The Notch Gene Accelerates Colon Carcinogenesis

In mice, abnormal activation of these two signalling pathways increases the number of benign tumours-adenomas-in the intestine by a factor of over twenty compared with activation of the Wnt pathway alone. Moreover, these tumours grow extremely fast in the colon, mimicking the pathogenic process observed in humans. Cooperative action between these two pathways creates a favourable environment for malignant transformation.

These findings (published online in PNAS) show that Notch acts as an "accelerator" in the development of colon cancer in humans, constituting an essential component of the pathogenic process. The question now is to find a "brake" that can counter this.

The gut, which represents a surface area equivalent to that of a tennis court, is in constant turnover completely renewing itself every five days. This turnover depends on the presence of stem cells and progenitor cells found in the crypts between intestinal villi. The stem cells give rise to progenitor cells which can in turn differentiate, over successive division cycles, to give the various different cell types that populate and form the gut. The key factor is to maintain a balance between differentiation and proliferation in the intestinal epithelium.

The Notch and Wnt signalling pathways are important in maintaining this balance, thereby ensuring normal development and organisation in the gut. These two systems control the proliferation and differentiation of stem cells in the intestinal crypts. The Wnt signalling pathway is tightly controlled by the APC (adenomatosis polyposis coli) gene which is associated with early-stage colon carcinogenesis: mutations in one of the two copies of this tumour suppressor gene underlie familial adenomatous polyposis, a condition characterised by the growth of hundreds or even thousands of polyps in the large intestine from adolescence on. This disease accounts for 1% of cases of colon cancer. The vast majority of sporadic cases of colon cancer are also associated with mutations in the APC gene.

The central Notch pathway

The Notch gene product acts as an "On/Off" switch. When it is On, the Notch protein triggers a cascade of intracellular signals essential to the development of all tissues in all multicellular organisms.

Notch is usually qualified as an oncogene and could represent a promising therapeutic target.

Professor Daniel Louvard, working together with Spyros Artavanis-Tsakonas, recently showed that the Notch and Wnt pathways act in concert to control the proliferation of progenitor cells in the gut. In animal models in which Wnt is aberrantly activated, the activation of Notch dramatically accelerates the rate of tumour formation in the gut, especially in the colon. In most mouse models, tumours are rarely found in the colon, unlike in human patients; the development of multiple adenomas in the mouse colon therefore mimics the human pathogenic process.

Such synergy between the Notch and Wnt genes has been observed in different animal models, suggesting that the mechanism is highly conserved throughout evolution. Professor Louvard states that "the Notch gene seems to act as an accelerator of colon carcinogenesis: its activation leads to increased cell division and therefore, an increased likelihood of mutation". However, malignant transformation requires a whole series of genetic events. Aberrant activation of the Notch and Wnt pathways creates a favourable environment for the accumulation of mutations that ultimately lead to colon cancer. Synergy of Notch and Wnt signals contributes to the earliest stages of tumourigenesis-when the tumours are referred to as polyps-the stage at which screening is so important.

Understanding the mechanisms involved in the formation, growth and transformation of these tumours will help in the search for novel therapeutic targets.

In 2005 in France, colon cancer struck more than 37,000 victims and caused 17,000 deaths. The chances of surviving this form of cancer (the third most common malignancy in the country) are closely linked to the stage at which the disease is diagnosed.

A mass colon cancer screening programme was set up at the end of 2008: every two years, everyone betwee n 50 and 74 will be sent a letter inviting them to ask their general practitioner about screening for colon cancer and consider, on a case by case basis, having a test to detect blood in their faeces.

(1) The Morphogenesis & Cell Signalling Group of the Curie Institute Cellular Compartmentalisation & Dynamics Unit; CNRS UMR144

(2) Professeur at the Collège de France and at Harvard Medical School (United States), and Director of the Curie Institute Genetics & Biology of Development Group; CNRS UMR3215/ Inserm U934