Stretching, Connective Tissue, Inflammation and Cancer

good morning my name is darshan meth I'm the director of education at the Osher Center for Integrative Medicine and medical director at the Benson Henry Institute for my invitee Medicine just before I introduce our speaker for a talk I wanted to just highlight a few things one is at the end of this month there is a research clinical and policy conference on a beta and its role in cancer and palliative care and the information is out on the podium we also have our next month which will be on Tuesday July 2nd locus on O from Massachusetts General Hospital we'll be speaking on photobiomodulation treatment and so basically the role of infrared light in the treatment of depression and we'll have a case presentation on that so please please come it's going to be exciting sort of new technology type of presentation and and then in the fall we have our network the Osher Center hosts it's by every other year we have a network forum and please register it's free and we have professor George Church who is going to be our keynote presenter there as many of you know he's a eminent geneticist based here at Harvard so lots of very exciting events and if you're not on any of our listservs thus far make sure you sign in or ask atra or jessica for information I just okay so with that it's really my honor to present dr. Helen Longman who's the director of the osher Center for integrated medicine here at Harvard Medical School and Brigham Women's Hospital she is professor in residence of medicine and at Harvard Medical School she's also a visiting professor of neurological sciences at University of Vermont College of Medicine and she has multiple accolades and multiple NIH research awards but has really been a pioneer as I've come to appreciate particularly in the last several years in the role of connective tissue and really its interface with many of the different integrative modalities that all of us are seeking to better understand and incorporate and has developed really amazing groundbreaking and provocative models to help us understand what they do how they do it and what might they be able to do so thank you darshan it's a pleasure to be to be back I'm going to be talking about something a little bit different that some of some of you might know some of the work that we've done in my lab for a long long time we focused on chronic pain musculoskeletal pain low back pain the role of connective tissue in in this in the development of chronic pain and also mechanisms of manual based therapies acupuncture and movement based therapies so why so why cancer all of a sudden well my my lab got interested in cancer for the same reason a lot of labs are interested in cancer it's because it is it's just this very enormous problem very mysterious problem that we have spent a lot of countless energy time money I try to understand how does cancer happen and and how do we treat it how do we prevent it how do we treat it successfully how do we keep it from recurring and so it's it's it's really we we have I'm gonna tell you a little bit the story of how we kind of drifted in that direction and and some of the recent studies that we've done on how stretching something very simple like stretching can actually affect the development of cancer so what is cancer well for a long long time people have been pondering about this question and we think of cancer as being sort of cancer cells right that are dividing out of control that's the hallmark of cancer cells in the body under normal conditions have a job to do they have specific instructions from their their genetic material from the signals that they get from around them and they obey these commands and they do what they're supposed to do cancer cells don't do that they just marched by their own drum and they divide and divide and then gradually they invade right they just rogue and so naturally for a long long time the vast majority of efforts to understand cancer have focused on the cancer cells right the culprits and so along one of the hallmarks of cancers these cells are dividing out of control they're there they're not stopping their cell division when it's appropriate they just keep dividing and multiplying and so pretty early on a lot of focus was really sorry sir CH was even by the time people had a microscope and were able to look at these cells and they saw that these look different they look abnormal they had abnormal nuclei they just they didn't have the right kind of shape and so really people focused on on these cancer cells and then when when we started getting more sophisticated about understanding cell division people looked at chromosomes these are the little units of where DNA is packaged and people started noticing that some cancers some catcher sales had abnormal chromosomes one of the earliest one was called the Philadelphia chromosome it was a chromosome that was associated with some types of leukemias and so that gave clues that really maybe there's something wrong that that that's maybe how cancer happen is that cell division goes awry and then we got even more sophisticated and we started understanding the DNA itself inside the chromosomes and we are able to measure and and and precisely see the mutations like the little abnormal little units of DNA that could lead to cancer and some of the carcinogens that people started to understand ionizing nation and and environmental toxins smoking things like that that actually caused breaks in the DNA mutations and that that in animal models led to the development of cancer so this enormous focus inward on the cells on the division machinery of the cell but there were some researchers now in the minority that started to really zoom out instead of zooming in in in in and really try to understand the cancer cell really started to look at the cancer but in a in a lower power in its environment inside the body and started thinking about well the cancer needs to grow in something right on on something in the tissues it's not just growing in a vacuum and some of the earlier investigators started looking at what we call the micro environment right of the tumor when we say micro environment is because these tours when they start they they're not enormous tumors they start small they're start just a couple of cells and these cells get ahold someplace and they start growing one of the earlier observations that were here at Harvard at dr. Judah Folkman slab at the Children's Hospital started thinking about that the cell the cancer needs nutrients to grow it needs a blood supply and so this whole concept that the cell need the cancer here in blue needed blood vessels to feed it so it needed to somehow hijack the blood the body's blood supply in order to serve its purpose which is to grow right and so this research was very promising in that people felt well not only that but there was a discovery that the cell secretes substances that actually promotes the growth of new neovascularization new new blood vessels these are called angiogenic factors and so the thought was well if you could somehow interrupt that and and suppress the growth of these you blood-vessels perhaps this tumor would stop growing and so there was a great sort of enthusiasm for developing angiogenesis inhibitors these are these are drugs that slow slow down the formation of new blood vessels but just like a lot of times when there's early enthusiasm for something but they're these drugs also had side effects some of these drugs actually caused a lot of bleeding side effects and and so and some of these drugs are still being used but there was not the initial enthusiasm for their use was not transformed as they translated into sort of widespread use meanwhile there was also an understanding of the immune environment inside the cancer extremely important so why well the body does not just sit there and and sort of stand by when a cell starts to transform normally what happens is the body fights it this is very similar to what happens during a viral infection if you have a virus you're the virus goes inside yourself and then it sort of hijacks the DNA machinery of the cell to try to make get it to make more viruses and replicate it so that causes the virus infected cell to become abnormal and it expresses receptors on its surface and then the the the immune system of the body recognizes that and starts attacking those abnormal cells in destroying them well similar things happen in cancer specifically lymphocytes leukocytes or cells that can have both innate immunity and also acquired immunity so that what they do is they recognize something that's wrong and they will go and and attack it so the thought was okay how could we enhance that how can we help the body to get rid of these wrong cells and so there was that there's a whole sort of an area of very intense research that is going on to this day very very promising what is immune therapy right so how do we give drugs again that either block areas that impair the immune system or enhance areas where the immune system could use a little boost and attacking these cells the problem is that this process of killing cancer cells causes damage because you don't it's it's like it's if you you're gonna kill some cells there's there's going to be some collateral damage to that right and that damage is inflammation and so there's a lot of inflammation inside inside tumors and so the idea is well and we know also that inflammation can be can promote the growth of the cancer so there was also in parallel to the immune efforts to enhance you a new responsive it's to decrease the inflammatory response and so you could see this kind of seesaw goal very tricky to achieve and a lot of the immune therapies unfortunately have very strong severe inflammatory side effects so this is tricky right but these does this is ongoing and and we you know we it's still very very obviously promising research but as you can see it's not easy so what about this green stuff here well that is the connective tissue of what we call the stroma the tumor associated stroma and what is that that is essentially the bed on to which the tumor sits and the connective tissue was has been described for a long time I you know century ago microscopy thought August would look in the microscope and see that there was the cancer cells are essentially surround surrounded by structure of connective tissue that's what allows the connected the cancer cells to have the tumor to have a shape otherwise the cells would just be sort of floating around so this tour associated stroma became interesting to some people because they people noticed that when the that some of the characteristics of the stroma may had something to do with how invasive the cancer was and specifically when the stroma is very thick and stiff that can encourage the growth of the tumor and so people got really interested in suppressing the stroma so I guess what they made up some drugs to reduce the amount of stroma and to energies would call stroma suppressors or inhibitors while those didn't work so well because these are very strong substances like metalloproteinase inhibitors are things that wreak havoc with the rest of the body right well then the idea is let's let's deliver the stroma inhibitors only in the tumors and there's a lot of efforts with that but generally these efforts were disappointing so what's in common with all of these efforts well they're all drugs right they're all substances that you inject or take in the form of a pill or things that are you know administered pharmacologically and there's a reason for that because our whole real approach to therapeutics is very much determined by our approach to understanding physiology and really our understanding physiology is very much dominated by our whole approach to biochemistry right we really since the beginning of the 20th century when we discovered biochemistry and sort of the metabolic pathways for example and even now he's what we call complex systems right of metabolic pathways and genetic pathways and all kinds of signaling pathways and metabolomics and you know Gino makes the lipid omics and everything Oh mix well these are still still biochemistry it's still molecules that are essentially floating around right and when you the general sort of logical approach to biochemistry is a biochemical treatment or chemical treatment directed at the sort of the the systems of molecules that are sort of governing all of these physiological process well recently I would say in the last twenty thirty years there has been another shift towards really understand not just the biochemistry but also the physical environment where all is biochemistry is happening and there's been a realization recently that over the most of the 20th century we've sort of ignored the fact that mechanical forces interact with every single process of the body from every tiny little molecule inside the cell even even with DNA replication and everything and and and and cell division and the functioning of organs and the whole body at every single level there there there's an inner interface and interaction between the biochemistry and the biophysics and a nice example of that I've Illustrated here where as microscopy techniques became more and more sophisticated we used to think that cells are basically like little bags right where there was these molecules floating around that were sort of going along concentration gradients well we now know that that's not true the cell is actually filled with these sort of structural proteins that we're that influenced how molecules get together and come apart and come in contact with each other it's not random so for example here you have what we call illustrated the cytoskeleton of the cell that we've discovered with more powerful microscopy techniques where you have for example actin filaments or microtubules or intermediate filaments where they're these these the molecules which are for example illustrated in green here are come either come together or go or fall or come apart depending on how this pile of gelatin is organized and so you we've had also techniques where you can apply a tiny tiny little force on the outside of the cell using a little magnet and you can pull on the cytoskeleton and see the molecules come apart and go together and and at the same time molecules docking in and out of their receptors it's very very elegant and and amazing actually to be able to actually see that under the microscope so this obviously is a young field the field of mechanobiology right we have not this is a new relatively new I mean there's been research on this for a long time but it's really been relatively recent that people have realized the extent of it and the importance of it and of course now the idea of Meccano therapeutics this is a really nice poster I've Illustrated right here at the VESA Institute a couple of years ago there was a whole symposium on Meccano therapeutics and it's very interesting to see how this has galvanized a lot of researchers from a lot of different disciplines including engineering molecular biology genetics and you know rehabilitation anyway to come together and to really start looking at the effect of physical based treatments that are not drugs right okay so going back to cancer there is now the very strong realization throughout the research community that factors such as stiffness architecture tissue forces have effects on all four of these components that I have explained here we nobody denies this the question is would what do you do about it you know and that's the trickiest thing because it it's tricky measuring these forces not only that but then how do you apply a force and and how do you control it and these are things that we not you know back in you know in the 19th century where we were measuring forces and pressures and for example if during breathing respiration cardiovascular events and things like that it's quite crude right measurements of forced pressure volume we're still haven't really developed these measurements as much as we have developed our measurements of biochemistry for example so we have some catching up to do so as I said before cancer we know that connective tissue stroma is important we also know that in some cases for here for example I've Illustrated a picture of a tumor where you see these lobules here these sort of collections of cells are surrounded that this pink stuff this is a human toxin and eosin staying very very standard pathology where you can see these sort of roundish sort of lobules of stroma of connective tissue that surround the cancer cells and sometimes we see something like this this is a cancer where these are the cancer cells here and all this pink stuff is the is the connective tissue and you can see it's very thick and this is called what we call a dismal plastic response this is where our pathologists have known for a long time when you see this under the microscope this is not a good prognosis it's it's a bad sign and people can even feel if you palpate a tumor and it feels very hard to the touch that's usually also not a good prognosis so the the role of connective tissue has always been sort of known in the background but now people are really starting to pay attention there's the concept that some time ago some people proposed that cancer had something to do with wound healing why is that well normally in the body when you have a wound any type of who wound know that at the beginning you have what we call acute inflammation so it's red cardinal signs of inflammation right boob Oracle or dole or it hurts it's painful it's red it's swollen and then the body gets to work right acute inflammation is the only way you're gonna heal a wound right you didn't have acute inflammation the wounds would just stay gaping open and you would get it probably infected you might die so inflammation then normally has to do its job we pay the wound closed it and then stopped right and that's called resolution so within a certain number of days if it's an uncomplicated little cut within you know 48 72 hours you see the ready the redness starts to subside the pain starts to decrease and then gradually you see a little you know scab and then your your caucus history you don't never think about it again but if this for some reason doesn't happen then you have what's called failed resolution and it can turn into chronic inflammation some inflam infections for example are like that tuberculosis they it it doesn't heal it doesn't resolve its current turns into what we call a granuloma there's there's some factors interactions between the host and the and and the and the infectious agent that fail to actually clear the bacteria and therefore the body tries to sort of contain the inflammation and you get some amount of chronic inflammation in the tissues and then that lead I can lead to what we call fibrosis which is essentially an exaggerated scar like when you heal a normal wound you get a tiny little amount of scar that essentially is the repair of but if you keep repairing all the time you just keep building up scar tissue and that can cause some pathology in organs for example in a lot of organs pulmonary fibrosis liver fibrosis when there's chronic inflammation that keeps going all the time and that that doesn't resolve so what about cancer well cancer has been described some time ago as a wound that doesn't heal that keeps going why is that well because in addition to having all of these cells that keep multiplying you also have chronic inflammation and chronic this kind of fibrotic response of the connective tissue right around the tumor that makes it look a lot like a chronic inflammatory situation pathologists have seen this but they would didn't quite know what to do about it for a long time but there was this association between chronic inflammation and cancer has been known for a while what has recently been described which is very very important is that there is a biomechanical relationship between the chronic inflammatory and fibrotic response and the tumor in the form of stiffness if the tissue underlying the tumor is stiffer and you can you can measure this in some models you could this encouraged us the cancer cells to not only grow but also spread right conversely the cancer secrete factors that increase the stiffness of the tissue so you can see it's a two-way circle right the cancer makes the tissue stiffer the stiff tissue helps the cancer grow so there is this kind of this almost this positive feedback vicious feedback that that was noticed by some investigators that are doing some very very important work in this area in trying to really nail down what is it about the stiffness of the tissue and it's we found it it's actually not just the stiffness it's also the architecture it's how the collagen bundles are organized there's some very nice work that was done at the University of Wisconsin dr. Patricia Keeley da who unfortunately died last year but her her her work very elegant showed that when you look at in biopsies of breast cancer in women who have had metastatic disease compared with those that did it and you can see that the collagen bundles around the tumor are oriented almost like what they describe it's like little highways where our collagen bundles that come at 90 degree angles perpendicular to the tumor whereas when the collagen is or rent and those are those are associated with more invasion when the collagen fibers are more wavy and sort of randomly organized that's not so the prognosis is better so that's it so the organization if the architecture of the tissue is important as well as its mechanical properties so in my lab we've been interested in chronic inflammation fibrosis connective tissue stiffness and inflammation resolution for quite a while now and a couple of years ago I gave Grand Rounds and I talk about the work that we've done on inflammation and resolution and some of you may have already seen our little rap model that we've used we used for many different experiments in our lab we use it mice we use it in rat and this is this is where we induce the animal to stretch and the way we do this is that we've developed de la vela this model back where when I was at University of Vermont where if you hold very gently the animal by the tail and you lift its back its hind feet its instinct is if you allow it to grab onto something so we let we let the animal grab the edge of the bar of the cage or the edge of a table and then what they do is they stretch so they they do this spontaneously so they extend their front their back feet back and then they pull with their front feet and their entire body essentially stretches they can hold this position for several minutes once they're trained we don't make them do this you know initially non-stop we start with a few seconds and then a few minutes and they can actually hold this position for up to 10 minutes if you can believe it and it's it's really quite remarkable how they can they can stretch their body and they really relax into this they don't struggle they just kind of hold hold the pose it's very similar to yoga and it's very interesting how when one of the things that we were interested at first is inflammation and we induced a tiny tiny little inflammation amount of inflammation on top of the thoracolumbar fascia which is in the back and you can when you do this when you stretch you couldn't if you hold your arms up and you can see that that really stretches the connective tissue of the back you really have to hold the arms up and that's what the rat is is doing essentially it's stretching the thoracolumbar fashion and what we found with this model is that when you induce a tiny little amount of inflammation in the back the inflammation resolves faster when the animal stretches for ten minutes once a day so we've showed that we published it and we became very interested in the mechanism by which this happens well there is a lab here at the Brigham dr. Charlie Sirhan who's been doing some very groundbreaking research for several decades now and and discovered that there there are molecules in the body that are that we fabricate derived from dietary omega-3 fatty acids in our diet like wouldn't we when you have like fish oil for example these are the fatty acids that you need to ingest but then once you have them you can make these molecule called Pro resolving mediators and these are called resolved ins protect ins Maryse ins these are different types of the ones that are mostly studied are called resolved ins and what these molecules do is they orchestrate the end of inflammation