ASU PSOC Workshop, Thursday May 19th – Friday May 20th 2011
Invasion: How cancer cells spread around the Body
Ninety per cent of cancer deaths occur when the neoplasm spreads beyond the primary tumor and invades other organs. This process, known as metastasis, normally signals a sharp deterioration in prognosis. The manner in which cancer cells migrate around the body remains an ill-understood process, but it is clearly a topic in which physical science is deeply involved. Normally cells quit the primary tumor and enter either the lymph system of the blood system (“intravasation”).
Listen to Audio Interviews and Read Transcripts
The physics of the vasculature is fairly well understood, but the motion of cells circulating in the bloodstream involves many subtleties. The fate of a circulating tumor cell will depend on physical variables, including the size, shape, mass, elasticity and surface adhesive properties of the cell. Some of these variables will be a function of time, and also will change according to the physical micro-environment. Cells may travel individually or in clusters bound by platelets. They may arrest in capillaries or other locations in the vasculature, and then may burrow out of the bloodstream (“extravasation”) into the host organ via complex mechanical processes involving rolling, adhesion, crawling and squeezing.
What is clear is that most cancer cells do not survive this sequence of migratory events, opening up the prospect that if any one stage of metastasis, from intravasation to post-extravasation dormancy, could be disrupted by physical means, a rare event – the successful colonization of a distant organ – might be turned into an even rarer event, effectively delaying the development of secondary tumors and conferring significantly enhanced life expectancy. The workshop sought to expand this theme of controlling cancer by physical means, by bringing together experts in cell motility, the mechanical and surface properties of cells, the physics of the vasculature, the process of extravasation and cell mechanics, and experimental oncology.
Audio Interviews from the Workshop
- Interview with Erin Rericha from the University of Maryland reveals her impressions of the meeting and describes areas of research that she feels need more attention.
More Info: http://www.ireap.umd.edu/ireap/personnel/Rericha/Rericha.htm
- Interview with Isaiah J Fidler (Josh Fidler), DVM, PhD is an eminent cancer biologist based at The University of Texas MD Anderson Cancer Center, Houston. He discusses the urgent need to standardize research procedures to allow easy comparison between the findings from different groups. He goes on to talk about his latest, encouraging, findings regarding metastases in the brain. His approach has not yet been tried on people.
More Info: http://faculty.mdanderson.org/Isaiah_Fidler/
- Interview with Michael King is a biomedical engineer at Cornell University who studies the adhesion of cells in the blood stream – white blood cells, platelets and circulating tumor cells. He describes his research, but begins by describing the metastatic process .
More Info: http://www.bme.cornell.edu/people/faculty/profile.cfm?id=15822
- Interview with Peter Kuhn, Associate Professor of Cell Biology at The Scripps Research Institute discusses the importance of a multi-disciplinary approach in order to make progress in understanding and treating patients with metastatic cancer..
More Info: http://kuhn.scripps.edu/default.aspx
Peter is also director of the Physical Sciences Oncology Center focused on Four Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB Center):http://physicsoncology.org/default.aspx
- Interview with Owen McCarty from Oregon Health and Science University discusses the intriguing relationship between heart attacks and cancer cells circulating in the blood.
More Info: http://www.ogi.edu/people/dsp_person.cfm?person_id=A5F13A0E-F483-1F80-4F4E9CF7E2998924
- Interview with William (Bill) Muller is the Magerstadt Professor and Chairman of Pathology at Northwestern University Medical School. He’s also an expert in leukocytes, white blood cells that fight infection, but until this workshop had not considered applying his research to investigate properties of circulating tumor cells.
More Info: http://www.pathology.northwestern.edu/Faculty/FacultyBio.cfm?ID=100
- Interview with Jean Paul Thiery, Deputy Director of the Institute of Molecular and Cell Biology, and Chief Scientific Officer of the Experimental Therapeutics Centre, in Singapore. In this lightly edited interview he discusses how pharmaceutical companies need to collaborate with each other and with the scientific community to develop new combination therapies and better clinical trial protocols.
More Info: http://www.imcb.a-star.edu.sg/php/jpt.php
Interview with Erin Rericha
Erin Rericha: My name is Erin Rericha and I’m currently at the University of Maryland and the National Cancer Institute.
Pauline Davies: And what are you studying Erin?
Erin Rericha: My training is in physics but I spent the last six years learning cell biology, so I feel like I’m both a physicist and a cell biologist and now I’m trying to figure out how to link those two disciplines together.
Pauline Davies: And what in particular is your project?
Erin Rericha: Well, I don’t know that I have particular projects. So I’m interested in how cells move and what triggers guide them in their process, and so I’m going to ask that question on all sorts of different scales in order to get the answer as opposed to just one particular approach.
Pauline Davies: So what did you get out of this meeting on metastatic cancer?
