Colon Cancer Treatment Relies on Disassociation of Eph Receptor Signaling

Cancer researchers have found that that it is possible to separate the pro and anticancer activities of a group of proteins called Eph receptors and have formulated a chemotherapeutic regimen that affects only the procancer functions.

EphB receptors promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. However, elevated levels of Eph expression and activity have been correlated with the growth of solid tumors, with Eph receptors of both classes A and B being over expressed in a wide range of cancers including melanoma, breast, prostate, pancreatic, gastric, esophageal, and colon cancer as well as hematopoietic tumors. Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Eph's governing cell movement.

In the current study, investigators at the Karolinska Institute (Stockholm, Sweden) showed that cell migration and proliferation were controlled independently by the EphB2 receptor. EphB2 regulated cell positioning was kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulated cell proliferation through an Abl-cyclin D1 pathway.

Data published in the November 13, 2009, issue of the journal Cell revealed that cyclin D1 regulation became uncoupled from EphB signaling during the progression from adenoma polyps to colon carcinoma in humans, allowing continued proliferation with invasive growth. This growth could be stopped by the drug imatinib, a component of Glivec, which is used in the treatment of certain forms of leukemia. The dissociation of EphB2 signaling pathways enabled imatinib to selectively inhibit EphB2's stimulation of cell division without affecting its tumor suppressor function.

"Imatinib or a similar substance could possibly be used for preventing the development of cancer in people who are in the risk zone for colon cancer instead of intestinal resection," said first author Maria Genander, a doctoral student in cell and molecular biology at the Karolinska Institute.

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Karolinska Institute