New research surprisingly shows that mutations in known cancer genes are not directly associated with the development of metastasis. The research also shows that, except for the emergence of treatment-associated resistance mutations, the mutational profile does not change much when metastatic tumours develop. A researcher says that this indicates that the cancer cells themselves do not acquire the ability to metastasise. Instead, a compromised immune response may drive the development of metastatic cancer.
A cancer diagnosis is never positive, but some types are worse than others. This applies especially to metastatic cancer that has spread from the primary tumour to metastatic tumours in the lungs, lymph nodes, brain and other organs.
Scientists always thought that the tumour itself has the most important role in becoming metastatic and that the cancer cells must acquire certain mutations to do this. A new study from Denmark refutes this hypothesis.
The researchers show that the mutations in genes do not differ between metastatic tumours and primary tumours, suggesting that the cause of cancer metastasis must be found elsewhere.
This discovery surprised the researchers.
“We were quite sceptical when we first got these results. Nevertheless, we examined our data again and clearly found that metastatic tumours are almost identical to primary tumours. This was surprising and means that we are now looking for other causes for metastatic cancer,” explains a researcher behind the study, Nicolai Juul Birkbak, Associate Professor, Department of Clinical Medicine, Aarhus University.
The research has been published in Cancer Research.
Genetic data from more than 40,000 people with cancer
The researchers examined data from the GENIE database, which receives data from analysis of tumours from researchers all over the world. They analysed 40,979 primary tumours or metastatic tumours for which they had genetic data.
They then determined whether the two types of tumours differed in mutations in 174 genes that are associated with the development of 25 types of cancer. These 174 genes carry about half of all known cancer-associated mutations and are among the most important cancer-associated genes.
The researchers hypothesised that a tumour cell requires specific mutations to acquire the ability to metastasise.
“We investigated whether the mutations differ between cells from primary tumours and metastatic tumours and whether these differences could determine what makes cancer develop and metastasise,” says the lead author behind the study, Ditte Christensen, doctor and PhD student.
Mutations do not cause metastatic tumours
The results surprised the researchers because they had expected to find genetic differences between the cells in primary tumours and metastatic tumours, but they did not.
The researchers looked for mutations in specific genes and for the degree and the number of mutations, but the genetic profiles looked quite similar.
“Pretty much everything that defines a cancer cell was the same. There was almost no difference biologically, and that is surprising,” explains Nicolai Juul Birkbak.
The discovery was supported by data showing that although smoking is associated with considerably increased mutational burden and the development of lung cancer, it does not cause more mutations in metastatic lung cancer.
According to Nicolai Juul Birkbak, if mutations caused metastasis, the increased number of mutations in the lung tissue associated with smoking would be expected to lead to more mutations associated with metastasis – but this does not appear to be the case.
Metastatic tumours acquired mutations associated with therapy resistance
However, one type of mutation did differ between primary and metastatic tumours. Cells from metastatic tumours had many mutations in the genes associated with resistance to treatment.
The researchers found mutations in the genes associated with resistance to hormone therapy among women with breast cancer and men with prostate cancer and in the genes associated with resistance to anti-EGFR therapy among people with lung cancer and treatment with the anticancer drug imatinib among people with gastrointestinal cancer.
According to the researchers, this discovery indicates that tumours that become metastatic emerge through an evolutionary bottleneck where anticancer therapy has forced the cancer cells to develop a counterresponse that is especially strong in the metastatic tumours, since these managed to avoid being affected by the therapy.
“Our results indicate that an external rather than an internal factor in the cancer cells causes them to metastasise. Now the goal is to determine what this external factor is,” says Nicolai Juul Birkbak.
Immune response must be bolstered during anticancer therapy
The researchers suspect that the immune response plays a role in metastasis and that it probably arises based on the interaction between the cancer itself, the person’s general condition and the immune response and how weakened this is.
The researchers will now investigate the role of the immune response in preventing cancer from metastasising.
“We are not saying that treating cancer leads to metastasis and that we should therefore stop treating cancer. If the treatment had not worked, the cancer cells would have had no reason to develop resistance mutations. Instead, this discovery improves our understanding of how to limit cancer from developing and metastasising, perhaps with the help of immunotherapy, which can strengthen the immune response and prevent cancer from metastasising,” concludes Ditte Christensen.
