Nicola McCarthy

Maria Genander and colleagues have found that the ability of the EphB receptors to regulate both cell proliferation and migration is mediated through two distinct downstream pathways. These findings indicate new targets for the treatment of patients with familial adenomatous polyposis (FAP).

Eph receptors and their ephrin ligands can limit cell migration through repulsion, a function that underpins their role in axonal guidance. More recently, Eph–ephrins have been found to induce cell proliferation in stem and progenitor cells. To understand how these two different pathways are mediated, the authors inhibited EphB receptor clustering (which leads to activation) in the mouse intestine through the injection of an ephrin-B2–Fc protein. Analysis of gene expression levels in the colonic cells indicated that the expression of genes involved in cell migration was altered earlier than those involved in proliferation.

To follow up, the authors used various EPHB2-mutant receptors and expressed these in the intestines of EphB3-null mice. They compared the outcomes with those of EphB2^−/−; EphB3^−/− mice, which show reduced proliferation and disrupted cell positioning in intestinal crypts owing to migration defects. They found that the expression of kinase-dead EPHB2 reduced proliferation, but did not disrupt cell positioning. Further investigations showed that EPHB2 regulates the activity of cyclin D1 through a pathway involving the kinase ABL1. Indeed, cyclin D1-null mice had reduced proliferation of cells in the colon and were unaffected by the suppression of EphB2 signalling using ephrin-B2–Fc or ABL1 inhibition by imatinib, both of which limit proliferation in the intestines of wild-type mice.

How does EPHB2 regulate cell migration? PI3K has previously been implicated in EPHB signalling, and so the authors used a PI3K inhibitor and found that suppression of PI3K in vivo resulted in cell migration defects in the intestinal crypt, but had no effect on cell proliferation. Moreover, the catalytic subunits of PI3K were among the genes showing reduced expression in colonic cells after injection of ephrin-B2–Fc.

Expression of EphB receptors is selected against during progression of colon adenomas to carcinomas, which seems strange given the function of EphB in proliferation, but is in-line with the capacity of EphB receptors to suppress the migration of colon cancer cells owing to the expression of ephrin-B2 by the surrounding normal cells. If EphB expression is reduced, how do colon cancer cells maintain proliferation? Initial data indicate that expression of cyclin D1 through ABL1 is maintained by the epidermal growth factor receptor and insulin-like growth factor 1 pathways.

These results imply that cyclin D1 and ABL1 are potential targets to suppress the progression of adenomas to carcinomas and that drugs, like imatinib, could be used as an alternative to resection of the colon in patients with FAP.

Author: Nicola McCarthy - Copyright © 2010 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission