Abstract
The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.
Highlights
Colorectal cancer (CRC) is the third most deadly cancer in the world, affecting thousands of people every year, especially in developed countries due to unhealthy western diet and physical inactivity [1,2,3]
In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice
As statistical analysis revealed that only the oral administration of UniPR129 at the dosage of 30 mg/kg for 8 weeks significantly decreased the formation of adenomas, we decided to focus on this compound and to neglect the study of UniPR139 and UniPR1331
Summary
Colorectal cancer (CRC) is the third most deadly cancer in the world, affecting thousands of people every year, especially in developed countries due to unhealthy western diet and physical inactivity [1,2,3]. The EphB4 expression relates with stage and grade of colon cancer, contrary to EphB2, whose expression is reduced [10] with the tumor progression, and it is firstly abundant on colon progenitor cells [11] The levels of these two receptors are regulated by the Wnt/β-catenin/T-cell factor 4 pathway through the usage of different coactivators, as p300 for EphB2 and CBP for EphB4 [10]. In light of these findings, it was thought to evaluate the effects of the Eph-ephrin antagonism in a model of intestinal tumorigenesis, by using C57BL6/J mice carrying the APC min mutation This strain spontaneously develops a large number of adenomas and sporadic carcinoma especially in the small intestine and generally do not survive for more than 120 days [12,13].
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