Targeting a protein in order to fight against intestinal cancer

As recently stated by The Foundation Against Cancer, “cancer of the large intestine is the second most common form of cancer in both males and females in Belgium and it is also the second most common cause of death by cancer in our country”. More than 8,500 new cases were diagnosed in 2012. In a recent study (1), Alain Chariot and Pierre Close, of GIGA (University of Liege) identified the gene coding for the ELP3 protein as a key factor in the development of intestinal tumours.

Fotolia 66830781 SThe structure of the intestine is today well-known and understood. Its inner lining is composed of villi (folds of the intestinal mucosa and the underlying connective tissue) which broaden the surface of the intestine. It is therefore designed for an optimal exchange between the commensal bacteria and nutrients and for the absorption of the nutrients. At the bottom of these villi are intestinal crypts which are composed of different types of cells. “In a normally-functioning intestine, there is a large amount of cell regeneration: these cells can be considered as completely renewed, giving rise, in a manner of speaking, to a new intestine every week”, explains Professor Alain Chariot, Director of research at the FNRS in the GIGA research centre of the University of Liege and principal investigator at WELBIO. “At the bottom of these intestinal crypts, there are stem cells surrounded by Paneth cells which protect them. Every day, the stem cells divide and proliferate to create the transit-amplifying compartment. These proliferating cells push older cells towards the top and can differentiate and specialise. They stop dividing in order to become either enteroendocrine cells, which produce various hormones, or enterocytes which absorb the nutrients or Goblet cells which synthesise a mucus the function of which is to protect against disease-causing infectious bacteria. Higher up in the crypt are Tuft cells which are rarer and whose exact function is as yet unknown. The cells that reach the top of the villi therefore die over time”.

This is what is happening during normal intestinal function. The molecular mechanisms which enable differentiation are beginning to reveal their secrets.

Double role of Wnt

To ensure that this intestinal regeneration and therefore the proliferation of stem cells and the differentiation of cells emerging from the transit-amplifying compartment occurs, there is a mechanism called the Wnt signalling pathway. When this is not activated, there is no proliferation. It must be activated in a transitory manner at the right time. When the Wnt signalling pathway is not active, a complex of proteins – axin, glycogen synthase kinase 3β (GSK3β) and APC (adenomatous polyposis coli) – degrade the β-catenin, another protein which plays a role in cellular signalling. The objective is to make sure that β-catenin is expressed in small quantities. If β-catenin is no longer degraded, it accumulates in the cytoplasm then moves into the nucleus of the cell, associates with LEF-1 /TCF transcription factors to induce the expression of several genes which will ultimately leads to cell proliferation. The transient stabilization of β-catenin takes place when ligands bind to a specific receptor and trigger the Wnt signalling pathway which ultimately prevents the complex of proteins required for the degradation of β-catenin from fulfilling its role.

“In the case of cancer cells”, explains Alain Chariot – and this applies to 80% of human intestinal cancers – “the activity of the Wnt signalling pathway is not controlled: it remains active and therefore the β-catenin is not sufficiently degraded and it accumulates: this leads to an uncontrolled proliferation”. A defect in the degradation of β-catenin can occur when the APC protein is mutated, which interferes with the assembly of the degradative complex”.

Therefore, the Wnt pathway plays a double role here: on one hand it is essential for the proliferation of stem cells, an essential step for the generation of new intestinal crypts but only when it is transiently activated. On the other hand, when permanently active, it favours the production and proliferation of cancer cells.

(1) Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. A. Ladang*, F. Rapino*, L.C. Heukamp, L. Tharun, K. Shostak, D. Hermand, S. Delaunay, I. Klevernic, Z. Jiang, N. Jacques, D. Jamart, V. Migeot, A. Florin, S. Göktuna, B. Malgrange, O.J. Sansom, L. Nguyen, R. Büttner, P. Close*, A. Chariot*.
The Journal of Experimental Medicine (2015), Nov 16;212(12):2057-75. *Contributions équivalentes

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