Breast cancer cells break away and spread to other parts of the
body relatively late on in breast tumour development, an
international team of scientists has shown. The research, jointly
led by Dr Peter Van Loo at the Francis Crick Institute, could help
refine cancer therapy.
The team of scientists in the UK, Belgium, Norway and the USA
tracked the genetics of particular cancer cells that can go on to
form secondary tumours in other parts of the body, such as the bone
marrow. Such cells are known as disseminated tumour cells or
DTCs.
The group's findings suggest there is a longer window than
previously thought for cancer to be diagnosed and treated before it
spreads. The majority of people who die from cancer lose their
lives when it spreads throughout the body, a process called
metastasis.
Dr Van Loo worked with colleagues from Oslo University Hospital
in Norway, the University of Leuven in Belgium and the University
of Chicago in the USA.
The team used the latest single-cell sequencing techniques to
read out the full DNA genomes of 63 individual cells isolated from
bone marrow samples donated by six breast cancer patients. The
scientists have not only shown that cancer cells spread late, but
also that when DTCs are present elsewhere in the body they are
genetically very similar to the patient's original tumour.
This knowledge could help clinicians to choose the therapy most
likely to destroy the cancer. Although the project focused on
breast cancer, the team believes the results could be applied to
other cancers too.
Dr Jonas Demeulemeester of the Francis Crick Institute, one of
the joint first authors, said: "Although how tumours spread
throughout the body is not well understood, we do know that some
mutations increase a cell's ability to move about. Cells like this
may leave the crowded environment of the primary tumour and enter
blood vessels. Swept away by the bloodstream, they may exit the
vessels again at distant sites and nest themselves in other
tissues, such as the bone marrow. Cells surviving this whole
process are known as disseminated tumour cells and can lay
undetected and dormant for many years, often resisting therapy,
before re-activating and giving rise to a new tumour, a
metastasis."
The study focused on patients diagnosed with localised breast
cancer - people with a tumour in their breast but no evidence of it
having spread anywhere else in the body. The team took tumour and
bone marrow samples when the patients were diagnosed and in one
case, took samples again three years later.
Next they looked at the genetic information held in cells from
both the tumour and bone marrow. The team developed sensitive
methods to interrogate the genome of each sample that allowed them
to spot both large and small-scale genetic changes.
Cancer happens when a series of genetic changes corrupts cell
behaviour. The changes, or mutations, create a DNA signature
specific to the cancer cell and the copies it makes of itself. By
tracking mutations in cells from the original tumour and cells
found in the bone marrow, they could compare the evolution of their
DNA signatures and figure out when DTCs sprang from the tumour.
They found that when DTCs are present they are genetically very
similar to the patient's original tumour.
"This knowledge is crucial to help determine the right therapy
for patients. If a treatment is chosen specifically to target a
mutation present in all cells of a patient's primary tumour then it
is most likely the disseminated tumour cells will also carry this
mutation and will also respond," explains Dr Demeulemeester.
The number of tumour cells detected in bone marrow also has a
value in figuring out a patient's prognosis: the more tumour cells
are found, the worse the outlook for the patient.
The new study suggests the number used as an indicator of
outcome could be considerably refined.
The team discovered that some cells found in the patients' bone
marrow didn't share any genetic history with the original breast
tumour cells. These cells nonetheless had large-scale genetic
changes and appeared to accumulate over time, suggesting that
genetic mistakes can occur in normal, healthy tissues as well. The
next stage of research is to look at what the relevance of these
intermediate cells is to the development of cancer.
Dr Demeulemeester said: "Only a subset of those cells previously
believed to be cancer cells have really spread from the patient's
primary tumour. A refined indicator means a more accurate prognosis
and a more tailored therapy for patients, avoiding over- or
under-treatment."
Dr Justine Alford, Cancer Research UK's senior science
information officer said: "Understanding more about how and when
tumour cells spread is important, and this early research sheds
light on the origins of these cells in breast cancer patients. When
cancers spread they are often harder to treat, but this new study
could help researchers develop new ways to tackle the disease more
effectively."
The paper, Tracing the origin of disseminated tumor cells in
breast cancer using single-cell sequencing, is published inGenome Biology.