Genetic changes control metastasis formation in colorectal cancer microbiologystudy

Colorectal cancer is one of the most common types of tumor and is responsible for around 10% of cancer-related deaths worldwide. The tumor is particularly dangerous when it forms metastases—i.e. secondary tumors—in other organs. This occurs primarily in the liver and lungs, and more rarely in the brain.

A research team led by Dr. Dr. Björn Sander, pathologist at the Institute of Pathology at Hannover Medical School (MHH), has investigated how genetic changes in the chromosomes, the carriers of genetic information, influence the formation of metastases and what differences exist between different types of metastases.

The results have been published in Nature Communications. They could help to better assess the individual risk of metastasis formation and develop new therapeutic approaches.

Exact processes not yet well understood

Bowel cancer often develops from benign polyps in the intestinal mucosa. If these growths are not removed in time, they can grow into malignant tumors. These tumors often have complex genetic changes in their chromosomes. Certain genes are lost or duplicated, which influences the behavior of the tumor cells.

The chromosomal changes not only differ from patient to patient, but can also vary within a single tumor. Because the exact processes of metastasis formation are not yet well understood, it is particularly difficult to make prognoses or develop targeted therapies.

“We have now examined more than 3,800 cases of colorectal cancer in detail and found that brain metastases exhibit a particularly high number of genetic changes compared to liver and lung metastases,” says Dr. Dr. Sander.

Mutations in the KRAS gene promote tumor growth

The KRAS gene plays a central role in this. It carries the information for a protein that plays an important role in signaling and regulating cell growth. KRAS mutations occur particularly frequently in various types of cancer, especially lung, bowel and pancreatic cancer, and can promote the growth of tumors.

In brain metastases, the researchers found a particularly frequent combination of mutations and duplications of this gene. Colonization of the brain poses particular challenges for tumor cells.

On the one hand, the cancer cells have to overcome barriers such as the blood-brain barrier, a natural barrier in the blood vessels that protects the brain from harmful substances in the bloodstream. Secondly, they have to adapt to the unique tissue environment, which is characterized by a reduced availability of oxygen for the tumor cells.

“The brain itself has a high oxygen consumption. Tumor cells with detected changes in the KRAS gene show an advantage in adapting to the limited oxygen supply in the brain,” explains the pathologist.

Patterns in brain metastases develop late

Another finding from the scientific study is that the diverse genetic patterns in brain metastases tend to develop late—in contrast to the less complex changes observed in liver and lung metastases. This suggests that the genetic development of the tumor cells influences in which organ the metastases form.

“By examining samples from colorectal cancer patients who had not yet received targeted therapy, we were able to ensure that the observed genetic changes actually occur naturally and not as a result of the influence of new targeted drugs,” says Dr. Sander.

However, the results of the study not only provide insights into the mechanisms of metastasis formation, but also reveal possible weak points in the tumor cells.

One approach for future therapies could be to therapeutically utilize the weak points resulting from chromosomal instability. Dr. Dr. Sander and his team hope that the findings will contribute to the development of personalized treatment strategies for colorectal cancer patients in the long term.