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New insight into how colon cancer arises

October 21, 2015

 

In this week’s issue of Nature, Dr. Alex Gregorieff and his colleagues from the laboratory of Dr. Jeff Wrana published evidence linking gut repair after damage and progression of colon cancer.

By Stéphanie Heyraud

The Secret Life of the Gut Wall

  Figure 1.
 

Figure 1. A) The gut epithelium is a single layer of cells organized in highly folded structures called crypts
and villi. At the base of the crypts, stem cells give rise to all the specialized cell types of the gut, essential
for the digestive, secretory and immune functions. B) Intestinal stem cells shown in red (arrowhead) can be
visualized by detecting gene products specifically expressed in the stem cells
.

The gut (or intestinal) wall is composed of several cell layers. The internal layer, made up of epithelial cells, is highly folded up to create creases (crypts) and hills (villi) (see figure). The intestinal epithelium primarily functions to absorb the food we eat, while also acting as a barrier to potential pathogens lurking within our guts. Under normal circumstances, most epithelial cells live on average less than a week, thus are continuously replaced. This balanced replacement of cells, called homeostasis, occurs thanks to intestinal stem cells, a small group of cells that sit within the epithelial layer in the crypts (see figure). Intestinal stem cells have the remarkable capacity to replace themselves through cellular division and also give rise to other intestinal cell types in a process termed differentiation. As a result, intestinal stem cells can replace any epithelial cells ever lost.

How Gut Repairs After Injury

But what happens when our gut suffers damage? Following injury to the gut—resulting from food poisoning or chronic conditions such as inflammatory bowel disease—a large number of epithelial cells may suddenly die, which calls for quick replacement. The intestinal stem cells answer the call and go into hyper-drive to rapidly replace the lost cells, a process referred to as regeneration. Consequently, to avoid unruly expansion and potential tumour formation of the intestinal stem cells, their proliferation and differentiation must be tightly regulated.

The new work from Gregorieff and colleagues—who used various techniques, including animal models, that allows the researchers to follow the intestinal stem cells during regeneration—sheds light on how intestinal stem cells fuel the regenerative process. The team discovered that a protein called Yap (a potent stimulator of tissue growth in many organisms) plays a key role in reprogramming intestinal stem cells and in allowing them to replace the cells lost to injury.

“In the gut, Yap’s function is quite intriguing because of its multifaceted effects” says Dr. Gregorieff. Yap reprograms intestinal stem cells by temporally switching off genes that govern homeostasis; it blocks their differentiation, which otherwise can exhaust stem cells; and it turns on genes that promote stem cell survival. When regeneration is no longer necessary, Yap’s activity is switched off to prevent overproduction of unnecessary cells. The intestine then returns to its normal homeostatic state.

Relevance in Colon Cancers

So what does this have to do with colon cancer? Tumours typically result from cells that get errors (called mutations) within specific genes that control cell proliferation. Some 70% of colon cancers arise due to mutations in a large gene called Apc. Since Apc acts to police over-proliferation, once mutations render it ineffective, the gut cells begin on a track towards tumour formation.

However, according to the study by Gregorieff et al., a tumour needs more than Apc mutations alone to start; it also requires Yap-dependent regenerative programs. They are activated at the earliest stage of tumour formation and act as they do during regeneration. On the one hand, Yap prevents differentiation of Apc mutant cancer cells and, on the other hand, drives a pro-regenerative program in mutant cells. Together, these critical activities of Yap may allow Apc mutant cells to expand into small tumours, called polyps, that if left unchecked can progress into an aggressive disease.

One of the great challenges in cancer therapy lies in trying to restore the function of a wrecked cellular brake like Apc. This new evidence however offer hopes for an alternative strategy. As Dr. Gregorieff explains, “Now that we have identified this key molecular circuit promoting tumour growth, the next, great challenge for future research will be to develop drugs that specifically block the effects of Yap during colon cancer progression”. Under the leadership of Dr. Wrana and other Investigators at the Lunenfeld-Tanenbaum Research Institute, the team next aims to do just that. By employing state-of-the-art screening platforms in the Network Biology Collaboration Centre, they are now hunting down new drug candidates that target the molecular circuit to which Yap belongs.
 

 

References:
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature15382.html
http://research.lunenfeld.ca/rss/files/image/media_images/New-nsight-into-how-colon-cancer-arises-(Figure).pdf

 

 

 

 

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