Duplication of genes makes pancreatic cancer very aggressive

Pancreatic cancer: what makes tumors so aggressive

In Germany, more and more cases of pancreatic cancer are registered. Pancreatic carcinoma is one of the most aggressive cancers and so far barely treatable. Researchers have now discovered what makes the tumors so aggressive.

Extremely aggressive form of cancer

While advances in prevention, screening and therapy have reduced mortality rates in most other cancers, they are increasing dramatically in pancreatic cancer. Pancreatic cancer is one of the world's highest mortality rates. Researchers have now discovered what makes the cancer so aggressive.

Pancreatic cancer is one of the world's highest mortality rates. Researchers have now discovered what makes the tumors so aggressive. (Image: Coloures-pic / fotolia.com)

Diagnosis often takes place late

"Pancreatic cancer causes no symptoms for a long time and is therefore discovered late," explained the CEO of the German Cancer Research Center (DKFZ), Michael Baumann in an earlier release.

"The tumors spread very early metastases and develop to all excess very quickly resistance to chemotherapy," said the expert.

Scientists at the DKFZ found out years ago that a specific enzyme is the cause of tumor resistance.

And an international research team found that the aggressive form of cancer is promoted by a specific protein.

A research team from the Technical University of Munich (TUM) and the German Cancer Consortium (DKTK) have now also found an explanation for the aggressiveness of the tumors.

Genetic causes so far unclear

So far, scientists have failed to associate pancreatic cancer characteristics, such as their aggressiveness, with changes in the genome of the tumor, called mutations.

In addition, pancreatic cancer forms metastases much faster than other cancers. Again, the genetic causes are unclear.

A team led by Prof. Roland Rad and Prof. Dieter Saur at the TUM University Hospital on the right side of the Isar and the German Cancer Consortium have come a decisive step closer to both problems.

Using various mouse models to study pancreatic cancer, they were able to discover in detail the molecular pathways of tumorigenesis. You can understand how different characteristics of the disease arise.

The study was recently published in the journal Nature.

Tumor cells have multiple defective copies of a cancer gene

Healthy cells in humans have two copies of each gene. For their experiments, the researchers mutated one of the two copies of the Kras gene in mice.

The gene plays an important role in cell proliferation and is activated in 90 percent of all human pancreatic tumors. Such genes are also referred to as cancer genes or oncogenes.

The team led by Roland Rad made a surprising discovery: The mutated gene was often reproduced in very early stages of cancer.

If a tumor had not doubled the mutated Kras gene copy, the researchers discovered duplications in other cancer genes.

"It seems like the cell needs to increase the growth signal through the extra gene copies. This model of dose enhancement during tumor development has not been considered yet, "said Sebastian Müller, first author of the study, in a statement.

He added, "We also showed that as the number of mutant Kras copies increased, the aggressiveness and the ability for metastasis increased."

Disruption of the body's own protective mechanisms determines the evolution of the cancer

Usually, healthy cells have their own protective mechanisms so that mutations do not accumulate. So why could the cells even manage to increase this dose without being hindered??

"This shows the importance of mouse models. They enable us to comprehensively observe and experimentally test the extraordinarily complex processes of molecular cancer development: from the healthy cell via cancer precursors to aggressive tumors and their spread to various organs, "says Prof. Dieter Saur.

After the Kras mutation caused by the researchers, further mutations in so-called tumor suppressor genes first developed. To prevent the development of a tumor cell, a healthy cell has a whole series of such protective genes.

A fundamental finding of the researchers was: Depending on which tumor suppressor gene was affected and how much its function was impaired, either the mutated Kras gene or another cancer gene is amplified.

The most important development steps have been clarified

Only by switching off the cell's own protective mechanisms and the subsequent "dose boosting" can a tumor emerge at the end.

Which path the cell takes and which genes are involved, then significantly determined the properties of the pancreatic tumor.

The "dose enhancement" model allows the definition of genetic patterns that explain its aggressiveness and metastasis.

"We have indications that our discovery is a fundamental principle in the development of tumors and is important in other cancers as well. We now address the question of how these new insights into tumor biology can be used to develop new therapeutic strategies, "explained Prof. Roland Rad. (Ad)