Mechanical Properties of Cancer Cells
No area of research better illustrates the constructive engagement of physics and cancer biology than the burgeoning field of cell mechanics. This workshop focused on the mechanical properties of healthy and cancer cells and the surrounding tissues. It covered topics such as changes in the elastic properties of cancer cells, the internal chemical and genetic changes triggered by the physical properties of the micro-environment (such as its hardness or surface adhesion) and the motility of cells, with special emphasis on metastasis. It brought together physicists, oncologists, cancer biologists, engineers and computer scientists, with the goal of determining whether cancer could be better understood and even controlled by manipulating the physical properties of the cancer cells’ environment.
Listen to Audio Interviews and Read Transcripts
In February 2010, a diverse group of scientists from physicists to astrobiologists and cancer specialists got together at Arizona State University for 3 days of thrashing out their latest thinking about the mechanical properties of cells. The workshop was organized by the Center for the Convergence of Physical Science and Cancer Biology. Some of the participants spoke to Pauline Davies as the workshop ended.
Audio Interviews from the Workshop
- Interview with Don Coffey, Ph.D.Donald S. Coffey, Ph.D. is a Professor of Urology, Oncology, and Pharmacology and Molecular Sciences at the Johns Hopkins University School of Medicine. He is Director of the Research Laboratories of the Department of Urology.
More Info: http://urology.jhu.edu/about/faculty.php?id=44
| Interview Transcript
- Interview with Sanjay Kumar, M.D., Ph.D.Sanjay Kumar is an assistant professor of bioengineering who studies cellular mechanics and biomaterials at UC, Berkeley.
More Info: http://kumarlab.berkeley.edu/ | Interview Transcript
- Interview with Jack Tuszynski, Ph. D.Dr. Jack Tuszynski is a professor of biophysics at the University of Alberta, cross-appointed in the Faculties of Science and Medicine
More Info: http://www.phys.ualberta.ca/~jtus/ | Interview Transcript
Transcript of the audio discussions follow…
Interview with Don Coffey, Ph.D.
Pauline Davies Here is what Don Coffee, a professor at John Hopkins School of Medicine in Baltimore, had to say about the event.
Donald Coffee Well this is an amazing conference because this mix is a group of people you don’t normally get together. That is physicists, mathematicians, people who work in evolution, space, and outer solar systems and things. So, its just wonderful to hear all this talent come together and wrestle with the question of how can we get through and make a difference on cancer.
Pauline Davies Have you learned anything?
Donald Coffee Oh, absolutely! What’s come out of this, is by hearing people who are experts on how life can exist under very extreme conditions and understanding how the cell is organized, we are hearing all sorts of amazing things because the way you tell a cancer cell is that the cell is out of shape. Now obviously it has to be growing and this. But you can just look at an individual cell and tell it’s a cancer cell, like a pap smear.
Pauline Davies We don’t know why it’s out of shape?
Donald Coffee No, what we found is there’s a little a little skeleton inside, called a cytoskeleton that means a cell skeleton. And that structure is out of shape, so it makes the building out of shape. Like changing the beams in the building, so the building is out of shape. Then we found out that the cancer cell is actually capable of crawling and moving, so it actually crawls through people, called metastatic, it’s malignant and it invades things. So, when a bunch of cells grow its called a tumor and many women have lumps in their breasts and men have lumps in their prostate. About 90 percent of these are benign that means that they won’t bother you. But the others are malignant. Now the difference is that the benign ones grow like your fist, they grow as a little contained structure. So you can take those out like you sort of to take a tangerine out of a tangerine peel. So they easily have surgically. But if they look like your hand, they look like a crab, they are invading the normal tissue, they are not round and compacted, so the word for cancer from the zodiac was already here years before the disease was really recognized. So, in essence we are trying to find out why they spread, why they invade like this. But a tumor just means that its an abnormal growth; cancer means that its malignant. Then when pieces of this break off, they are metastatic, they go to other organs and cause trouble.
