Cancer Latency and Dormancy

February 27, 2013 – February 28, 2013 all-day

tempe-viewCancer cells often remain quiescent for years of even decades. This fundamental, and still mysterious, property of cancer is the subject of the next workshop. Latency refers to the fact that cancer cells, or even small tumors of the sort that are detected in screening programs, may never progress to cause clinical symptoms. Dormancy describes the well-known phenomenon that, following the removal of a primary tumor, the same cancer may reappear years later in a more malignant form. Cancer latency and dormancy offer a clear challenge to the physical science and oncology program. If cancer is stabilized in a quiescent phase as a result of certain physical parameters in the micro-environment (e.g. pH, oxygen tension, pressure), then controlling those parameters may offer a way to extend the phase. A cancer that lies latent or dormant for many decades may cease to be a serious health issue.

Audio Interviews and Transcripts from the Workshop

Interview with Anne Chambers

(Back to Audio)

Ann Chambers: Well I was giving my perspective on what happens in our experimental models and how it might lead to hypothesis that suggest what we look for in patients as a way to try and determine who is at risk for dormancy and what we should do about it.
Pauline Davies: What conclusions are you coming up with?
Ann Chambers: Well in all of the models that we have looked at, we’ve seen more dormant cells than we have seen metastatic cells. So in a metastatic cell line, even a very, very metastatic cell line, most of the cells behave as non-metastatic, many of them get to an organ and simply sit there. We’ve been using some novel imaging procedures, MRI type procedures to track these cells, and we see a population of cells that seem to sit in the organ and remain dormant. We don’t know what regulates them, but we certainly see that in patients as well.
Pauline Davies: And how long do they stay dormant?
Ann Chambers: Well in our models, it’s shortened. If the models get metastasis, then the metastasis will take over. But in patients, in breast cancer you can have dormancy that happens for 20-25 years. So the struggle in the field is to try and get some models that will help inform what is going on in these patients who are at risk for these dormant cells. One of our big problems is that we know for some cancers that some patients will be at risk for dormancy but we don’t know which ones. So the big challenge is, if you’re going to treat dormancy, you better know which patients are at high risk for dormancy, and which patients are not. There are clinical studies that show that you can actually treat dormancy as a phenomenon. There was a Canadian trial where they looked at long term hormonal therapy in women with breast cancer that was hormone responsive. And you can treat women for 5 years, 10 years, 15 years, and you can benefit some women clearly, but it’s also at some risk of toxicity. So, we need to know what the target is better before we move in and say okay, we are going to just treat all women with something.
Pauline Davies: When you say treat for dormancy, do you mean wipe out the dormant cancer cells or do you mean keep the cells in the dormant condition?
Ann Chambers: Neither, actually. In the models that have been done so far, women with hormone responsive therapy, the cancer can come back 5, 10, 15, 20 years later. The thought is that over this period of dormancy, some cells start to wake up. So, if you are treating them continuously with an anti-hormone therapy then you are going to catch them when they wake up. This requires therapies that can be given long term without too much toxicity. But there is a lot of speculation about wouldn’t it be nice to make the cells stay dormant? Or to kill them while they are dormant? Or higher risk to wake them up and to kill them with some side of toxic therapy that kills them only while they are dividing.
Pauline Davies: Now I’m amazed that you can actually see these dormant cells. But you say that there are imaging techniques that allow that to be seen?
Ann Chambers: We are imaging mice. So the MRI technique that we have is actually a very neat technique. You load the cells before you inject them into the mouse, with iron, and the MR machine will pick up the iron as a little black spot. When the cells start to divide, they lose the iron so you can’t see them anymore. So you have a marker of non-division, as long as you see a black dot the cell has not divided. The only way that we know they are real in patients is after the fact. You are treated for cancer, you think you are cured maybe, but we don’t know that, and if the cancer comes back you know you were in a state of clinical dormancy. It is a very retrospective thing, you don’t know which patients have dormant cells, that is part of our problem.
Pauline Davies: Could it be the case that most breast cancer patients have dormant cells but in most cases they don’t go on to cause any problems?
Ann Chambers: That’s certainly one belief that people have. The problem is that there is so little data. And one of the things that I am really pushing for is some detailed autopsy studies that will just figure out the prevalence of perhaps irrelevant dormant cells in patients? We don’t know that. Some people think that all high risk breast cancer patients probably have dormant cells and for many of them they will just stay there forever and they will die of something else. So, we really don’t know the lay of the landscape in patients.
Pauline Davies: So more research needs to be done to actually discover the prevalence of dormant cells. That seems a very basic thing to do, doesn’t it?
Ann Chambers: I think so, but it’s hard to get the data. Other than things like autopsies, there are people who are doing these circulating tumor cells, which is a marker of a cell being somewhere. There are people doing disseminated tumor cells in bone marrow, and they find them. But, in a non-invasive fashion, it is going to be very hard, other than statistically, to find out who is at risk. That’s why I’m pushing for detailed autopsy studies. In starting, say, women who are at high risk for recurrence, either they do or don’t get recurrences. But can you do autopsies carefully after they have died of either breast cancer, or of something unrelated just to see whether they are common but not causing problems? We don’t know that.
Pauline Davies: Do you think that your mice are realistic models for human disease?
Ann Chambers: No… I don’t know. Ha ha. It’s always an issue. In every single model we have looked at, we see dormant cells. It seems to be associated with how aggressive the tumors are in the mice, but in a mouse experiment that takes 6 months, is that corresponding to twenty years in a patient? We don’t know. All I can do is give us testable hypothesis that you can take to patients and see if it leads you someplace interesting.