Erin Rericha: So, I learned a lot. One of my take-aways is there’s different time scales in this process. So there’s the tumor growth itself which seems to be slow, and because it’s slow maybe not so much is actually known about how it progresses and whether it progresses constantly or at different rates or where it’s triggers to change it’s growth pattern. The actual process of metastases seems to be really fast. So, once a cell leaves the blood stream, the data’s not clear but it seems that on the order of a day, the cell has now found a new site and now it’s going to go and turn into a tumor, which is again going to be a very slow process. So, its an interesting question to me right now as to whether we go after that really fast, but perhaps vulnerable state that happens in a day, or do we go back and concentrate and think about how do we make the slow phases even slower or less likely to start.
Pauline Davies: So when you say the slow phase, you mean the primary tumor, is that right?
Erin Rericha: The growing phase of a tumor. Whether it’s the primary tumor or the result of a metastasis event that happened, and then has to grow to reach a clinical detection stage, or a place where it’s having an effect. Those two processes seem to happen over orders of years, or depending on the environment, by the time you would detect you have two months, but nobody is saying that that process happens in a day, but they are talking about metastasis happening on the order of hours to a day.
Pauline Davies: But no one knows how long those tumor cells might circulate in the blood?
Erin Rericha: No, that seems to be an open question too , as to really how long that they’re going through there and what fraction remains a circulating tumor versus get cleared by your immune system, and really what are the factors that are helping that clearage process go. So I think that becomes really interesting targets for experiment, is if you can figure that out.
Pauline Davies: One thing that I heard that I was quite interested in is where these cancer cells might actually leave the blood stream.
Erin Rericha: Right, so the question of where the cancer cells get out of the blood stream; so the feeling in it was that they behave and get out of the blood stream in similar places as your white blood cells get out of the blood stream. And that makes a lot of sense, but I was surprised that nobody’s seen it, that it’s not a definitive knowledge. So, is it again that it happens so fast that it’s something we can’t experimentally get at? Or are there multiple mechanisms that allow them to get out different ways, but that seems to be an important problem to figure out. Is it the capillary? Is it the post-capillary venule? Nobody thought it was the artery but nobody actually looked either. So yeah, I think it’s a very good question as to where it gets out. I don’t even necessarily care how it gets out, but where seems to be an important question.
Pauline Davies: And then people still don’t know where these cells actually go and hide out and how long they hide out for…
Erin Rericha: Right, that seems to be a stage of considerable confusion with quite a few people having very strong beliefs that that is a regulated organized process, and other people arguing that this is still somewhat stochastic, in that if you get enough cells in the blood you will have them search out all spaces and only a few of them will win. So those seem to be somewhat competing pictures and I left interested but not sure about a resolution.
Pauline Davies: What were the other main issues that you heard about?
Erin Rericha: I think that the practice of experiment and interpretation of data and the controls seem to be a major issue because the science is so complicated it’s difficult to reproduce and so coming from a physics background where things are simple and we insist that another group can be able to do them, it seems that, I don’t want to say, rigor because that passes judgment, but because of the complexities it’s difficult to synthesis information because it comes with different caveats.
Pauline Davies: So how do you think things should change?
Erin Rericha: Well, I know that in my own lab I’m going to do multiple different cell culture conditions. So if varying cell culture means you get different answers, then I think that needs to be one of the dials in my lab, because I can’t just pick one favorite person that I happen to be friends with and use their cultural style, right, because everybody’s doing something different, and so I would only be leashing my horn to one particular approach. So that is going to be a new dial in my laboratory. We’re going to try things ten different ways and see which features of cancer are robust to these sorts of changes and concerns that people have.
Pauline Davies: Were you encouraged by the stuff you heard today? Do you think we are making progress or, what’s your opinion?
Erin Rericha: That’s a good question. I would say my enthusiasm waxed and waned. I think last night and this morning I was really raring to go, I felt I had some good ideas that there were places to go that we could make progress. Right now I think I’m tired. I think I’ll get back to that. I do think that this notion of trying to pool large peoples together and at least talk about problems in order to figure out the right ones to go after can only be beneficial. So I leave hopeful.
Pauline Davies: So lots of issues, lots of things to study, lots of discussion maybe for another conference?
Erin Rericha: Yes, it would be nice to do a follow up, at least those who are interested who end up doing some science as a result of this it would be interesting to see a follow up and get the feedback from these individuals as to where they think it should go next, that would be fun.
Interview with Josh Fidler
Pauline Davies: Josh, how long have you been working in cancer research?
Josh Fidler: In general, from 1969. So, how many years?
Pauline Davies: A long time.
Josh Fidler: It is a long time.
Pauline Davies: OK. Now have you seen much progress in that time?
Josh Fidler: Very much so. In our deep understanding of the most complex problem in cancer, which will be why cancer cells spread and grow in other organ, which is the major cause of death from cancer; we have a significant additional understanding; not what we did 40 years ago.
