 This finding comes from a research article titled dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. It was published by Elena Sancho and Edward Batley'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 is usually treated by 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, they enter the blood vessels, and they 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, such as in the lungs, in the liver, in 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 metastases. 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 focus on a molecule called TGF-beta. TGF-beta blocks the growth of most cells. Because cancer cells want to keep growing forever, you can imagine that the presence of TGF-beta 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-beta, so they are able to grow even in the presence of TGF-beta. 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-beta is that even though cancer cells are not able to respond to it, cancer cells actually produce very large amounts of TGF-beta. So 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 scientists were able to determine that the levels of TGF-beta produced by cancer cells are highly predictive of disease recurrence. In other words, patients that had colon cancers that produced high TGF-beta had a lower chance of being cured from therapy, whereas patients that had colon cancers that produced very little TGF-beta had a greater chance of being cured. The scientists found that the levels of TGF-beta 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-beta that they could not sense or respond to. Yet, TGF-beta seemed to be doing something to cancer growth since it is highly predictive of disease-free survival. So what is TGF-beta 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-beta, 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. In fact, they often need the help of surrounding stromal cells at all stages of tumor genesis. So what did the scientists find in the cells surrounding the tumor? Well, they found that the stromal cells themselves were highly responsive to the presence of TGF-beta. To find out if TGF-beta 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-beta. And what they found was very surprising. Cancer cells that made a lot of TGF-beta produced more tumors by helping cancer cells survive and form a tumor. The cancer cells that produced a lot of TGF-beta were also more efficient at making metastases in the liver and the lung. Because we are always trying to find better ways to target disease, the scientists asked if there was any way to block this effect by blocking TGF-beta. Well, it turns out that there is. If the scientists blocked TGF-beta 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 which causes tragic outcomes in patients. 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, number one, levels of TGF-beta production by colon cancer cells are a reliable predictor of disease-free survival. Number two, TGF-beta 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-beta in metastasis. For example, how do the cells in the stroma help the cancer cells metastasize? There are a few possibilities. Does TGF-beta act on the cells around it and instruct them to make space to let the cancer cells through? Or, does TGF-beta 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? And lastly, 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-beta levels is a better predictor of disease progression. It also provides a strong basis to develop effective TGF-beta 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-beta inhibitors, not just the cancer cells as was done here, could also 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 disease process to open new doors for investigating other diseases. Thank you.