Discovery of a protein activity that suppresses the growth of malignant tumors in colorectal cancer

A study on the development of colorectal cancer shows for the first time that the activity of several receptors of the Eph family, responsible for the regulation of intestinal epithelium structure, prevents the further expansion and malignant progression of benign lesions. The results from this study, performed by researchers at the Institute of Biomedical Research (IRB Barcelona)and the Netherlands Institute for Developmental Biology (NIOB), have been published in the scientific journal Nature.

During last year alone, more than half a million people around the world died of colorectal cancer, making this disease the second cause of death from cancer. The onset of colorectal cancer is marked by the appearance of small tumors in the colon epithelium (adenomatous polyps) and the disease develops through several stages towards the formation of malignant tumors, called carcinomas. Co-directed by Eduard Batlle, principal investigator of the Colorectal Cancer  Laboratory at the IRB Barcelona, and by Hans Clevers, principal investigator of the WNT signaling and Cancer Group at the NIOB, the study demonstrates that for tumor progression to occur, the tumor must “learn” how to block the activity of these receptors. Most malignant colorectal cancer tumors are composed of Eph-negative cells, indicating that the loss of these receptors favors tumor growth.

The researchers have shown that Eph receptor expression must be silenced for initially benign lesions to develop into malign tumors

"We knew that benign intestinal tumors show Eph receptor expression as a result of mutations in the familial adenomatous polyposis gene, which are common in colon cancer”, commented Eduard Batlle. By analyzing a wide sample of tumors at distinct stages of development of the disease and by using animal models of colorectal cancer, in this study the researchers have shown that Eph receptor expression must be silenced for initially benign lesions to develop into malign tumors. “The mechanism by which these receptors suppress colorectal cancer is unknown. We believe that in the presence of these receptors, colorectal tumors are highly compartmentalized, which prevents their progression”.

The results of this study contradict previous studies that propose Eph receptors as therapeutic targets for the treatment of this kind of cancer. This proposal arose after observing the over-expression of these receptors in initial stages of the disease. According to Eduard Batlle, “the use of these molecules as therapeutic targets could have devastating effects on patients with initial stages of colon cancer and may be ineffective in more advanced stages. In this regard, our work emphasizes the need for meticulous evaluation of potential therapeutic targets that have been identified because of their over-expression in colon cancer samples in comparison with healthy tissue”.

This study has also involved the researchers Elena Sancho, from the Cancer Laboraty II at IRB Barcelona, and Núria Malats, from the Municipal Institute of Medical Research, in addition to the group headed by Anthony Pawson at the Samuel Lunnefeld Research Institute.