Why does cancer spread so fast after surgery!
by the famous
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NARRATOR: Long before promising
results like thalidomide, Judah Folkman was forced to make a difficult decision
between surgery and research. He chose research. But his surgical background
continued to prove invaluable, especially with a very dangerous
aspect of cancer called metastases.
JUDAH FOLKMAN: Cancer cells don't stay at home. Thyroid cells never wander around the body to other organs and liver cells don't wander around. As soon as they would enter the blood supply and start to circulate, they die.
NARRATOR: But cancer cells do travel. A marble-sized tumor can release about a million cancer cells every day. And some of them survive very long journeys, from the breast to the lung, or the colon to the liver.
JUDAH FOLKMAN: Cancer cells can enter the blood stream, stay alive, and come out some other place, like the brain or the lung and grow again.
BRUCE ZETTER: Now what you have are hundreds or even thousands of tumors in the liver. And as each one of those tumors grows up, what happens is that the whole liver becomes replaced with cancer and can no longer function.
NARRATOR: Sometimes the metastases will settle in a new location but they don't call in new blood vessels and they don't grow. They're not dead. They're just dormant. When they'll wake up is not known except in one unusual circumstance. Sometimes when the primary tumor is removed, the metastases suddenly come to life. New blood vessels appear and the metastases grow rapidly. It only happens to a small percentage of patients, but it has troubled surgeons for more than a century.
JUDAH FOLKMAN: Always that had been thought to be blamed on the surgeon. "It must have come from the wound that he made, some factor."
NARRATOR: But was it the surgeon? Or was something else at play, keeping the metastases dormant until the primary tumor was removed?
It was a medical mystery that would unravel in a most unusual way. And the answer would ultimately provide Dr. Folkman with one of the most important insights of his life.
It all started when NoŽl Bouck wore a new pair of shoes to a cancer meeting.
NOňL BOUCK (Northwestern University Medical School): My feet were killing me. So I found a room where nothing was going on, and I just went in and sat down. And then people started coming in, just slowly, and then my row started to fill in. And I just couldn't gracefully get out of it.
NARRATOR: Dr. Judah Folkman was giving the next presentation. NoŽl had never heard of him.
NOňL BOUCK: I had never heard the word angiogenesis before. I had never considered the fact that tumors needed new blood vessels. And by the time he got through I thought, "This guy is right. He's absolutely right. I believe it."
NARRATOR: NoŽl was so impressed, she changed the focus of her research from cancer genes to angiogenesis. Two years later, Dr. Folkman was at home reading with his wife when he came upon a paper that astounded him. It was from the lab of NoŽl Bouck. She had discovered something remarkable.
There are some normal cells that secrete angiogenic inhibitors all the time. Shown here in yellow, the inhibitors are part of the body's natural defense against disease. They keep our blood vessels quiet.
But when normal cells switch to cancer cells two things happen. First, they start producing blood vessel stimulators, the blue molecules. At the same time, they drastically reduce the inhibitor they were previously making. It is a delicate balance of chemicals in which the stimulator must overwhelm the inhibitor before blood vessels can emerge.
But why would a tumor cell continue make a blood vessel inhibitor at all? Dr. Folkman would think about that question every day for the next several months, until one September morning on the Jewish holiday of Yom Kippur. And suddenly, everything made sense.
JUDAH FOLKMAN: It was exactly ten o'clock in the morning and...I can remember exactly...we were in the corner...I can remember the seat we were in because suddenly it explained everything.
NARRATOR: In the back of a Boston synagogue Dr. Folkman finally understood that century old mystery about metastases. When the primary tumor is in place it makes a small amount of inhibitor, the yellow substance. It's not enough to overwhelm the much more abundant blue stimulator.
But the inhibitor is very stable. It can survive the long journey through the blood stream to the distant and much smaller metastases, preventing them from calling in new blood vessels. But when the primary tumor is removed the source of the inhibitor is also taken away. Now the metastases are able to call in their own blood supply and grow.
Suddenly, it was crystal clear to Dr. Folkman that the powerful blood vessel inhibitor he'd been seeking for decades could be found in the primary tumor itself. Now all he had to do was inspire one of his students or colleagues to look for it.
JUDAH FOLKMAN: Nobody would do the experiment in 1989, nor 1990. And I kept saying, "This is a great experiment." And in 1991 no one would do it. And Michael O'Reilly came to the lab in July of '91.
NARRATOR: Michael O'Reilly had no idea what he was in for. He started looking for the inhibitor in a mouse tumor.
MICHAEL O'REILLY (Children's Hospital/Harvard 1991-2000): When we ground it up, it was very easy to see the simulators because the tumors were making so many of them. But there were just so many proteins that we couldn't tease out the one that was responsible for inhibiting angiogenesis.
NARRATOR: If Michael couldn't find the inhibitor in the tumor maybe he could find it in a place where there are fewer proteins. Since substances that don't get used by the body often end up in the urine, that's where he decided to look next, in the urine of mice with large primary tumors.
MICHAEL O'REILLY: What seemed like a great solution at the time, in retrospect, made it much more difficult, because I then had to work with mouse urine, which smelled pretty bad.
NARRATOR: Not only did it smell but he needed gallons of it. So Michael designed a high speed collection system. He strung three mouse cages together (later it would be 6 and then 12). The cages had open mesh bottoms. The urine ran down the funnel went through the tubes and into a collection jar below.
JUDAH FOLKMAN: The problem was he had to collect urine from a mouse. Now a mouse urinates only one cc a day. A little...that's a thimble-full.
MICHAEL O'REILLY: So the solution was to give the mice sugar water and they enjoyed it quite a bit.
JUDAH FOLKMAN: They drank all day and they urinated all day. So we got huge volumes of urine from one mouse. The total body weight of the mouse was in urine.
NARRATOR: After processing the urine, it was time to purify it--separate the protein molecules to find the one that inhibited new blood vessel growth. The tedious process began. Column after column, drip after drip, egg after egg. The search lasted for more than two years, until finally he found the molecule he was looking for.
They called it angiostatin. Angio for blood vessels, statin for stop. With the molecule identified, it was time for the ultimate test--treating cancer. Would this protein keep the metastases dormant?
Michael used 20 mice with a special cancer on their back, which he knew sent many metastases to their lungs. But while the primary tumor was in place the metastases stayed quiet.
MICHAEL O'REILLY: I removed the original tumor and then divided the mice into two groups. One group of mice had no treatment. The other group of mice were (sic) treated with angiostatin. And we gave the angiostatin every day and then just waited and saw what happened to the mice.
NARRATOR: When some of the mice started to look sick it was time to end the experiment. Dr. Folkman rushed through the lab gathering people to witness the moment.
JUDAH FOLKMAN: In a few minutes Michael's going to open the angiostatin mice. If you can join us as a witness it would be good.
KEVIN CAMPHOAUSEN : I'll come down.
JUDAH FOLKMAN: Okay, thank you.
In a few minutes Michael's going to open the angiostatin mice.
I knew that if we had a good result no one would believe it. So we invited everyone in the lab who was there that day. And this is probably the high point in the history of the laboratory.
MICHAEL O'REILLY: Opening the abdominal cavity...
NARRATOR: Nervously, Michael operated on the first mouse. It was treated with Angiostatin.
MICHAEL O'REILLY: The lungs look very good. I really don't see any metastasis here.
NARRATOR: The lungs were clear. No metastases.
MICHAEL O'REILLY: Okay, now we're going to open up one of the untreated mice.
NARRATOR: The second mouse had no treatment at all. The difference was stunning. The lungs were heavy, bloody and fully burdened with tumors.
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