Colorectal - colon or rectal - cancer is the third most diagnosed type of cancer worldwide.

Up to 80% of the cases are related to environmental factors and lifestyle, such as poor diet, sedentarism, obesity, smoking or excessive alcohol consumption.

Most colorectal cancers arise from adenomatous polyps, a precancerous lesion that may progress to a malignant tumour unless it is detected and removed in time.

A recent study published in Nature Communications describes a new molecular mechanism involved in the formation of colorectal tumours, which favours their progression towards more aggressive forms.

The research has been led by Nabil Djouder, Head of the Growth Factors, Nutrients and Cancer Group, at the Spanish National Cancer Research Centre (CNIO).

This discovery opens up new avenues for the development of colorectal cancer prevention strategies.

Shortage of p53, the cell division guardian

In research with mouse models, the authors observed that a protein, called p53, began to degrade - to decrease its presence - in the early stages of tumour formation.

This led to the emergence and development of cancer.

The anti-tumour function of p53 is known.

This protein blocks cell division and helps to destroy them when they present some kind of dysfunction, so p53 is considered to be a tumour suppressor.

When p53 loses its function, the cells are able to grow uncontrollably.

However, the finding that p53 degradation initiates the tumour process in colon cancer is completely new.

This study, with Irene Herranz-Montoya as first author, has found that the shortage of p53 favours tumour formation due to uncontrolled cell proliferation and also makes it easier for tumour cells to accumulate other mutations which jointly drive progression to more aggressive tumours.

Furthermore, the CNIO group has identified an unprecedented mechanism in the regulation of p53 levels.

It is a protein called URI, which is known for its expression in other types of cancer.

This study shows that p53 decreases when URI levels increase in cells.

New avenue for prevention

Previous studies, particularly that of Nabil Djouder's team, have already linked the URI protein to other types of cancer, especially cancer of the liver.

However, this is the first time that URI has been linked to colorectal tumours.

“URI levels start to rise very early on, leading to the formation of the adenoma, an aberrant growth that is not yet a cancer, but it is at the stage when p53 starts to be degraded”, explains Herranz.

In experiments on mice, it was found that if URI was eliminated or p53 levels were increased in polyps, the polyps did not develop into tumours and the mice with colorectal cancer lived longer.

"Our results provide a more detailed understanding of how colorectal cancer develops. If we focus on investigating the molecular mechanisms that cause p53 degradation, including the increase in URI, in the future, we may be able to intervene in the early stages of cancer and prevent its progression to more aggressive forms of the disease”, according to Herranz.

Therefore, the team is now focusing its work on the development of URI inhibitors.

“The future lies in URI inhibition, a strategy that we are developing in the laboratory. We are looking for specific inhibitors that block the activity of this protein, preventing p53 degradation and stopping the onset of colorectal cancer. These inhibitors may have an impact on the treatment of colorectal cancer and other URI-related cancers, offering an innovative therapeutic approach to slow down tumour progression and improve patient care”, explains Djouder.

Furthermore, the published work demonstrates that URI expression is regulated by MYC, an oncogene that plays a crucial role in the initiation of colon cancer due to its involvement in cell proliferation and the regulation of other key cancer genes.

MYC activates URI expression, which degrades p53 and favours the initiation of the tumour process.

Relationship with environmental factors

Djouder highlights that this new mechanism may shed light on recent studies that investigate the possible causes of the increased incidence of colorectal cancer in young adults, in relation to environmental factors and lifestyles.

“Previously, my team has also shown that URI expression is related to certain environmental factors, such as poor diet, in other cancers and in the intestine. This suggests that URI and p53 degradation at the onset of colorectal cancer may be associated with these factors”, explains Djouder.

On the other hand, the gradual reduction in the p53 protein appears to occur independently of another previously known process: the loss of the TP53 gene, which encodes the p53 protein, in late stages of colorectal cancer.

Both processes may occur and influence cancer in parallel: degradation of the protein in the early stages, and loss of the gene in more advanced stages and in the context of increased aggressiveness and the spread of metastasis.

The study has been validated on human samples from patients with adenomas and advanced colon cancer, donated by the Biobank at Ramon y Cajal Hospital and in collaboration with Cristian Perna.

Furthermore, the data analysed has been complemented with bioinformatic methods.

Funding

The CNIO is a public research centre attached to the Ministry for Science, Innovation and Universities.

This study has been financed with funds from the Ministry for Science, Innovation and Universities, the Spanish Cancer Association (AECC), the BBVA Foundation and the Spanish public science system.

Source: Centro Nacional de Investigaciones Oncológicas (CNIO)