This finding comes from a research article titled "Dependency of colorectal cancer on
a TGF-B driven program in stromal cells for metastasis initiation" it was published by
Elena Sancho and Eduard Batlle's group at the institute for research in biomedicine
in Barcelona, Spain in November 2012 in Cancer Cell Journal.
To understand this finding, let's learn about how cancer cells work and how they cause disease
in patients.
Whereas normal cells divide a limited number of times to produce a finite number of cells,
cancer cells keep dividing beyond what is normally allowed and this produces a tumor.
A tumor produced this way is very localized.
We call this a primary tumor, which usually can be treated with radiation therapy or surgery
in patients.
But what is more detrimental to patients than the primary tumor is if cancer cells have
metastasized.
Metastasis is a process where cancer cells leave the primary tumor, enter the blood vessels,
travel all over our bodies, and then leave the blood vessels to produce a tumor elsewhere.
This new tumor is distant from the primary tumor and can be found almost anywhere in
the body: in the lungs, the liver, the kidneys, etc.
It is these metastases that often lead to tragic outcomes for cancer patients because
they are numerous, uncontrollable, and hard to find.
One type of cancer that makes many metastases is colon cancer where 40-50% of patients will
develop metastasis.
The scientists of this paper were interested in finding out why some patients with colon
cancer have metastases and some do not?
What is the underlying biology that explains these differences?
If we can understand what predisposes a patient to get a metastasis then we can predict disease
outcome and treat patients based on what their disease is likely to become.
So to start answering their question, the scientists focused on a molecule called TGF-B.
TGF-B blocks the growth of most cells.
Because cancer cells want to keep growing forever, you can imagine that the presence
of TGF-B does not make them very happy...
So to overcome this, cancer cells have disabled their ability to sense and respond to the
presence of TGF-B.
This type of adaptation is very common in cancer and is one of the reasons cancer is
so hard to target.
But what is interesting about TGF-B is that eventhough cancer cells are not able to respond
to it, cancer cells produce very large amounts of TGF-B.
This seems highly contradictory: why would cancer cells secrete an anti-growth molecule
that they do not respond to?
These scientists were intrigued by this question and looked into it further:
By using historical data of patient outcome and some biological samples the authors were
able to determine that the levels of TGF-B produced by cancer cells are highly predictive
of disease recurrence.
In other words, patients that had colon cancers that produced high TGF-B had a lower chance
of being cured from therapy, whereas patients that had colon cancers that produced very
little TGF-B had a greater chance of being cured.
The scientists found that the levels of TGF-B produced by colon cancer cells are highly
accurate predictors of disease recurrence, much more than the current methods of determining
disease-free survival.
So the scientists were intrigued by this idea that cancer cells were making all of this
TGF-B that they could not sense and respond to, yet TGF-B seemed to be doing SOMETHING
to cancer growth since it is highly predictive of disease-free survival.
What is TGF-B doing to the growth of cancer cells, how is it doing this, and can we block
it?
Because the cancer cells don't respond to TGF-B, the scientists decided to look at the
cells that surround a tumor which we call "stroma".
The cancer cells don't act alone in making a tumor.
They often need the help of surrounding stromal cells at all stages of tumorigenesis.
So what did the scientists find in the cells surrounding the tumor: the stroma?
Well, they found that the stromal cells themselves were highly responsive to the presence of
TGF-B!!
To find out if TGF-B was acting on the stromal cells to influence cancer growth, the scientists
injected mice with colon cancer cells that produced high or low levels of TGF-B. And
what they found was very surprising:
Cancer cells that made a lot of TGF-B produced MORE tumors by helping cancer cells survive
and form a tumor.
The cancer cells that produced a lot of TGF-B were also more efficient at making metastases
in the lung and the liver.
Because we are always trying to find better ways to target disease, the scientists asked
if there was a way to block this effect by blocking TGF-B?
Well, it turns out that there is!
If the scientists blocked TGF-B production in the cancer cells, they were no longer able
to efficiently produce tumors and metastasize: so the tumors were smaller and few went to
the lung or liver.
This finding is very exciting because it describes a new pathway that we can target to prevent
tumors from metastasizing or establishing other tumors at distant sites in the body.
This would be HUGE when it comes to therapy because we understand very little when it
comes to the biology underlying the process of metastasis and how to target it.
This finding also highlights the complex relationship between cancer cells and the cells in the
stroma surrounding it and how that influences cancer growth.
So what did this study show?
This study showed that
1- Levels of TGF-B production by colon cancer cells are a reliable predictor of disease-free
survival
2- TGF-B produced by colon cancer cells can act on the cells around the tumor that we
call stromal cells to promote both tumor initiation and metastasis.
There are still many questions that remain before we can fully understand the role of
TGF-B in metastasis.
For example, how do the cells in the stroma help cancer cells metastasize.
There are a few possibilities: Does TGF-B act on the cells around it and instruct them
to make space to let the cancer cells through?
Or does TGF-B produced by cancer cells travel in the blood to distant sites where it changes
local normal stromal cells to change the environment to provide a nice little bed for cancer cells
to go to and make a metastatic tumor?
Does this process also control tumor initiation and metastasis in other cancers such as breast
or lung cancer?
So what does this mean for cancer treatments?
This study definitely provides strong evidence that measuring TGF-B levels is a better predictor
of disease progression.
It also provides a strong basis to develop effective TGF-B inhibitors for treatment of
colon cancer, which are being tested in clinical trials.
Although It would have been nice to see if treating the whole mouse with TGF-B inhibitors
(not just the cancer cells as was done here) could reduce metastasis in the whole animal.
From what you can see in this paper, there are still many important pathways that we
have yet to discover that play key roles in some of the most important disease processes.
It is only through basic research that we can move forward in our understanding of a
disease process to open new doors for investigating other diseases.