Pauline Davies We have been hearing a lot about the extra cellular matrix and how important that is. What do you make of all that?
Donald Coffee Well what happens is cells are sort of like coke cans, if you stack them up—that’s normal; but if you get a big stack that’s a tumor growth its abnormal accumulation. But if they are out of shape, as we said, then that is cancer. And what happens is they break loose from the plane they are sitting on. So imagine that you had a table, like a desk, and you had a can sitting on it. The table would be the extra cellular matrix and the can would sit on there and it is sort of locked in place. Now what happens normally is if that can comes off of that table, the cell is automatically programmed to self-detonate and kill itself, and that is called apoptosis like. But in a cancer cell, when they come off they keep growing. So they can spread to other spots. So the extra cellular matrix and how it talks and keeping the cell where it belongs, in the chest, in the brain, in the prostate, is very important. So here at this meeting, all sorts of experts in breast and prostate and a lot of scientists and people who understand a lot about how life is formed and how its controlled and how they are speaking together. This is a great meeting; lots of great ideas are coming out of it. I am fifty years in the field of cancer research at John Hopkins, so I’m up the ladder to say the least, and at least two-thirds of these people I have not meet before. Usually, when I go to a meeting I know everybody in the room. Here, there are all sorts of different disciplines; it’s really an exciting meeting.
Interview with Sanjay Kumar, M.D., Ph.D.
Pauline Davies Sanjay Kumar teaches in the bioengineering department of UC Berkeley. His lab investigates how cells sense and process mechanical forces, particularly from the extracellular matrix. And they are especially interested in studying this in relation to the nervous system looking at the control of self renewal and differential in neural stem cells and the growth of malignant brain tumors. I asked Dr. Kumar why the matrix is so important in controlling the growth of cancerous cells.
Sanjay Kumar I think it is one of the most exciting and in some ways unexpected developments in cell biology over the past 10 to 20 years. One cannot know everything there is to know about cells simply by knowing their genome and by knowing the soluble signals, the size of growth factors, and empartary factors their exposed to, what their attached to and not just the biochemical identity of what their attached to but the mechanical property of what they are attached to turn out to be very very important and if you think about why that might be cells have specific receptors on their surfaces that bind these molecular and the extracellular matrix and these things transduce signals and the degree to which they trasduce signals depends on very physical parameters, like the degree to which they are clustered for example the ease with which they can be brought together, can recruit proteins on the interior surface of the cell and then in some ways in retrospect it kind of makes sense that the composition and physical properties of the matrix itself can influence cell behavior. And certainly observations everyday in the lab working with cells makes this even less surprising. So, some cells for example need to be attached to a surface in order to grow; they don’t grow if they are detached. So, many normal cells once they grow such a degree that they make contact with one another they will stop growing and remain as a quintessence model there. But, cancer cells are often distinguished by the fact that they loose this contact inhabitation and tumor cells are often also capable of growing on very soft surfaces and regular cells are not; in fact this is a very assay used to select tumor cells called the soft edgar assay. Non-tumor cells don’t usually grow on this material, soft edgar, but tumor regenetic cells do.
Pauline Davies They have lost their adhesion properties?
Sanjay Kumar Yes, in a sense they have the lost the degree to which they depend on adhesion to support in order to grow.
Pauline Davies And do you understand why they lose that?
Sanjay Kumar Well I think the whole field is trying to come to grips with this question. And as I was saying, I think part of the key is the signally that essentially emanates from the receptors on the cell surface that recognize these extracellular matrix molecules depends on a great degree on their physical state of association and this has consequences for every signal that sort of falls down stream. So, for example, a cell sitting on a very soft substrate, because the material is very soft, it won’t be able to support large forces, cells capable of generating. So the cells limited in how much stress or strain it can impose on the substrate and this in turn affects force dependent molecules that are present inside the cell. So there are some mechino-sensers some of whose identities we know, some of which we don’t know that its activities, biochemical activities, are very strongly dependent on mechanical force. You can imagine that a cell sitting on a very stiff substrate might have the opposite situation that is capable of exerting great forces on the substrate because the substrate can with stand it and so it would differentially activate these mechino-senstive molecules and lead to sort of cell wide changes in bio chemistry.
