One defective gene in breast tumour cells can promote metastases
elsewhere in the body by steering the immune system in an
undesirable direction. This is the p53 gene, which is deleted or
mutated in the tumour cells of nearly 40% of breast cancer
A paper about this discovery by the research group of
immunologist and tumour biologist Karin de
Visser of the Netherlands Cancer Institute was published in
Nature on July 31.
'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,' says researcher Max
Wellenstein, first author of the publication.
Research leader Karin de Visser: '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
Max D. Wellenstein et al., 'Loss of
p53 triggers Wnt-dependent systemic inflammation to drive
metastasis of breast cancer, Nature, 31 July 2019. DOI:
Systemic inflammation and metastases
Cancer-associated systemic inflammation, which makes patients
feel ill and run a fever, is generally not a good sign for the
course of the disease and is associated with metastases. Metastatic
cancer is virtually never curable. But how is that inflammatory
response related to the primary tumour itself?
High neutrophil levels
For a number of years, it has been known that patients with
metastases have relatively high circulating neutrophil levels:
immune cells that "eat" foreign invaders such as bacteria. An
increase in neutrophils is part of a normal systemic inflammatory
response. In cancer, however, those neutrophils turn against their
allies in the immune system: the tumour-cell-destroying T
In 2015, Karin de Visser's research group already 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.
Two unsolved questions
But two major questions remained in 2015. The first was: how do
tumour cells mobilise neutrophils elsewhere in the body? Where and
how does the chain reaction that leads to metastasis start in the
tumour cell? The second question, by extension, was: why do some
breast tumours mobilise neutrophils that stimulate metastatic
behaviour, while others do not?
Research leader Karin de Visser: "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."
In this new study, the researchers show that the source of the
entire chain reaction is one missing or defective gene in the
tumour cell. This 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 signaling molecules (Wnt signalling) 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.
These new 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.