3 cell migration and leading to defective CIL [36].…”

EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex

“…Thus, cancer cells may circumvent the tumour-suppressive effect of Eph signalling by downregulating the expression of ephrin ligands, as an alternative to either losing Eph receptor expression or acquiring Eph receptor-inactivating mutations 35,36 . Further adding to the complexity of Eph receptor function in cancer cells, ephrin-B2-dependent EphB3/EphB4-Cdc42 signalling has been shown to enhance migration and cause defective contact inhibition of locomotion in prostate cancer 37 . Therefore, the tumour-promoting or tumour-suppressing effects of the Eph receptors appear to be determined on the cellular context.…”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…Héroult et al (2006) tested the effects of EphB4 over-expression on the migration of A375 melanoma cells, and concluded that EphB4 alone confers an enhanced migratory phenotype independent of ephrin-B2-induced forward signalling [20,22]. Other significant findings in this study…”

“…These results were also demonstrated in murine mammary and ovarian xenograft models [15], and compared to models that over-expressed EphB4 which showed accelerated tumour progression and increased lung metastasis [145]. In the second key study with direct relevance to this study, Héroult et al (2006) showed that EphB4 promotes site-specific metastatic TC dissemination through interaction with EC expressed ephrin-B2 [22].…”

“…Numerous studies have indicated that over-expression of EphB4 contributes to a more aggressive and invasive PCa phenotype that develops into metastatic cancer [20][21][22]. How EphB4 contributes to metastatic dissemination of PCa is not well understood.…”