Pauline Davies Now are you talking about these very stiff substrates in terms of what you put cells on in lab? In other words, how reasonable is it to use these stiff substrates?.
Sanjay Kumar Now, I think that is an outstanding question. So the vast majority of cell biology is done with either tissue culture polystyrene or with glass which is extremely stiff material and is much, much stiffer, in particular than what one normally finds in physiology. Tissues are typically something like 1000 or one million times less stiff or softer than what we use in the lab. And I think the field of cell biology has kind of come to grips with the idea that this fundamentally changes the biology of the cell and sort of a sister problem with that is that cells in the body often exist in three dimensional microenvironments and are surrounded on all sides by other cells and extracellular matrixes. And this by and large is not how we do cell biology in the lab—its two dimensional substrates. And there are many reasons why we do this: its easier, its more reproducible in some sense as there are fewer things that we need to worry about. But, the challenge I think is translating what we learn in these very simplified stripped down experimental systems to what we actually expect in a physiology setting.
Pauline Davies So now I guess there is a move to try and do these experiments in 3D?
Sanjay Kumar Yeah, absolutely! A huge challenge in the field is trying to develop platforms that essentially enable on to do cell biology in a high through put, low cost, very reproducible fashion in three dimensional matrixes so that one can have some of the advantages we normally enjoy with two dimensional substrights but perhaps at the same time have a context that’s a little bit closer to the living organism.
Interview with Jack Tuszynski, Ph. D.
Pauline Davies Jack Tuszynski is a biophysicist at the cross cancer institute at the University of Alberta in Ebten, Canada, who designs drugs for chemotherapy. He spoke about this work and his particular interest in microtubules, structural components in the cytoplasm of cells that also play a crucial role in many other vital functions, including cell division.
Jack Tuszynski At this conference I was mainly talking about the role of microtubules in cell division, mitosis, which is a central problem in the progression of cancer because, first of all, no cell will divide without microtubules, so if you find ways of stopping this process then we will have a sure way of stopping cancer.
Pauline Davies And have you thought of any ways of stopping this?
Jack Tuszynski Yes I have. So, currently there exists a number of families of compounds, pharmaceutical compounds, which target these structures and inhibit their growth or assembly or disassembly. More or less anything you do to interfere with their normal function will work, unless it is too toxic to other cells.
Pauline Davies Well, that surely is the issue because if you stop microtubules functioning and stop the cells dividing, then you’re affecting normal cells as well.
Jack Tuszynski That’s correct, but fortunately most of the cells do not assemble microtubules as frequently as cancer cells. They assemble them only for either motilities or movement of cells, or for cell division and of course we have a number of cells which are dividing non-stop and these are the epotheo cells in the skin and hair is growing of course you need to consistently build these cells, as well as the immune system. If you target microtubules these are the cells that take collateral damage. On top of that, there is of course of microtubules in neurons in the brain and nerve cells. So there is an associated damage to the nervous system, unfortunately; but this one is typically only temporary during the chemotherapy.
Pauline Davies Yes, in fact, is this very much different from any other form of chemotherapy? I know that chemotherapy acts in very different ways but is this better than traditional forms of chemotherapy.
Jack Tuszynski Well chemotherapy targets three or four different structures in the cell—DNA, is of course the natural target, and here again DNA is normally kept hidden in the nucleus, so dividing cells expose DNA building chromosomes and duplicating the genetic material. So, you also have side effects, if you target DNA the same way as you target microtubules. The second form of chemotherapy is to stop the growth and the receptors of the signals that trigger growth processes. These are much more targeted, they call it targeted therapy, and they are often quite more successful and have fewer side effects but they don’t always work. In fact, only on sub-groups of patients, so they have to have these types of receptors unregulated for this therapy to be successful. And as with any therapy quite often large segments of people do not respond after a while and relapse.
Pauline Davies So, this could be another tool in are arsenals against cancer cells.
Jack Tuszynski Well, exactly and on top of that there is a whole host of other unexplored therapeutic targets in the cell. And, currently, we only have about 68 to be exact targets, for which there is any kind of medication available at all. And in principle, we can target up to 500 proteins and bio-molecules in the cell. So that is why I am going to be very busy in the next little while trying to find drugs for many of these targets.
Pauline Davies You said something to me a little bit earlier that I thought was quite amazing, you can count the number of microtubules associated with each chromosome.
Jack Tuszynski That’s true and that depends on the species because microtubules are built not only by human cells but any so called eurokaryotic cells, which have nuclei. So even a simple organism as a paramecia has microtubules. But a paramecia has one microtubule per chromosome; the humans have 30 microtubules per chromosome on either side, so that is interesting and quite species specific and also indicates an aspect that is very little known, namely not all the genetic code is probably in the DNA because the region on the chromosome where microtubules bind is called centimere and is finely tuned to the size of the microtubules binding to it and it has apparently no coding around. So that is kind of a different level of coding, functional maybe not structural.
Pauline Davies And, why do you think we need 30 microtubules per chromosome?
Jack Tuszynski That’s a very interesting question and I think as a physicist I can probably shed some light this. We know that the pairs of chromosomes are quite robustly connected by physical and chemical means and so cell division requires segregation of these chromosomes and a physical force to pull them apart. Interestingly, microtubules by shortening or depolarizing provide such a force and we know that by approximately 25 picon neutrons. The number is interesting to note so 25 picon neutrons per microtubule is the force generated by one microtubules. We know that to segregate chromosomes in 700 picon neturons. So one microtubule will never do the job, 30 microtubules will provide you with 750 micon nuturons so its just enough but knowing biology and the drive towards redundancy and drive to control and faithfulness, I know that there is more to it than just microtubules. So that also leads to an enigma, for which at the moment we have no clear answer. What else is there to provide the missing force? I would except there to be at least double that is needed make sure that chromosomes will always be divided.
Pauline Davies And yet other species have many fewer microtubules. Paramecia have, you say, just one, does it contain more force or how does it do it?
Jack Tuszynski That’s a good question. I honestly don’t have an answer to that question. During the workshop we definitely discussed the issues of force and mechanical integrity of the cell, and mechanical strength and rigidly, also fluid mechanicals. So there could also be additional forces obtained by flows of fluid inside the cell. And perhaps this balance changes from species to species or even from cell to cell.
Pauline Davies Absolutely, fascinating! What was the most surprising thing for you, that you discovered at the conference.
Jack Tuszynski Well at the level of sociology was surprising and very reassuring that a number of people who come from different fields found so much in common and so much similarity in the way they were thinking about the problem. And also the openness of the eminent scientists representing cancer cell biology to new mathematical and physical ideas, so that definitely a very positive outcome of the conference.
Pauline Davies And you personally, have you found out anything that might change your practice?
Jack Tuszynski Definitely a lot of things. I do want to try some experiments actually that we discussed here at the meeting. Experiments measuring the rigidity of microtubules and rigidity of the membranes and how this changes as a result of for example the therapeutic agents. Actually the most novel aspect of the workshop that I didn’t appreciate before was the emphasis on things outside the cell that may drive it into a malignant state, the extracellular matrix and most of the cancers are in the epothumum, on the surface of organs. But, apparently they are driven to the malignancy strugmea, so the cells of the tissue underneath—I didn’t have a clue about this.
Pauline Davies Very intriguing lots to think about. Thank you very much.