Chapter 03: Metastasis: A Regulated Process

Chapter 03: Metastasis: A Regulated Process

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Description

Dr. Fidler begins this segment by explaining that, in contrast with the prevailing belief (in the 70s) that cancer is the “ultimate expression of cellular anarchy” and that metastasis is random, his work has shown that cancer is a regulated process along every step of the way; similarly, metastasis is predictable. In response to a question about why scientists held (and still hold to) these conventional assumptions about cancer, Dr. Fidler notes how difficult it can be for a scientific community to accept innovative ideas. He then talks about significance of training clinicians in research and the basic sciences.

Identifier

FidlerIJ_01_20110926_C03

Publication Date

9-26-2011

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherStory Codes The Researcher Career and Accomplishments Discovery, Creativity and Innovation Definitions, Explanations, Translations Influences from People and Life Experiences Professional Practice Evolution of Career Understanding Cancer, the History of Science, Cancer Research On Research and Researchers Character, Values, Beliefs, Talents

Transcript

Tacey Ann Rosolowski, PhD:

So the prevailing idea at the time about cancers were that they were -- all of the cells in a tumor were similar.

Isaiah J Fidler, DVM, PhD:

No. But nobody could prove that they were not similar.

Tacey Ann Rosolowski, PhD:

That they were not. OK.

Isaiah J Fidler, DVM, PhD:

In fact people treated at the time cancer as cancer of this. Cancer is a disease.

Tacey Ann Rosolowski, PhD:

A big C, yeah.

Isaiah J Fidler, DVM, PhD:

Yeah. I’m telling you now. And we can talk about it tomorrow, another date. Maybe I should show you some pictures tomorrow.

Tacey Ann Rosolowski, PhD:

Sure.

Isaiah J Fidler, DVM, PhD:

Cancer of the breast. If it grows in the breast or if it metastasize to the bone or the brain or the liver are four different diseases in the same patient. They’re not the same. So to even say breast cancer, thinking that -- and I say, “Where is it growing?” Because of the next chapter that I’ll come to right now. So the next big challenge was OK, the tumors are growing in the lung. The lung is not tissue culture. It’s not plastic. It has lots of cells. The lung, if you’re a pathologist, I can show you lung, I can show you liver. They’re different organs. Don’t they have to say something about it? And I then realized that King Solomon -- if you know who he was -- supposedly according to my tradition the wisest man that ever lived -- said a few things. And one of the things upon his deathbed. He said, “There is nothing new under the sun.” He was very disillusioned. He thought that his big brain is going to discover new things. And he concluded that everything that he thought about somebody else thought about before. So working about the organ environment as we’ll call it now, came to my attention that in 1892 a British pathologist by the name of Stephen Paget in Lancet issue number one, 1892, yeah, wrote a phenomenal paper called On the Seed and Soil Hypothesis. And Paget said when a seed goes to soil it will germinate if the soil is fertile. It will not germinate if the soil is not fertile. But not all seeds will germinate even in fertile soil. He was a botanist, OK? I always when I lecture about that, I’m going to do it in Boston in about two weeks, I say that you know when I was in Frederick, Maryland I used to buy Burpee seeds for Big Boy tomatoes. And I have a picture of me with a tomato that was like two pounds. Was a huge tomato. And I buy the same seeds. $1.25 packet of seed. Put them in Houston. I get a six-foot weed. Because the soil and the climate here are not what the tomato needs. Weeds love Houston. But not tomatoes. You want to grow tomatoes, you got to go and buy a bag of garden soil and you know what I mean.

Tacey Ann Rosolowski, PhD:

Yeah I do.

Isaiah J Fidler, DVM, PhD:

OK. So began to read with my English postdoc Ian Hart I-A-N H-A-R-T. Ian Hart. About the Paget work. And reading other reviews discovered that a very influential person in America, name of Ewing, E-W-I-N-G.

Tacey Ann Rosolowski, PhD:

James Ewing.

Isaiah J Fidler, DVM, PhD:

James Ewing. In fact dismissed the Paget hypothesis and said that patterns of metastases can be explained merely on the vasculature. And Paget wrote something fascinating. He studied thousands of patient records. Among which were thyroid carcinoma. And Paget said, “How can you explain the thyroid carcinoma metastasize preferentially to bone?” Bone. Thyroid to bone. There is a direct connection? Cannot be. OK. But he didn’t say that, because he didn’t know Ewing in 1929 is going to dismiss. So anyhow Paget was dismissed literally. And Ian Hart and I decided to do -- now, even now, it looks like a very sophisticated type of experiment. So we took the lung and kidney and ovary from one-day-old mice. And implanted them into the leg muscle of adult animals. Because it was ovary it was all done in female mice. So it wouldn’t be male-to-female rejection. And two weeks later when the wound -- you open the muscle, you put the organ, and you close. Being two surgeons, for us it wasn’t a big deal. And two weeks later we injected the mice when the wound completely healed with melanoma intravenously. Into the tail vein. Where the tumor reach, OK? Will reach the right heart, go into the lung, oxygen comes into where the CO2 goes out, oxygen comes in, and everything goes to the left heart, and from the left heart you go to the body, and that’s the cycle. So the first major organ they will encounter after the heart when you put them into the vein will be the lung. And we said the following. If metastasis merely can be explained on the circulation, then the mice will have tumors in the natural lung but not in the implanted lung in the leg. And not in the kidney, not in the ovary. If, however, Paget is correct, that there is some synergy, some magic, between the interaction of the tumor cell and the organ environment, we will expect to see tumors in the natural lung, of course we’re putting them there, but if he’s correct we will see it growing in the lung in the leg but not in the kidney or in the ovary. And that’s exactly what happened.

Tacey Ann Rosolowski, PhD:

It seemed like James Ewing’s was a real mechanical understanding of body systems, and Paget’s was --

Isaiah J Fidler, DVM, PhD:

It’s OK. It’s 1929. Paget was a little more advanced.

Tacey Ann Rosolowski, PhD:

Yeah. They had a much more organic understanding of how --

Isaiah J Fidler, DVM, PhD:

Paget. OK. I can show you two people in 2011 that still think like they’re in the Middle Ages. What can I do? OK? Arbitrary, OK? He was the chairman of a department and what he said everybody agreed with him.

Tacey Ann Rosolowski, PhD:

Which one? Ewing?

Isaiah J Fidler, DVM, PhD:

Ewing.

Tacey Ann Rosolowski, PhD:

Ewing.

Isaiah J Fidler, DVM, PhD:

And Stephen Paget was the son of one of the most famous surgeons in England. And was always living in the shadow of his father. I’ll show you in a minute why I mean that. But in any event, we also used in that publication, we also used radioactive labeled cells. And we showed that just as many cells reached the kidney implant as reached the lung implant, but they only grew in the lung and not in the kidney. So it’s not getting there. That paper was published so rapidly, I thought ooh. And many years later Nature had their review of the field of cancer or what did they call it, milestone in cancer research. And number one milestone in fact was to reinvigorating the seed and soil. That seeds are unique and the soil is unique. And they fully gave me and my people the credit for everything I told you so far.

Tacey Ann Rosolowski, PhD:

Can I ask you? The papers were accepted just with light speed. What about a more general acceptance of the ideas that you were putting out?

Isaiah J Fidler, DVM, PhD:

It took a lot. It took a lot to. It’s now accepted completely. But it was not easy to convince individual but --

Tacey Ann Rosolowski, PhD:

What was the resistance about?

Isaiah J Fidler, DVM, PhD:

It was not convenient. Today when I say that tumor cells are clonal -- because that’s what we wrote -- and there were progenitor cell for metastases. Today you can read papers. Clonal, progenitor, stem cell. OK. They give it different name but it’s same idea. Seed. Paget called it a seed. I called it a progenitor. Organ microenvironment. Niche. Host factors. It’s all the same. But everybody feels like they have to reinvent the wheel. That’s another thing that Solomon said.

Tacey Ann Rosolowski, PhD:

I’m just struck that in so many fields there’s a natural resistance to change and --

Isaiah J Fidler, DVM, PhD:

But that’s human nature.

Tacey Ann Rosolowski, PhD:

Yeah. But it’s frustrating.

Isaiah J Fidler, DVM, PhD:

So I want you to see that.

Tacey Ann Rosolowski, PhD:

So what’s this?

Isaiah J Fidler, DVM, PhD:

A good friend after I gave a lecture. A friend said to me, “You will enjoy it more than I would.” So he sent it to me. The memoirs and letters of Sir James Paget. That’s the father of Paget, OK?

Tacey Ann Rosolowski, PhD:

Oh. That’s the father, yeah.

Isaiah J Fidler, DVM, PhD:

And guess who wrote it? He was the father, OK? James Paget. Stephen wrote --

Tacey Ann Rosolowski, PhD:

Stephen wrote it.

Isaiah J Fidler, DVM, PhD:

Stephen wrote it. Dedicated by permission to the Queen, Alexandra. These memoirs, Paget’s, etc. Stephen --

Tacey Ann Rosolowski, PhD:

So a biography of his father.

Isaiah J Fidler, DVM, PhD:

And as I leafed through this book, this falls out. My dear pater, we are sending you with our love the collected essays, OK? They make a goodly volume, etc. This was written in 1902.

