A defective gene in breast tumour cells ‘hijacks’ the immune system and can promote metastases elsewhere in the body, a new study published in the journal Nature has revealed.
The gene, p53 is erased or mutated in nearly 40% of all breast cancer patients. It then steers the immune system in an undesirable direction, the researchers from the Netherlands Cancer Institute and Oncode Institute said.
Research leader Karin de Visser said: “Our study shows that the genetic make-up of tumours has a major impact on the immune system and on the spread of breast cancer. These insights lay the foundation for the future development of new forms of immunotherapy that focus on the DNA code of tumours of individual breast cancer patients.”
First author Max Wellenstein said: “We were quite surprised that a single gene not only regulates processes within the cell but also has such a dominant effect on the immune system throughout the body.”
Linking neutrophils with the spread of cancer
This work follows on from a previous study by de Visser. It was previously known that patients with metastases have relatively high circulating neutrophil levels: immune cells that "eat" foreign invaders such as bacteria. In cancer, however, those neutrophils turn against their allies in the immune system: the tumour-cell-destroying T cells.
In 2015, Karin de Visser's research group demonstrated that some breast tumours mobilise neutrophils outside the tumour in the patient's body via a chain reaction of signal molecules. These neutrophils were subsequently found to promote the spread of breast tumours by counteracting tumour-killing T cells. Inhibiting neutrophils, as is also done for inflammatory diseases such as rheumatism, may, therefore, be a way to prevent metastases.
This discovery raised two questions: Firstly, how do tumour cells mobilise neutrophils elsewhere in the body, and where and how does the chain reaction that leads to metastasis start in the tumour cell? Secondly, why do some breast tumours mobilise neutrophils that stimulate metastatic behaviour, while others do not?
Karin de Visser said: "If we understand that, we can use those insights to identify patients who might benefit from the inhibition of neutrophils. We could also develop new strategies to redirect tumour-stimulating interactions between cancer cells and immune systems to tumour-inhibiting interactions."
Finding the defective gene
In this new study, the researchers found that the source of the entire chain reaction is one missing or defective gene in the tumour cell. That gene is p53, an extremely important gene and an old acquaintance of cancer researchers because, when it's working properly, it protects against unrestrained cell growth. The gene now appears to have a much broader impact.
In a unique set of 16 different mouse models with all possible forms of breast cancer, Wellenstein, in collaboration with Jos Jonkers' research group, discovered that all mice that suffered from an inflammatory reaction in the blood had one thing in common: the absence of the p53 gene. This excited the researchers, as almost 40% of breast cancer patients have a defective p53 gene in their cancer cells.
Only tumour cells that lack this gene inform their environment via signalling molecules (the Wnt signalling route) that there is damage, and then trigger an inflammatory response in the blood, which eventually leads to metastases elsewhere in the body. In mouse models with p53-deficient tumours, inhibiting these signal substances prevents the hijacking of the neutrophils and also inhibits the metastasis process.
This new insight could lay the foundation for the future development of new forms of immunotherapy that focus on the DNA code of tumours of individual breast cancer patients.
For more information on the study visit: Max D. Wellenstein et al., ‘Loss of p53 triggers Wnt-dependent systemic inflammation to drive metastasis of breast cancer’, Nature, 31 July 2019. DOI: 10.1038/s41586-019-1450-6.