Interview with Khashayarsha Khazaie

(Back to Audio)

Khashayarsha Khazaie (Kash): My name is Khashayarsha Khazaie, but they call me Kash because it’s unpronounceable for many people here. I’m a cancer immunologist
Pauline Davies: So tell me the story as you’re seeing it.
Kash: Well, I wasn’t trained as an immunologist, so I have a rather naïve view of immunology and sometimes that helps because you don’t have preconceived ideas.
Pauline Davies: What were you trained as?
Kash: I was trained as a molecular biologist. Actually, my PhD. Was on aging and then I decided the subject of aging was too complex and not so easy to solve. So I decided that if I became a microbiologist, I could understand how molecules come together and create life, or destroy life. That’s why I became a Microbiologist.
Davies: You gave a very nice presentation today, what did you talk about?
Kash: I talked about the concept that the field of cancer immunology is changing. People, for the past century, have had this preconceived idea that our body is designed to defend us against cancer. We are starting to look at what is going on in each organ, and understanding the biology of it. I think that this is the way to go. The surprise is, the host immune response is actually helping the tumor. There are of course two sides to this. The tumor has evolved with us, and the reason that it is successful is because it can use all the resources it has, which are resources that belong to us. They (the tumors) use them for their own purpose.
Pauline Davies: So that really is turning the tables isn’t it?
Kash: There is a protective side to it, but that protective side is losing the battle because the cancer is smart and knows how to manipulate the system to its own advantage. I’m not the only person who has come up with this idea. What we are doing that is unique and different than others, is that we are looking at regulatory mechanisms which actually get out of control and create immune responses that help the tumor.
Pauline Davies:So why is the tumor able to manipulate the immune system?
Kash: The tumor manipulates the immune system by definition. It is successful; it can only be successful if it manipulates the host, wins it over and destroys the host. That is the definition. At least up to here we can see that if we interrupt that communication, that pathologic communication, between the tumor and the host, not only will the tumor have difficulty growing, but the other side of the immune response, which people have been dreaming of for one hundred years or so, comes up and starts rejecting the tumor. The big question is, up to what point can you get rid of the tumor? That’s a very important question.
Pauline Davies: Do you have any clues?
Kash: Well actually, yes. It just so happens that my better half is working on genomic instability in cancer. If you can interrupt genomic instability, you might be able to limit the flexibility of the tumor and then get rid of it, maybe then there will be no limit. What has always driven me, it may be cultural, whenever I read something or see something, the first thing that comes to my mind is, ”What is wrong with that?” Obviously the way that we are thinking is not correct. I really admire Harold Varmus’ philosophy, which I stated during my presentation, that changed the philosophy of NIH into more provocative thoughts. Into thinking, “What is wrong with all the dogmas that are around?” And I think that this is the way to go forward to break the dogmas to break the dogmas.
Pauline Davies: What do you think of this meeting?
Kash: It’s been excellent! For me, it’s been really exciting for me because it’s a stimulating meeting. First of all, it is a cross fertilization of people in different fields. There are people who have never thought about the subject that is being presented and they have a completely blank sheet of paper in front of them. They ask questions that people who have worked in this forever and have been engaged in a certain train of thought, have never thought about. That becomes thought provoking and stimulating and I really enjoy it.

Interview with Jeff Green

(Back to Audio)

Jeff Green: I think what I was trying to convey is the idea that the changes in a matrix in surrounding a tumor cell can have profound influences on how the tumor cell behaves. There is an association between increased stiffness of the matrix leading to more aggressive tumor behavior and metastases, but the whole process is complex. There is a complex interaction between multiple cell types that communicate with each other and tumor cells. This can lead to a change in what is laid down in the extracellular matrix and how these different proteins are processed that can lead to a change in signaling within the tumor cells and alter their biological behavior. The idea is, can we understand this in a way that we can inhibit tumor cells from growing? Or prevent dormant tumor cells from proliferating? Unfortunately, I think the process is very complex and it is going to take an enormous amount of work and creativity to sort out how each component within the tumor environment is influencing the tumor. And what the crosstalk is between the different components, different cell types, and even how the cells can influence other parts of the body that are far away. Also, how the metastatic site can be conditioned to become a host for the tumor cell.
Pauline Davies: : You were describing some cross links that you thought are very important in cells that enabled the tumor to actually spread.
Jeff Green: Right. Again, as an example, just trying to point out that while certain proteins may be laid down in the extracellular matrix, their influence and activity on tumor cells and stromal cells can change depending on how the protein is processed. In certain cases, enzymes may be produced by the tumor cells that have a dramatic influence on how the components in the extracellular matrix are processed, cross linked, leading to changes in alignment of components and ultimately how these components may react with receptors on the tumor cell leading to alterations in signaling and phenotype and biology of the tumor.
Pauline Davies: : You were looking at intervening in some way to prevent this stiffening?
Jeff Green: In our case, we have looked at a signaling pathway that we think transmits the changes in the extracellular matrix through a cell surface receptor and a signaling cascade that can dramatically alter or switch a cell from being quiescent to proliferative. By understanding what components are in the signaling pathway, we can think about ways of targeting and inhibiting some of those components. It would of course make a lot of sense to try to see if there are potential pharmacological ways to alter the processing in the extracellular matrix, or augment, or reduce, the production of certain components of the matrix that may be influencing the tumorigenic process. There is a lot we need to understand first before we can target some of those complex systems.
Pauline Davies: : Is there anything else you would like to add about your work?
Jeff Green: It is built upon the work of many other people. We still have a lot to try to understand about the complex interactions of all the components; cellular components and extracellular components, in influencing how cancer progresses and determines whether tumors recur as metastatic disease that can kill patients. We’re just at the beginning of some of this understanding.
Pauline Davies: : What have you gotten out of this meeting?
Jeff Green: Several things. I think I have been educated about some very interesting systems that other people are performing. I have been impressed with the advances in trying to isolate tumor cells from metastatic sites where the tumor cells have not begun to proliferate, being able to pull out individual tumor cells from the bone marrow, and apply genomic techniques to understand their genomic phenotype, I think is an extraordinary advance. I’m impressed with the way people think in terms of a system and not individual genes. I think while we are focusing on genes within individual tumor cells, this meeting has emphasized, we need to think of tumors as a new emerging tissue with its own emerging order and understanding that process will be the key to hopefully defeating cancer someway in the future.

Interview with Colm Morrissey

(Back to Audio)

Colm Morrissey:So my talk was based around the identification of cells in the bone marrow of patients are that have no evidence of disease for over five years. So these cells supposedly are dormant, for that period of time. What we want to do is characterize those cells and look at the molecular signature, and compare those cells to cells that are actually in patients who have recurred, to determine what is keeping these cells in a dormant state?
Pauline Davies: So are you assuming or have you actually measured that there are these dormant cells in prostate cancer patients who seem to be fine?
Colm Morrissey:Certainly. So, we have over the years looked at quite a few hundred patients. We’ve looked at patients are tyrannical prostatectomy and taken bone morrow’s from these patients and shown that about 60% of these patients have disseminated tumor cells in their bone marrow at time of radical prostatectomy. So, the surgeon is, removing the prostate, to get rid of the cancer but we know that there are actually cells present in the bone marrow at that time in those patients. We also have looked at patients who after, radical prostatectomy, have had the primary removed, 5, 10 -15 years later also if you go to the bone marrow and see if you can see in the cells are in fact disseminated cells in there. We know there are cells present in the bone marrow, and we know they haven’t produced metastases. Those cells could be considered either dormant or as senescent. However, in many cases from patients who have had their cells removed with the radical, find that they do progress later, suggesting, some of these cells have the ability to produce a metastases.
Pauline Davies: What proportion of patients goes on to relapse if they have had their prostate gland removed and they seem free of metastatic disease at that time of prostatectomy?
Colm Morrissey:Well that will depend, of course, upon the timeframe. Most patients will recur within a two-year period, and then as a stretch of time less and less patients recur. The problem with answering that question is that you don’t know if it depends on the surgery. In some cases, patients will arrive and they will have extra-capsulary extensions and the tumor may have already left the primary at time of radical. In some cases, the radical prostatectomy has a very low Gleason and grade so aggressiveness as such. Really the question is, for a particular grade or particular stage, at which the patient has the prostate removed, what is the recurrence rate for that. You can give an average about 15% of patients recurring, but really it breaks down into how aggressive the disease is in the patient at the time of radical.
Pauline Davies: Does anyone know how aggressive it is at that time?
Colm Morrissey:Based upon Gleason and grade, based upon some seminal vesicle invasion, based upon some extra-capsule extension, age of patient, ETC. We call this the Partin tables. In prostate cancer, they can estimate the aggressiveness of the tumor.
Pauline Davies: We’ve been hearing that tumor cells escape through the blood system. What is the significance of cells actually breaking through the capsule?
Colm Morrissey:If you look at patients, one study has shown, who have had radical prostatectomy and five years later they still have no evidence of disease. Between five years and 10 years out, the patients who recur are generally patients who have had extra-capsulary extension or seminal vascular evasion. Indeed, our data set independently shows that for patients who have at least a six month period of all no evidence of disease, I.E. they don’t have any PSA in the bloodstream, we find the patients that recur earlier after a certain length of time are indeed in patients who have extra-capsulary extension. Patients who do not have extra-capsularycan indeed recur, but it is at a later stage.
Pauline Davies: Doesn’t the prostate have blood vessels? Why is it so important, if you break through the capsule, you get invasive cancer? Where as the prostate has blood vessels, can’t the cancer escape that way? Isn’t that the more natural way for it to go?
Colm Morrissey: So what you’re describing it when you describe the extra-capsulary extension, isn’t so much that the cells are escaping the prosthetic capsule and entering the body to that mechanism. What you may be describing is actually a certain phenotype of a cell. So, those cells that have the ability to break through the capsule Etc, may have a more migratory phenotype. Therefore certainly they may go through the vasculature, and going through the vasculature +, having a more aggressive phenotype may allow them to actually seed more effectively and survive more effectively in the bone marrow or indeed in another visceral tissue while they remain dormant before they lead to eventual metastatic disease.
Pauline Davies: Does your research in any way suggest changes that should be made in the treatment of men?
Colm Morrissey:No, currently. I think we are really in our infancy. We have a lot more experimentation to do. We have to look at both patient samples and indeed in models to get a better understanding of dormancy itself. I think this meeting shows very clearly that needs to be more information so we have a clear picture of what we’re defining as dormancy.
Pauline Davies: That was one of the most surprising things to me, listening to the discussion after the meeting. No agreements on what constitutes dormancy.
Colm Morrissey: I think part of the reason is because most of the molecular signatures, most of the knowledge that we have is based around dormancy is based around experimental models. They’re not based on patient samples. It is very difficult to go to a patient and ask them for a sample when they have no evidence of disease. And to go into that sample and try and find individual cells, a small number of cells and indeed to characterize those cells and to follow those patients over long periods of time, to see whether those patients actually end up recurring, to see whether your molecular signatures are relevant or not. I think that one of the major challenges is to actually have clinical samples of dormant cells from patients. Rather than using model systems to identify and profile and find molecular markers for dormancy that you actually have patient samples where it is actually occurring on those markers may be more relevant.
Pauline Davies: Unless a study is started now, I know it would be a long term study, nothing will ever happen. Surely, someone should be asking these men (when they have their prostate removed) if you can take a bone marrow sample.
Colm Morrissey:Certainly, we have an idea in or group, along with another group that is here, we have been isolating cells from bone marrow samples a long period of time. It requires Buy-In from your oncologist, they have to be able to go to the patient and request that of them and the patient has to be willing to take part in research. It is ongoing and in a number of institutions, but of course in diseases like prostate cancer, which is what I focus on, your recurrences occur five years, seven years, nine or 10 years out. You’re right you have to start now with such, or have done so in the past. I think, at least from our perspective, our groups perspective, we are coming to the culmination of that in that we helping collecting samples of years. We can actually characterize these samples and have the clinical follow up so we can reference the clinical follow up to the electro signature that we observe, and therefore identify genes that may be involved in the process.
Pauline Davies: And that’s where changes in treatments can begin?
Colm Morrissey:Yes, certainly. As I said, we still don’t have sufficient information to suggest a treatment and even if we did have sufficient information, there may not be a treatment out there currently to actually approach this problem.
Pauline Davies: There is a lot more research that needs to be done.
Colm Morrissey:Yes, Definitely.
Pauline Davies: Have you enjoyed the meeting?
Colm Morrissey:Oh yes, absolutely yes. It’s great to see what everyone is doing, it’s great to have different perspectives and certainly it makes me look at my data again from a different perspective. So I can go back to what I have and try to reanalyze it from a different perspective, but at the same time other number of individuals with her interest in collaborating. It will be good to see where we go from here.

Interview with Cynthia Buness

(Back to Audio)

Cynthia Buness: With each session I attend, I learn a little bit more. Due to the fact that I do not have the background to understand the science, it’s been a slow learning process. With each one (session) I gain a little bit more knowledge and I understand a bit more than I did in the previous session. For example, when we were talking about the matrixes today, we had a lunch lecture about a month ago on matrixes, so that made some sense to me.
Pauline Davies: Well that’s good. Have you been interacting with the speakers?
Cynthia Buness: Absolutely. There are a few speakers whom I have understood most of what they are talking about because I know patients who have conditions that are relevant to what they have talked about. Even with some of the lectures where I don’t understand a lot of the biology, I understand enough to be able to call my friends who have had breast cancer, for example. It’s all very interesting to me.
Pauline Davies: You’re able to make that bridge between the research science and the people in the community?
Cynthia Buness: Yes, I feel like I can. It’s a little bit scary probably from the scientist prospective because my bridge might not be scientific enough. But at least, I am careful about how I disseminate that information.
Pauline Davies: Have you enjoyed yourself thus far?
Cynthia Buness: Absolutely. I feel like I am sitting amongst rockstars. It is amazing to see what these scientists and doctors, doctors and scientists both, are doing, with respect to their particular areas of interest. I am very excited to see the interaction. The speakers are challenged by those sitting in the room. They will state that they haven’t “done that” or “or I haven’t thought of that,” and to me that is the purpose of what we are doing here.

Interview with Christoph Klein:

(Back to Audio)

Christoph Klein:: My task was to provide some basic ideas about cancer dormancy as it is related to patient outcome and give a little bit of a historical overview of what was originally defined. The bottom line from this is yes, there are dormant cancer cells in patients, you can show the problem is that we do not know whether these dormant cancer cells are relevant during the natural clinical course of the patient. There is no evidence for this, its very difficult to prove and the only possible proof at the moment would be by therapy; by curing patients with therapies that specifically target dormant cancer cells.
Pauline Davies:: Do you think that there are dormant cancer cells but their relevance is in dispute?
Christoph Klein:: Yes, by definition of dormant cancer so does not kill a patient. As long as the cell is dormant it doesn’t do anything. I think this is very clear. The cell that is eventually killing a patient is a proliferating cell, it forms a metastasis and the contribution of dormant cancer cells reentering this proliferative stage is unknown in patients. We have no clue about this, but the relevance may come and I think this is for the field in the future. What we are doing by therapies? We are giving chemotherapies, targeted therapies. Do we reactivate dormant cancer cells? Do they become then relevant to the disease course of the patient? These are all questions that we should address.
Pauline Davies:: Well, what do you mean by causing the dormant cancer cells to come out of dormancy? How would treatment cause them to be reactivated?
Christoph Klein:: Well, I do not know this. I think nobody knows this because the question has not been posed so far, at least not in the systematic or analytical way. What we know, and that’s what I presented yesterday, on these cases of organ transplantation where the donor had occult cancer and recipient of these organs, be it heart, kidney or liver eventually developed a metastatic disease. This gives evidence that there are dormant cancer cells in the body of patient whose cancer was taken out 16 years before, for example, and that these cells survive prolonged periods and can reactivate. So since it is possible to reactivate them by transplantation, this may occur whenever we interfere or do anything to the patient.
Pauline Davies:: What would be your suggestion for moving forward, because there is a big debate going on in the room about the relevance of dormancy?
Christoph Klein:: I think all research that addresses early metastasis is very important because curing a patient who already has metastasis is very, very difficult and has not been achieved significantly so far. So what we have to learn is how is the early disseminated disease working? Which are the cells that go towards metastasis? Which do not? How are they regulated? Why are they put into dormancy? These questions can help us a lot on developing new ideas about future therapies.

Interview with Cyrus Ghajar:

(Back to Audio)

Cyrus Ghajar: Right. The phenomenon of dormancy on cellular level has been appreciated for many years now but there hasn’t been a real definition of what that microenvironment is. When a cancer cell travels from their primary or into secondary site and lies there and doesn’t divide for the “X” amount of time, what is maintaining that dormant state? There is evidence that in patients that there can be decades between dissemination and re-growth but there’s no real knowledge about what keeps them in that state. So, to the answer that we use mouse models, and zebrafish models, and also models of human cells that we’ve engineered so that the cells are all rehabitulating their invivo functions. With all those models we’re able to show that the cells are residing on blood vessels, on the on the basal side of blood vessels, so not where the blood flow is, but on the other side. The factors being expressed by the endothelial cells which are composing that micro-vasculature are actually inducing the tumor cells into a quiescent state.
Pauline Davies: And to do that you had to grow your own blood vessels?
Cyrus Ghajar: Yes, exactly. So we (humans), we’re not mice and we’re not zebrafish so I think it’s really important that we create models of human cells where we’re able to recapitulate the invivo functions of the cells, but we are also able to reduce our variables down. So if you want to show the endothelium is restricting tumor growth, you need a condition where tumors are growing and that only by adding endothelium you would be able to judge an effect, whether it’s as a pro or con or null. That’s what we’re able to do. We took cells from the stroma, these organs meaning that their non-epithelial and not endothelial, they are the others, like resin cell types and we laid those down. From the lung we took lung fibroblast, from the bone marrow we took mesochemal stem cells and when you see the tumor cells just on those they outgrow rampantly. If we see the stromal cells and endothelial cells, the endothelial cells self organized to a little micro vessels that recapitulate a lot of their invivo functions and now when you see the tumor cells I see them restrained and eventually become quiescent, and more importantly they stay quiescent.
Pauline Davies: So that’s a much more natural environment?
Cyrus Ghajar: It is, exactly. You’re showing this function that you see in humans with human cells and thus you can hopefully assume that the molecules that you are going to discover that are mediating this is some of the behaviors you see are for more accurate as far as human physiology is concerned as a result.
Pauline Davies: You showed some very interesting time lapsed film, over a period of 72 hours? You showed how tumor cells are much more likely to divide if they are near the tip of a dividing blood vessel rather than the stem. Explain that concept to me.
Cyrus Ghajar: There’s an idea that the mature micro-vasculature is secreting molecules as a result of being mature that are then inducing the cells into a quiescent state. All vessels in our body, whether epithelium, the ducts in the mammary gland that can carry milk, or even our endotheliums, which are the vessels that carry blood, need to know which ways up and which way is down. One way they know which ways down is because they secrete a basement membrane and that’s on the basal side of the vessel, this is like a extra-cellular matrix of proteins and sugars that not only service scaffolding but also have function. The function is a signaling function and there are molecules within the basement membrane that are telling the tumor cells that to calm down and go into a quiescent state, to hibernate essentially. When a vessel starts remodeling they lose that basement membrane and it’s not just that tumor cell so, by doing time lapse imaging we’re able to show that the tip cells, where were you don’t have a stable basal membrane, aren’t just permitting growth but they actually accelerating so, we were able look through a variety of approaches and shown that these tips cells are actually secreting molecules that turn out also be pro-tumor. Essentially, you have a dormant niche, by stable micro vasculature, and then you have a micro metastatic niche, by neo vasculature, or these endothelial tip cells.
Pauline Davies: It was a very clever experiment. What made you think of doing it?
Cyrus Ghajar: I Have a pretty good history with vascular biology and I was suspicious that this behavior was happening based on the experiments and the mid-to high throughput approach we’re taking, and we have a lot of different niches within our experiments. It’s looking a little bit more carefully at the behaviors rather than treating the system is one system as a whole actually looking at it as a bunch of subsystems and much like our bodies are and our tissues are.
Davies: Could that ever have any implications for treatment? For instance, you need growing tips of blood vessels from nearby tumor cells. If there were areas you suspected there were tumor cells, could you stop the blood vessels growth?
Cyrus Ghajar: This has been an approach that been taken with established tumors that they know that idea of anti-angiogenesis which was put forth by Judah Folkman in the early 1970s and has led to therapies like Avastin a lot of other ones that are in the FDA pipeline. The context shifts so we talk about disseminated tumor cells in secondary micro-environments. You have already treated the patient, hopefully you have remove the tumor and now you have these cells and we don’t really know if they are going to be the ones that are causing the metastatic growth that could eventually kill the patient or not. Is there a way to take to treat patients with low levels of some anti-antigenic molecule that would prevent tip-cell formation? That may be viable that may be like a long-term therapy you can give a patient that would prevent their tumor from ever being sparked to grow by these tips. These tips are essentially sparks of the get cells going out of dormancy. The other potential therapeutic that could result of this, is understanding what are that biochemical and physical factors that are maintaining dormancy around the stable micro vasculature, and seeing if we can somehow supplement those to patients in order to keep those cells dormant.
Pauline Davies: Looking at your experiments, it seems so clear cut that using a 3-D medium for growth is just the way to go. It strikes me that a lot of experiments done on 2-D flat surfaces are pretty much useless.
Cyrus Ghajar: While, I wouldn’t go as far as to say that they are useless, I think that we learned a lot about cell culture from putting things on plastic. Just the fact that we can take cells out of our body and maintain them is a huge advance in and of itself. As far as recapitulating function, we are three dimensional organisms and form follows function and function follows form. So you have to take the right form in order to look at function and that form is 3-D and the functions derived from that.
Pauline Davies: As you said earlier, cells behave very differently on a two dimensional surface; they grow much more than they do in a typical 3-D surface.
Cyrus Ghajar: So, yeah it is striking to me that when you look at invivo growth rates of tumors are not nearly the 24-hour doubling time you typically see with a cancer cell on plastic. In three-dimensional models, we’re able to not quite necessarily recapitulate the growth pattern invivo, but we got a lot closer. Especially when it comes to quiescence, and achieving quiescence on plastic without contact inhibition of a completely confluent model area, I haven’t really seen a good example of that before. In 3-D there are many good examples of that.
Pauline Davies: What have you gotten out of this meeting?
Cyrus Ghajar: A lot. I think it has been a fascinating meeting in terms of mixing together clinician scientist who actually deal with patients and want to know is dormancy something that they really need to worry about or do the cells that may be dormant in patients never actually result in metastasis that kills the patient. As well as the fundamental scientist and the mathematicians who are trying to model this process. I think there’s a lot of disparate data, and possibly or potentially, opposing conclusions that can be made from the patient data in the data in mice, in the data in these human cultures and trying to reconcile them, I think, one of the biggest keys. I think the discussion really got going at this meeting that points were raised that hopefully now, as we all leave, in subgroups that you have been talking during this meeting can continue to work together and try to solve problems and inconsistencies.
Pauline Davies: Do you see any collaborations coming out of this?
Cyrus Ghajar: I hope so. I mean I’ve definitely seen some really interesting work in the prostate cancer field and in the resources available with the rapid autopsy programs at the University of Washington, that are very rare, there are maybe two or three within the whole nation. An investigator like myself, at Berkeley, does not have access to (these programs) unless I collaborate with somebody who is doing that. I think that there’s a lot that we can learn about actually specifying the relevance of these niches is in human patients that we can’t do otherwise. Mice are only so good. We really are trying to solve a human disease and this we need to look at in humans.

Interview with Russell Taichman

(Back to Audio)

Russell Taichman: My laboratory looked at how blood stem cells circulate. Basically we start out trying to answer the question why does blood form inside of bones? From there we found that they live up against the bone surfaces and as a result of that there are certain properties that are conferred upon the blood stem cell. We then moved into the cancer realm because it looks like cancer cells seem to do the same thing that blood stem cells do. They leave the bone marrow, they go out into the blood and then they come back; that’s very similar to what cancer cells do. What we did is draw parallels between the two systems. As a result of that, we found that the tumor cells actually go to the same house that a blood stem cell will live in, take it over and that’s part of the problem. So what we reported here today is that that process not only puts those cells into a dormant state by going into the house of the stem cell, it gives them the phenotype of the cancer stem cell.
Pauline Davies: Why does it make cancer cells become dormant despite going into the house the stem cell?
Russell Taichman: That’s the major job of that organ, of that house, is to put things asleep. Because they were all dividing at once it would be a big problem for the organism. So it is thought that this niche, if you will, is a organ that for whatever reason was devised to keep coordination amongst the entire organism where we have these cells all over the body so and you only need one or two to divide at a time. If you have, say a finite number, or if they are all dividing at once; that’s called leukemia; so keeping them quiet is important. Most of the insults that occur to the stem cell compartment occurred to proliferating cells. So you have to keep them quiet if they are that valuable, so that the not susceptible to chemotherapy or toxins or whatever.
Pauline Davies: So what makes cancer cells susceptible to being put in this sleep mode, into this dormancy stage? Why don’t ordinary cells that are circulating get placed into that mode?
Russell Taichman: I don’t know. I think that for whatever reason the signals would say come to this place are very attractive to tumor cells. Once they get in there, I think they again are not thinking, but once they get in they’re put to sleep. It’s probably an area that has sleep signals and there are also, probably resources, that they are able to harvest. So for whatever reason it’s a safe haven but also it’s a place where they find whatever they need to survive; and it’s a survival of the fittest sort of thing.
Pauline Davies: That is quite interesting. So are the cancer cells picking up signals as they pass by these sleepy areas?
Russell Taichman: Exactly. Stem cells do the same thing. Part of the mechanisms have been worked, out one of the signals is a chemokine called stromal derived factor one, or SDF1. As stem cells pass by this SDF rich environment, they up regulate their receptors for different ligands, they can lock onto these areas and then they go to sleep. Tumor cells use the exact same mechanism as far as we can tell. For whatever reason, this is a very primitive system that is being co-opted or parasitized by the tumor cells.
Pauline Davies: Still makes me wonder why it doesn’t have that affect on ordinary cells?
Russell Taichman: They may not have the capacity to recognize the signals. They may go in there all the time, we just don’t know. We don’t have mechanisms to measure that sort of thing, they may go in and out. One of the things that our data shows, is that these so-called mature cells, these matured cancer cells, are actually able to go backwards in time into a more stem-like state. There is this hypothetical concept called IPS, induced pluripotentcy, where you take a series of genes, four or five, you stick them into a cell that’s mature, and you can drive it back to the stem-like state. I think this is one of the first examples of where microenvironment can do it, without doing it with genes. We just happen to be lucky to find this in the system. I think the pathways were always there, I think the other people that found those genes are activating systems that are already present and cancer cells have the ability to take that over.
Pauline Davies: Maybe if we could find ways of allowing those niche’s to recognize cancer cells as being different from regular stem cells, you would be on to some sort of treatment for dormancy?
Russell Taichman: One of the approaches we’ve taken, which I didn’t show here, is that when cells go into that environment, they sit there quiet. In the blood stem cell field, what they do today is, about half my numbers are probably wrong, but probably about half of the bone marrow transplants are done by taking out the marrow from a patient and giving it to another patient. The other half are done by mobilizing, with drugs, the stem cells out of that niche and into the blood. The data that we have, suggests you can do the exact same thing with tumor cells; get them out. Once they get out, we believe they begin to proliferate. And all of our cancer drugs today target proliferating cells. So, getting them out in combination with chemotherapy may be an effective therapy combination. The data we have suggest that that may be possible and so we’re going back and validating that in a slightly different system before we start thinking about putting it into humans, but we have plans to do that if it works.
Pauline Davies: That would be a bit scary; wouldn’t it, taking cells that lay dormant for decades and putting them back in the blood stream?
Russell Taichman: Exactly. Fortunately in the mice that we’ve done this with, limited study, we don’t see any progression as a result. So just mobilizing by itself doesn’t seem to make it worse, fortunately. Though, very limited study needs to be validated further, but yes it could be a really scary sort of thing, but if I’m the guy who has the tumor I’d like to maybe try that, knowing that these ticking time bombs are going to be there for the rest of my life. I’d love to see it. I’d like to see these cells out of my marrow.
Pauline Davies: Very interesting work. So have you enjoyed the conference?
Russell Taichman: I thought it was a fantastic piece of work for two reasons: 1. As I realize now the complexity of the field which I hadn’t really appreciated before and 2. I got to see somebody else functioning from a totally different field looking in my house and seeing what’s going on with interesting to them. So I thought that was really fun.
Pauline Davies: Are there any collaborations you can envision?
Russell Taichman: At least two. One: we’re trying to talk to Christoph by email and we’re going to exchange some protocols. Colm Morrissey, I’m going to give a talk about his institute as a result of this meeting, so that’s a start.
Pauline Davies: Thank you so much!
Russell Taichman: Thank you, it was fun.
Pauline Davies: In your talk, you had some very humorous pictures of polar bears. What relevance did they have to cancer?
Russell Taichman: I think that the polar bear analogy is that when they’re awake they’re extremely dangerous and when their sleeping we have a chance to sneak up on them and maybe get rid of them so I like the analogy a lot. From a personal standpoint, I showed a picture of my wife with her finger in polar bears mouth that was sort of a gag, but the truth this is that the when I proposed the next day two polar bears walked right where we been sleeping, so it was almost the world’s shortest engagement. Its good fun, so yeah, polar bears are special to me.

Comments are closed.