Tacey Ann Rosolowski, PhD:

Just for the recorder, I’m seeing that these are two blue handwritten sheets that fell out of the book. Stephen Paget, wow. He penned those.

Isaiah J Fidler, DVM, PhD:

Well, here he says, “Talking of moping, do you know the story of the little girl who was horribly disappointed because her baby brother could not talk? They said, ‘Why, dear, he won’t begin to talk till he’s a year old.’ And she said, ‘Well, they told me at Sunday school that God cursed the day he was born.’” Job. Excuse me. Job cursed the day he was born. “With best love to Betty. And affectionately yours. Stephen Paget. My dear pater.” Isn’t that nice?

Tacey Ann Rosolowski, PhD:

Yeah.

Isaiah J Fidler, DVM, PhD:

Anyhow.

Tacey Ann Rosolowski, PhD:

What a treasure --

Isaiah J Fidler, DVM, PhD:

Yes, it is, I’ll keep it.

Tacey Ann Rosolowski, PhD:

-- this is. It really is a treasure.

Isaiah J Fidler, DVM, PhD:

I only have two books of my --

Tacey Ann Rosolowski, PhD:

There it is, one of two books on your desk. What’s the other book?

Isaiah J Fidler, DVM, PhD:

Other one is The Talmudic Anthology: Tales and Teachings of the Rabbis. Which from time to time -- I tell you that there is nothing new under the sun. Anyhow. A man should not say, “I will study in order to attain the degree of a rabbi.” He should study for the love of it and the honor will come at the end as of the by-product. The Bible said it differently. The Bible says, “Don’t do good things in order to be rewarded. Do good things --” The recorder is paused.

Tacey Ann Rosolowski, PhD:

Now it seems to be happy again. So we had the recorder off for about five minutes, ten minutes, where we were looking at some pictures of tumors and visual summaries of some of Dr. Fidler’s experiments. And we were talking about the idea of -- well, your conclusion, your belief that there’s no such thing as cellular anarchy. There’s just --

Isaiah J Fidler, DVM, PhD:

No, no, I said that metastasis, when I started my research the prevailing viewpoint was that metastasis is the ultimate expression of cellular anarchy. Because the process of the pathogenesis of metastasis was not clearly delineated. And what we have done now, we know every step in the process that a cell must complete to leave the primary tumor and grow at a distant site. And it doesn’t appear to be an anarchy at all. It’s a very very very regulated process. And it’s regulated by tumor cells interacting with host factors at every step of the way.

Tacey Ann Rosolowski, PhD:

Can you describe? I’m sorry. Go ahead.

Isaiah J Fidler, DVM, PhD:

The other thing that I stated. At the computer -- at the microscope side, was that at the time that I started my research the prevailing viewpoint was that metastasis was a random process. And I never understood why a process could be called random when you predict the outcome. In other words, oncologists clearly know that if a patient has pancreatic carcinoma the tumor will metastasize to the liver. In renal cancer metastasis will occur to the lung and the bone. In glioblastoma there is no metastasis. Ovarian cancer primarily metastasizes in the peritoneal cavity. And I can go on and on. Breast cancer metastasizes to the lung, liver, bone and brain. Thyroid carcinoma metastasize only to bone primarily. There are some exception of course to everything I tell you. Melanoma is the real -- how shall I say -- highway thief, because it can grow anywhere. Melanoma is the most vicious tumor I know. But today and yesterday a good oncologist know precisely where to look for metastasis of a given tumor. Once the pathologist confirms the tumor. If they don’t know the pathologist will tell them. If it’s colon cancer you look at lymph node and liver before you search in the brain and the lung. How can you say that when you can predict the site of metastasis a metastasis is random? If it was random, you say, “I’m sorry, Mr. So-and-so, you have a tumor. And where it will go I have no idea.” That’s what random means. If you have no idea, you don’t belong in the field. People don’t come to you to hear “I have no idea.” You can say the truth is some tumors cannot be treated, some can. But “I have no idea,” then where were you in medical school? Where were you in fellowship? I mean playing golf? What do you mean you have no idea? We all know. So why was it such resistance to admit that metastasis is not random? When you began to read the literature, you see that the first one who said that metastasis is not random was Stephen Paget. Or maybe even before him. I could not search before. Most of that literature is in German. I don’t read German.

Tacey Ann Rosolowski, PhD:

Do you know where the -- what’s your suspicion about where the resistance came from? I mean why just keep mouthing those words?