Pauline Davies: And yet, what I picked up from your talk was the problems of methodology that still persist and permeate all of cancer research.
Josh Fidler: We have far more sophisticated questions now to reach the answers; we need different methods than what we have. Many of the simpler questions have been answered, but unfortunately they reveal the lack of understanding on a deeper level. We need to improve our methodology to answer those more specific and more complicated questions.
Pauline Davies: And you were mentioning that just changing the glucose composition of substrates that you grow cancer cells on makes a huge difference and there’s no standardization between groups in this country, never mind around the world.
Josh Fidler: Well, the specific illustration was that if one resorts to examining expression of specific genes, the mere change of glucose concentration of cells that grow in tissue culture leads to altered expression of these genes. While in the past, we used tools such as microscopes to study cells on the culture, or even staining with particular antibodies, we did not detect these differences. Now that we delve into far and far more sophisticated methods to determine differences among cells, we realize that every little thing can change expression of these genes and I would imagine if we go to other methods we may discover that the differences exist even on a deeper level.
Pauline Davies: And you were telling us about some of your new research…
Josh Fidler: Four years ago I decided to really dedicate all my effort to understand the biology of metastases to the brain. And the reason is that today when one diagnoses a patient with metastases to the brain their life expectancy can be measured in months and there is very little that we can do about that. What we have found, and its well known, is that tumor cells that grow in the brain are highly resistant to chemotherapy. And there was an explanation to that that said that it must be the blood-brain barrier that is a specific vasculature that does not allow chemotherapeutic drug to exit the circulation and kill tumor cells. In fact, most research shows, and especially clinical research, that by the time of diagnosis the blood-brain barrier is leaking and does not even exist. We know that because in many tumors that grow in the brain cerebral edema is a well known finding; well if you have edema, it means that the vasculature is leaking. And we asked a question differently: What else in the brain can render those cells extremely resistant to therapy? Some months ago we published our paper, took us about two and a half years to prove it, that a stromal cell in the brain called an astrocyte whose physiological role is to maintain stability in the brain to help neurons survive and so on, astrocytes, if they establish communication with tumor cell, protects the tumor cells from chemotherapy. We know the mechanism, we know how they do it and we now begin to interfere with the protective function of astrocyte on tumor cell, and fortunately it is extremely successful to the point that the clinical trial is almost ready to begin.
Pauline Davies: That’s amazing. And your other finding was that cells, cancer cells, from different types of tumors, all behave the same in the brain.
Josh Fidler: In some respects they behave the same because when they encounter the stroma of the brain, the astrocyte, microglia, and the blood vessels in the brain, these are quite stable, and they interact with the successful tumor cells, successful meaning they can grow in the brain in a very similar manner. So, the common denominator to metastases in the brain, be it from lung cancer or breast cancer or melanoma, is that they interact with the same stromal cells in the same manner. In other words, the microenvironment happens to be a common denominator, and if we can target that common denominator, whether the tumor originated from the lung or from the breast, I would hypothesize should not make a great deal of difference.
Pauline Davies: That is very encouraging. It almost implies that if you have metastases to the brain, that particular form of tumor may be treatable.
Josh Fidler: Our experimental results suggest that whether the metastases originated from lung cancer, breast cancer, or melanoma, the treatment was very, very effective regardless of the origins of the metastasis.
Pauline Davies: Fascinating work. So what’s your next step?
Josh Fidler: The next step is, I declare when I finish a lecture (that I did not deliver today) on brain metastases, that if you have a sick mouse, please send him to me. The question is will this approach work in the clinic, where the disease is established for years rather than months, and men and mice, although they are mammals, have a great deal of differences. So the great challenge is to translate these basic findings to the clinical reality and if it is, it will tell us that brain metastasizes one treats in this directions, lung metastases a different way, liver whatever. Every organ has a unique stroma, a unique microenvironment and using the Paget hypothesis, I advocate that one can attack cancer either by targeting the seed or by targeting the soil. The seed is extremely heterogeneous; tumor cells are genetically unstable and they create tremendous heterogeneity. Whereas the microenvironment is far more stable and if we can only understand the interaction of the microenvironment with the tumor and interfere with that interaction, we stand a good chance of treating cancer in a very different approach, but that hopefully will achieve a major success.
Pauline Davies: Thank you very much.
Josh Fidler: You are very welcome.
Interview with Michael King
Michael King: So you know, the paradigm of metastases were a primary tumor starts to grow and draws the growth of new blood vessels to feed it and what makes cancer particularly deadly, is metastases the formation of distant tumors, secondary tumors, so I think the people at this meeting and more generally a lot of people working in the PSOC network, are trying to understand that process, maybe control it or disrupt it.
Pauline Davies: So tell me how it all works from beginning to end, but not it in too much detail.
Michael King: OK, so the current thinking is that for some reason cancer cells in the primary tumor become invasive and leave the primary tumor, migrate through the surrounding tissues and if they can enter into the circulation now, cancer cells have access to the entire body. And so, what exactly cancer cells do when they enter the circulation is another topic that we’re certainly interested in and other people as well. Certainly, when cancer cells are in the environment of blood, there’s a lot going on. There’s lots of protein and blood cells, leukocytes, platelets, and so some of the people here started to look at those interactions, between cancer cells, leukocytes and platelets. And so the next question is how do cancer cells survive in the circulation, because many solid tumor cells are typically of epithelial type, where to thrive and survive they need to be spread out and attach to extra cellular matrix. So if they’re suspended and floating around in blood, the idea is that many of them will undergo anoikis, programmed cell death, but if they can survive in the circulation, then maybe they can make a journey to a distant organ and form a new tumor. And so it’s believed that cancer cells might have a better time of surviving in the circulation if they attach to platelets or to proteins like fibrin, or if they’re assembled into small aggregates and I think we saw some really nice data yesterday showing surprisingly large aggregates, clumps of cancer cells that are found in blood of cancer patients. And so, one of the things that we look at is trying to understand the mechanisms of how cancer cells get back out of the circulation. And so, one hypothesis that we have is that cancer cells act like white blood cells, and so they might follow some of the same processes of adhering, rolling, stopping on the blood vessel wall and then squeezing out of the blood vessel, a process called ‘extravasation’ and, sort of, they find cell junctions and squeeze their way out. And then once they leave the circulation, if they can graft and find a supportive niche in which to grow and then that can result in secondary metastases. So that’s the way at least the way, we think about metastases and a lot of others do, almost like a cycle where if a secondary metastases grows large enough maybe that will shed cancer cells back into the blood stream. Some cancers spread not just through the circulatory system but through soft tissues or through the lymphatic system, so those are some other routes.
Pauline Davies: This scenario sounds so complex that it’s surprising that so many cells make it, or maybe they don’t make it?
Michael King: It’s actually one of the things that’s been described is that metastases is actually a very inefficient process. So some of the numbers that have been quoted, the highly quoted number is that each gram of tumor tissue can shed a million cells per day into the circulation, which is a very scary number. But what we do know is circulating tumor cell counts that we can measure in patients, and it goes anywhere from one cell per milliliter of blood up to a hundred cells per milliliter of blood. So they’re very, very rare, sort of like a needle in a haystack in terms of trying to find them or detect them. But in truth, maybe one in a thousand or one in a million actually makes it to form a new tumor. And so it is an inefficient process and some of the ways that we can try and understand it is as a rare event, apply concepts of statistics and so on to try to understand what makes it work.
Pauline Davies: Does anyone know how long the cancer cells survive in the bloodstream?
Michael King: We don’t know and we don’t know the circulation time. It’s really hard to estimate. The closest data you can get are from animals. Most of the experimental evidence so far is taking really big human cancer cells and injecting them into mice. And so, in an experiment like that, most of the cancer cells that you inject that way immediately get lodged in the capillaries of the lungs. You can also get so called metastases to other organs that way, but it doesn’t seem so realistic as to what’s really happening with a human tumor. So a sort of step up from that is to have a primary tumor grow on a mouse either subcutaneously or spontaneously, form it in different organs and then to wait until the tumor gets large enough that it’s starting to shed its own cells into the blood stream. So that, I think, is a little more realistic.
Pauline Davies: It is surprising though that that sort of experiment hasn’t been done yet.
Michael King: Well there are certain mice, transgenic mice, that will spontaneously develop tumors. We’re starting to look at one that spontaneously develops prostate cancer, the males, and so we hope to learn a lot from it because with transgenic mice you can do a lot of different techniques. You can knock out different genes or try different drug therapies. And then afterwards you can get very detailed data of how many tumors there are and where they went.
Pauline Davies: And your own work, you’re working on cell adhesion, how does that play into this?
Michael King: Yeah, so we build small devices that we think resemble the post capillary venules, the small blood vessels in vivo, and so we can place whatever molecules are relevant, adhesion receptors and so on, and then flow human cancer cell lines through or cancer cells spiked into blood and observe in real time how those cells interact with the surfaces so we can create the conditions that we think are happening in vivo that allows cancer cells to interact with the blood vessel wall. Some of our colleagues take it a step further and grow endothelium on the inside of micro-devices, so that’s a step up in realism. A little harder to control, but when you have real endothelial cells you can actually observe extravasation.
Pauline Davies: Thank you very much.
Michael King: You’re welcome.
Interview with Peter Kuhn
Peter Kuhn: I’m Peter Kuhn, Principle Investigator of the Scripps Physical Science Oncology Center.
Pauline Davies: So what are the big questions to do with metastases?
Peter Kuhn: How does metastasis occur in a patient? How do we go from the primary tumor to the secondary tumor, and how to do we catch it in the process of doing so? If we would know one-hundred percent that we truly removed the entire tumor and we can just aide it with a little radiation therapy, these patients are actually cured. However, there are too many patients where we have occult metastases, meaning disease that we have not detected, or disease that exists in the blood circulation. If that’s the case, the patient does need additional treatment.
Pauline Davies: And how much do we know about these circulating tumor cells?
Peter Kuhn: Very, very little because we haven’t studied this in the past because we haven’t brought together the right scientific expertise, and technologies, and life and clinical sciences to really start addressing the problem because you can study this only in the actual patient and that just makes it a little bit more complicated.
Pauline Davies: Certain questions that sound rather basic like, how many times do tumors cells circulate in the body? People don’t seem to know the answer?
Peter Kuhn: That is correct. I don’t know anything about the lifetime of these tumor cells because I don’t know if they’re hanging out in the blood. Are they really alive for years and years and years? Is it just that these micromets are subclinical, meaning that they’re actually there, we just don’t see them? We really don’t know much about these cells, and how they evolve over time. We just know that they’re there; we know that they are the messenger, and that they carry the message of metastasis as the fatal event in the metastatic cascade.
Pauline Davies: Now cancer has been studied for a long, long time, decades….
Peter Kuhn: But the fluid phase of solid tumors, it’s a little of a paradox statement, but it’s an obvious one, right? Because that is how that metastasis occurs; by tumor cells migrating from the primary tumor through the circulatory system to settle down elsewhere. That fluid phase has not been studied a whole lot and that is due to, in part, because we needed to get a lot of other research in place first to refine how we would go about it. It also required a whole lot of analytical technique development; it required basic tool development, instrument development, processes and all that. And then we had to bring together the right people to have that conversation. And the whole point was that conversation had to be between the haemo-pathologist, the oncologist, the engineer, the physicist, the cell biologist, the immunologist, people who understand how to run assays, people who understand how to handle data, people who understand how to analyze data, and you have to bring all of them around the table and not just once but again and again and again over an extended period of time. And that all of a sudden makes it very, very complicated. So we have gone from sort of early conceptual thoughts and ideas around how to do this to actually doing this in patients. We have so many patient advocates working with us; we have so many clinicians working with us and we have now just finished our first observational study with almost 90 non-small cell lung cancer patients, and so we’re really excited that we are bringing up both the basic research program and the translational program that the interaction between the groups is working very well, and we see already the benefits from that.
Pauline Davies: When will you get some good results?
Peter Kuhn: I think we already have some really exciting results. We now have to understand these results and interpret them accordingly. What we have seen is already is that the data for example, in non-small cell lung cancer patients, looks very different from what it looks like in prostate, or breast, or pancreatic cancer patients. So now it is an interesting question as to of how do we go from exciting technical developments to quite exciting observations in the clinical setting to something that we can now interpret in its overall context.
Pauline Davies: Lots more work to be done.
Peter Kuhn: But if would be easy, then it would have been done before.
Interview with Owen McCarty
Owen McCarty: I’m Owen McCarty and I work in the Biomedical Engineering department at Oregon Health and Science University.
Pauline Davies: And Owen, you’re actually looking at the stickiness of cancer cells.
Owen McCarty: Yes, I look at what cancer cells are doing out in the microenvironment of the blood and how the blood coagulation factors and platelets and blood cells interact with the cancer cells.
Pauline Davies: Because this is very relevant, a lot of cancer patients die of heart attacks don’t they? Or strokes?
Owen McCarty: Yes, actually thrombosis and death from clots is the number two cause of death for cancer patients, behind organ failure being number one. So, there’s a strong correlation between the blood clotting and having a cancer prevalent in your blood.
Pauline Davies: And there are two possible scenarios and hypotheses aren’t there about all this? One is, the cancer cells are responsible for a clottyness and the other is that the clottyness encourages the cancer cells.
Owen McCarty: Right. So that’s kind of the question that’s in the field right now. Are the cancer cells actually acting on the blood coagulation cascades and actually enhancing clotting in the patient? Or, is it the actual coagulation factors in blood cells actually binding to and enhancing and promoting metastases? On the other hand, it could be interacting such as natural killer cells and then coating the tumor cells with fibrin and actually killing and phagocytosing the cells. So right now it’s an active area of research to understand what side of the coin is this falling on.
Pauline Davies: Yes, this is certainly sounding quite complicated.
Owen McCarty: Yes.
Pauline Davies: And how would you distinguish between those scenarios?
Owen McCarty: Well, I’m going to have to think about how to do that ! So, some of the work that we’re doing right now, in collaboration with Peter Coon, is we’re looking at the cancer cells from patients and, yeah, how to distinguish between those two? That’s the paradigm right now that people are struggling with. You know, what is the right experiment to do? Is it looking at single cells in vitro, is it looking at animal models, is it looking at the patient’s samples, or is it doing epidemiology studies trying to correlate risk of venous thromboembolism, or heart attack or a stroke with the prevalence of cancer? And so it’s hard to tease apart from the patient data and then look at your in vitro information and piece those together. It’s a challenge right now in the field.
Pauline Davies: And one of the reasons that the stickiness factor might be important is because the cancer cells tend to get stuck in the very small blood vessels, the cancer cells stick together with other factors, it’s a raft people have described it as, and then they get stuck and that’s the area where they might actually then extravasate and get into the tissues. Is that right?
Owen McCarty: Right. So, many of the blood cells, their primary job is to heal up the vasculature and when their there, such as platelets, they’re releasing a whole host of growth factors to actually stimulate angiogenesis and repair and wound healing. So these same cells, if they interact with your circulating tumor cells, they can help the cell, the CTC, actually lodge at a site in the vasculature, be it something that’s already inflamed or if somebody already has a little microtear a little microvascular injury, and once there the tumor cell now would have all of the angiogenic pro-angiogenic factors being secreted from the blood cells themselves. So that’s (how) some of the interaction of the CTC’s with platelets and white blood cells might actually potentiate the ability of these cells to land and to create a new niche at that secondary site.
Pauline Davies: Sounds like a really exciting area of research.
Owen McCarty: Oh, thank you very much!
Interview with Bill Muller
Pauline Davies: Ok you’ve been talking today about how leukocytes actually come out of the blood system and go into the extra cellular matrix, and trying to link that to the cancer story, how do you think they fit together.
Bill Muller: Well, I’m not sure that they do, the hypothesis is that since different types of leukocytes stimulated by different cytokines, different inflammatory conditions, all seem to take the same common pathway – whether they go para-cellularly or trans-cellularly – there seems to be one final common mechanism, that is the recruitment of the lateral boarder recycling compartment (LBRC) to surround the leukocytes as they go through. And the hypothesis is that maybe cancer cells have usurped a similar mechanism to get out of the blood stream and into tissues. We don’t know what recruits the LBRC to surround the leukocytes, or I should say, we know some of the signals but not all of them – there are clearly many of them. So if cancer cells happen to be able to give off some of these signals, which might be inserting the lamellipodia, or invadopodia, into the surface of the endothelial cell, or giving off a calcium signal – whatever it is, they may be able to recruit this mechanism to allow their passage across endothelial cells. So I came here to learn more about cancer and figure out if this is totally off the wall or might even be possible.
Pauline Davies: How is it that people don’t know yet how cancer cells invade?
Bill Muller: I think it’s because we only see the final effect. Nobody’s ever really watched this because it’s a very rare event; you have to be in the right place at the right time, and so even if you saw one that’s one, you might have to wait 15 years to see another event. We see cancer – I’m a pathologists – and we see cancer after it’s been taken out of the body, there are many cells, it’s grown and there’s no way to know how it got there. So we just see the final cancer sitting in the tissue. We don’t know whether it ate it’s way through the endothelial cells, whether it squeezed through like a leukocyte, or took some totally different route.
Pauline Davies: And what about experiments, can’t experiments be done in the lab to actually investigate this?
Bill Muller: Well, we’re doing it in vitro and have some evidence that the lateral boarder recycling compartment may in fact actually be involved. We just started these experiments and the next one is to look using live cell imaging to study the movement of cancer cells across the endothelium. So I think we will be able to do that in vitro. But that again, is in vitro: that says it could happen, it doesn’t say that it does happen. The real challenge is to go in vivo and try to find real metastatic cells coming from a real primary tumor, not one that’s you’ve injected, isolated tumor cells intravenously, but how do they break off a real tumor and try to see how they go across. That’s a very rare event; I think it’s going to be very difficult unless we can find some very sensitive mechanism or an in-dwelling, microscopic probe or something in a vascular system to look. But I actually, would be happy for injected, intravenously injected cells, be able to see enough of them move through and figure out what path they took.
Pauline Davies: And if you finally do discover how cancer cells cross from the blood into the rest of the body, what significance will that have?
Bill Muller: Well, since metastases is the way that people die, and if this is a major mechanism of metastases, we’re hoping that we can inhibit it, just the way that we’re hoping to be able to use inhibitors of this mechanism to block unwanted inflammation. So if we can block obviously unwanted metastases that would prevent a tumor from setting up shop and making more metastases which are going to harm the host.
Interview with Jean Paul Thiery
Jean Paul Thiery: I’m Jean Paul Thiery, I’m from Singapore but I’m visibly French.
Pauline Davies: So, Jean Paul, you’ve been here for a few days; why did you come to this meeting?
Jean Paul Thiery: I came to this meeting totally by serendipity, by accident. I met Roger [Johnson] in Singapore, one of the colleagues of Paul Davies, and he told me, “You absolutely have to come out Phoenix, Arizona.” And so I decided to come, and now I’m very satisfied. I visited the Institute; I went through all the labs and I see the potential of this multidisciplinary Institute.
Pauline Davies: Now, we’ve been the last two days sitting in lectures about metastasis, so this is your area of research, obviously?
Jean Paul Thiery: Well, it was my area of research, again by accident, because one day I bumped into Josh Fidler and all the old guys, and then they were telling me, “You should work on metastasis, you have to work on metastasis; we need brains, we need developmental biologists working together with us, and so on.” So, I am seeing that over the last thirty years, some progress has been made in understanding the disease, although we’re far from understanding basic principles that would help us in designing new therapeutics. The debates that we had in the last two days are really showing that we still have very different conceptual interpretations of the data and we are not quite sure exactly what we should do; this is where the debate is. I think we need quite a few more of those think tanks to decide the really critical options that we should follow.
Pauline Davies: Because people often say that no one dies of a primary tumor, it’s metastatic disease that kills.
Jean Paul Thiery: I am not completely agreeing on that. If you have a primary lung cancer that really propagates throughout the lung, you are going to die, ok? It’s not just that no cancer would make you die, but metastasis is really a final stage where under those circumstances, very, very few people will survive more than a couple of years. I have seen patients that survive ten or twenty years with liver metastases. So it’s not one hundred percent killing but it’s obviously more aggressive and the prognoses are extremely unfavorable. The primaries are also sometimes are very nasty.
Pauline Davies: What are the main things that we need to understand about metastatic disease, would you say?
Jean Paul Thiery: Well, I think we have to understand where the cells are that are fully capable of reaching the secondary sites and then would (survive and grow) afterwards. We are not quite clear where those cells are. Myself, I studied the initial dissemination; I tried to look at cells that were already installed at a distance from the primary tumor. For instance, in breast cancer, we’re looking at bone marrow micrometastases. However, the technology so far has not been good enough, it will come soon, to try to decide whether some of those cells are capable of forming secondary tumors, or even tertiary tumors because metastases can give rise to other metastases. So unfortunately it’s very hard, with the kind of technologies we’ve had until very recently, to decide whether those cells were capable of making clones or are, malignant and so on. And this is what we have to do now.
Pauline Davies: So I heard something that sounded a bit frightening really, that maybe a million cells will slough off each day ………
Jean Paul Thiery: So a tumor, a one gram tumor which is basically what you detect today, right? If you have a one centimeter diameter breast tumor that is a grade one with extremely low proliferative potential and if it is a primary tumor and very well differentiated, your chance of surviving twenty years is more than 95 percent I would say. But in 5 or 6 percent of the cases, the patient is going to relapse, within 5, 10, 15 years. Some patients even forget they had the primary tumor. And then sometimes they come to the clinic and they have a bone mass and then a vertebral mass, and so obviously these cells came from the primary, but they were residing clinically silently for a long time. So you have cells that are being released everyday and we find that 10 or 15 percent of those patients with a one centimeter tumor already have cells in their bone marrow. Not obviously all succumb from that , but they clearly show that the cells disseminate early so a one cubic centimeter tumor will release perhaps more than one million cells a day, and 99.99 percent are going to die but a few are going to find their niche somewhere; in the bone marrow, the liver, the brain, the lung. And so those ones are going to stay there, maybe slightly proliferative, slightly dying, so everything equilibrates. So they are undetected and you may have micro-lesions that will not bother you for the rest of your life. But for whatever circumstances, suddenly, one of these lesions begins to progress, then a couple of years later – difficult to say how many years – you will see a lump in distant sites and then the next two years are going to be quite traumatic because it is going to grow quite fast afterwards. So, the treatment of metastases is more difficult to deal with because they are much more clinically difficult to reach. Surgically speaking you often cannot remove them and even if you could remove them, there would probably be other distant metastases that would appear afterwards and this is basically what we see when you treat patients with very harsh chemotherapy like herceptin; you prolonged life by five years but then what you see is that the patient who normally would have died of the liver or lung metastases now will die of brain metastases because you have other cells elsewhere that they are going to take over and form additional metastases. So that’s what we see; the patients are not really curable in that case. So, you have unfortunately lots of cells being shed all the time; fortunately most of them are not really in a sense malignant, not going to progress. But it’s a very critical mechanism for disseminating.
Pauline Davies: And that’s where people like the scientists here at the meeting would like to intervene and do something.
Jean Paul Thiery: Yes, ….. In the last talk we heard that the big pharmaceutical companies have launched immense programs for making new drugs – there are probably a couple of thousand new drugs now on the shelf of the companies undergoing phase one, phase two, phase three clinical trials to show efficacy. I think, and this is my personal view, that clinical trial are not well carried out these days and I think (the companies) would absolutely like to see tumor shrinkage with a single agent. I think it is not the right strategy. I think what we have to use completely different parameters. However, you will need to biopsy the patient following the initial treatment and during the treatment to see the molecular, morphological and phenotypic changes that the tumor is undergoing. Then what I would like to do, using my EMT (epithelial-to- mesenchymal transition) based concept is to try to see whether we could revert the phenotype of those differentiated cells and then reapply the conventional chemotherapies, which are much more prone to kill cells. You know, the new targeted therapeutics are not good for killing cells. You would need immense amounts which are extremely toxic, and so I would prefer to use much lower doses in combinations, and then the next step would be to reapply chemotherapy that was not effective originally and hope to restore sensitivity to these drugs. But it is difficult to convince pharmaceutical companies to do that.
Pauline Davies: And do you think physicians would be allowed to prescribe their own combinations?
Jean Paul Thiery: Well, most physicians are not allowed to prescribe the combinations unless the FDA (Food and Drug Administration) has approved the drugs. If approved, you can use the drug in another way without asking the permission of the pharmaceutical company who produced the drug and is the owner of the patent on the drug. However, usually to make drugs in combination you have to contributions from at least two companies and usually the two companies are not going to accept such a deal. The two companies would both be very suspicious of each other and scared that one drug would damage the reputation of the second drug, and so they are not very willing to cooperate. And this is really the problem. Billions of dollars are spent and just wasted because a lot of the products are staying on shelves in laboratories and not used, and this is very sad. A lot of them are being dropped at phase two (of their clinical trials) and they will never be distributed to clinicians for doing an adaptive clinical trial with new protocols. So I’m quite unhappy about that. I think that at the last ACR (American Cancer Research) meeting, where 17,000 people attended, you started to see a little discussion about how pharmaceutical companies should stop antagonizing each other but rather should cooperate and synergize and add values to their own product in many ways, but they don’t quite understand that yet. You know the pharmaceutical companies are run mostly by financial people nowadays and have lots of regulations that would prevent (such cooperation). People are really scared there would be any kind of incident during the phase one – phase two clinical trials.
Pauline Davies: Do you think that issue will ever be resolved?
Jean Paul Thiery: If the issue were to be resolved there would have to be much more pressure from the public and the advocate groups. We’d have to explain to them that billions of dollars are being spent for probably nothing and that this money could be much better utilized if it could be done in a more reasonable cooperative setting, in which clinicians and the scientists could cooperate to establish clinical trials. Most clinical trials come to hospitals completely written down. There’s no chance whatsoever (the hospital) could modify a little bit of anything in the clinical trial; it’s all driven by the company and sometimes the company interest has nothing to with finding real cures; it’s something else. They have to rush into phase three, FDA approved clinical trials and they want their money back, and I think this is the problem. If you talk individually to clinical people in charge of clinical trials in pharmaceutical companies they will admit that. But if you (officially) ask the company, they will not declare that.
Pauline Davies: And you’re living in Singapore, do you know what the situation is in China? In the future will China be in a better position to actually have a more sensible approach to drug development?
Jean Paul Thiery: Well, a lot of pharmaceutical companies went to China to develop clinical trials in a much faster way because there are many more patients available for the clinical trials. So they hope that they will have a much larger market one of these days. Whether or not that will change the strategy there, I’m not completely sure.
Pauline Davies: But the government could insist.
Jean Paul Thiery: Yes. I know the minister of health from China. He has a PhD from Paris and he is a good clinical oncologist. He discovered that a simple product (that you can use to kill your mother-in-law), called arsenite, is very effective against a very rare leukemia. So yes, a guy like that could certainly implement maybe more reasonable strategies for cooperation and cost effectiveness, especially since they will need to treat 1.6 billion patients. We need to have something very different. I was working at the Comprehensive Cancer Centre for 15 years at the advent of herceptin and taxol to treat breast cancers. I was at the Curie Institute in Paris treating 3,000 new breast cancer cases a year. About 300 were allowed to get herceptin and taxol, and it was calculated immediately as to how much the budget was increased in one year at the Curie. The increase came to about 25% of the total annual budget of the Curie, just for these two products. So that’s about 100,000 euros per patient. It’s paid for by social security in France but in many countries this doesn’t happen and lots of people can’t afford to pay for (the drugs). In Singapore for example, people are not well covered by social security, so if they have cancer they have to pay 60% of their expenses. Often they have to sell their house, borrow money – the family has to support them – so it’s a very difficult situation for patients. In China, except for 0.01 per cent of the population, no-one could afford to spend more than $20 on a drug – like in South Africa with HIV. So I think we have to completely change the strategy and make drugs much, much cheaper. You cannot pay 5000 euros for an injection of herceptin and avastin. It’s a monoclonal antibody so it’s not that expensive [to make] but they [the company] want to have their money back. There is a big discrepancy between the cost of drugs and their effectiveness. I think we have to change that very soon because everyone is going bankrupt; the pharmaceutical companies themselves are going bankrupt. So I think you have to find a compromise, right!