Isaiah J Fidler, DVM, PhD:

Because tomorrow we’ll talk about brain cancer more as an example for the seed and soil. And you hear “The blood-brain barrier prevents me from doing thing.” Even this morning I heard it. I said, “There’s no such thing in cancer. Here’s the proof.” Said, “But that’s a small molecule.” I said, “Small, large, it doesn’t matter.” Data should speak, not suspicions. When you don’t have data you have suspicion. Now you can quote me on what I’m going to tell you now that’s mine. When a scientist says “I believe” means they don’t have data. “I believe” belongs in church or synagogue. In science you either know or you don’t know. What you believe is irrelevant. The minute you say “I believe” means you don’t have data. So you have to believe. Or “I speculate.” “I have a hypothesis.” That’s OK. Because you can test a hypothesis. But how can you test “I believe”? You either believe in God or you don’t. I mean I’m not going to convince you. There’s no way to convince you. If I could everybody would know. At the time with metastasis was a lot “I believe.” You go to meeting, you hear what people believe. They believe in this, they believe in that. They were frustrated because there were no answers. And very few people worked in the field. Very few. Even now. I would say there’s no more than 1,000 people in the world that work on metastasis, the number one killer.

Tacey Ann Rosolowski, PhD:

Killer. That’s amazing.

Isaiah J Fidler, DVM, PhD:

And there is 10,000 working on signals. OK? On this receptor. That receptor. Gene analysis. I don’t know. 20,000, 100,000. But on biology, on real pathology, there’s very few. Because it’s complicated. Makes life difficult. And unfortunately in research if you don’t do popular things you may not get a grant. I encountered it myself when I had a new -- I at my stage. If I have a hypothesis I don’t get it from thin air. I based on something. I said a hypothesis. Why tumors in the brain are resistant. And I went, wanted some seed money. They said, “Where are your data?” I said, “If I had data, I don’t need you. What do I need you? For seed money. I had data, I’d go to a drug company.” Which I did. But Paget was so revolutionary, was so -- and even today when you go around and ask graduate student, or ask the fellow that write paper, look at publication. I’ll take you one paper after another. Look at the -- here. We are now submitting this paper to -- our own paper. We’re submitting this paper. It will come out in PNAS about microarray to study transcriptome of metastasis. There’s lots of authors on this paper. I only edited part of it. Because a lot of it I really don’t even -- you see the famous tumor in the ear, etc., etc. 2009, 2002, 2008, 2003, 2005, ’94. Ooh that’s an old one. 2003, 2003, 2001, 2009, 2008, 2006, 2007, 2002, 2011, 2004, 2002, 2002, 2005. The world doesn’t exist before. If you published 15 years ago nobody knows who you are. That’s the way it goes. And with PubMed you rarely go beyond five years.

Tacey Ann Rosolowski, PhD:

PubMed?

Isaiah J Fidler, DVM, PhD:

PubMed, publication med. PubMed. So if I say to somebody -- I do when I teach graduate student. Now I’m going to Harvard to teach. OK? And just for fun I said, “Luria-Delbruck. Show of hands. You know who I’m talking about.” Nothing. They received the Nobel for medicine. I said, “Don’t feel bad. When you receive Nobel for medicine five years later nobody will know who you are anyhow.” So it’s only famous for five years. Your mother and father will say all the time, but anybody else on the street doesn’t know who you are. But there is such -- how shall I say it -- a pouring of information now that it’s impossible to read everything. But at the time it wasn’t. You see? There were a few journals that -- in my field there were three or four journals we published in. That’s it. And everything had to be typed by hand. You had to be very careful. It’s not like a computer, you can change things and move things. You want to redo it, you just redo it in five -- everything, secretaries hated you. You brought them handwritten. And “Why don’t you type it?” “I don’t know how to type.” And on and on.

Tacey Ann Rosolowski, PhD:

I’m thinking too of that Luther Terry Fellowship and I just wondered if that was unusual to try to encourage people to go from clinical --

Isaiah J Fidler, DVM, PhD:

Very very very very unusual. Very unusual. Look, the president of MD Anderson is a phenomenal scientist but he doesn’t have a PhD, he’s an MD. He decided he’s going to go into science. He’s lucky. He’s very lucky. Many people in the clinical area are MD/PhD but they did their PhD in two years at Yale, Columbia. And now it’s almost giving you a gift of a PhD. But they didn’t do fellowship. They didn’t do postdoctoral fellowship. I have trained more than 180 people by now. Many of them were MDs who had even a PhD. Never mind names. And came to me for two years just to learn how to do things. Because in two years what do you do? You just write a thesis. Luther Terry was revolutionary. Paget was revolutionary. We’re only mentioning people who really moved the field. And it was unconventional thinking. Even today you will hear that breast cancer is spread by the lymphatics and this tumor spread by the veins. Give me a break. Some tumors don’t grow in lymph node. Fibrosarcomas. It doesn’t mean they don’t penetrate veins. I can deposit them in the lymph node. They will not grow.

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Chapter 03: Metastasis: A Regulated Process

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