and they are released at the very beginning in the very first hours of an inflammatory response it's already programming the end and this is very smart because you you need a balance between inflammatory signals and resolution signals clearly if you have a bacterial infection that's going out of control you don't want to resolve that inflammation you need that inflammation right if your wound is infected if on the other hand everything's okay bacteria has been cleared out of the body it's cool well you want to resolve it and so the balance between these mediators and these and the resolving molecules the inflammatory mediators and the resolving mediators it's critical in deciding which way this is going to go okay and what we found is that stretching for 10 minutes once a day pushes the the response in the direction of resolution okay so what about cancer well we decided okay if it works for inflammation and let's try injecting a tiny little amount of tumor cells instead of causing a tiny little mud inflammation in the back we injected a very very small amount of tumor cells these were a breast cancer model a p53 p10 double negative mutant that we inject and you can you can grow these cells in culture and then we in objected it into the third mammary fat pad it's not exactly in the back but it's close enough that when when the mouse stretches it stretches that that area and so the tumor areas surrounding the tumor is directly stretched during the and we the stretching and we did this the mice after being injected is was stretched for ten minutes once a day and we followed these mice for four weeks and so in the open circles you can see these are the non stretched animals and the stretched circles are the stretched animals and you can see that over the course of four weeks the tumors are growing slower in the stretched animals than in the non stretched animals and this was highly significant we repeated this experiment so many times I can't tell you we wanted to be really really certain that that this was real and there is no question about it that the stretching causes the tumors to grow slower so the question then is well why and it was we spent a good amount of time in the last couple of years to try to figure this out we don't have the answer but we have some hints as to what maybe we need good may be going on actually I say the press it just got released just a couple days ago in a scientific report so no longer impressed so the first thing we went to look at is the pro resolving mediators right because we thought well if inflammation remember I was talking about the inflammatory micro environment of the tissues and we already knew that the the pro resolution mechanisms were activated by stretching we thought well maybe the same thing happens in the cancer so we measure the resolve ends in the whole tumors we after the Easter Rising the animal we chopped the tumor we do an extract of the whole tour and we looked at both RVD 1 and RVD 2 which are both Pro is all V meteors and quite a lot elevated in in the stretched animals and so that was interesting because right around the same time that we found that dr. Sir hams group in collaboration with dr. Deepak panagra he at the bee I found published a paper about the effect of resolving injecting the resolved ins in models of cancer and they found that when you inject the resolved ins you suppress the growth not only that but it was very interesting how they did the experiments I'm gonna show you a little bit about these experiments because they're very very interesting so they created a model of what they call tumor cell debris and what what does that mean well if you have a standard chemotherapy right the chemotherapy kills the cells very aggressively and what happens is that you have a whole bunch of dead cancer cells and what dead cancer cells do is they have little and also a poptart ik which is a sort of a the cells are in the process of dying and then they have on their so surface receptors that signal to the body that this is a dis tell that's in trouble and also once the cell has died there are little fragments of cells that remain what they call debris and these debris also have these little receptors on on them and so the body recognizes this and tries to you know deal with that and so what they wondered is does the effect of the cell debris influence the growth of the cancer and so they did an experiment where they injected what these are Louis lung cancer cells what they call a it's a sub lethal dose these are such a tiny little amount of cancer cells that normally they wouldn't grow but they also Co injected an increasing amount of debris dead cells so what they do is they they take a cancer cancer cells they kill them then sure there's no life cells going on in there but only the debris only the remnants and you can see that without dead cells the blue line the cancer doesn't grow the dead cells alone don't do anything but when you have an increasing amount of debris the the the the tiny little amount of living cells is able to proliferate and make a tumor so what that suggests is that the debris enhance the growth of the live cancer cells okay that was very important then what they did is they injected these the RVD one and RVD two and they compared that to the chemotherapy so here you have two chemotherapy agents and you then and they did not affect the growth of the tumor here and here this is it this is the same situation here where you have the cisplatin generated dead cells plus a tiny little amount of the living cells so this would be like the one up here right so this is tumor cells plus debris chemotherapy doesn't touch it you add the resolved ins they don't grow so what that suggested is that the resultant SAR helping the body deal with the debris right to make sure that that the cancer wouldn't grow so how did they explain this well they explain this this way when you have chemotherapy or radiotherapy as I said the tumor now generates all of these did a little degrees that happen one of the important molecules is all spectacle therian or PS and that really stimulates the macrophages to okay to really sort of secrete a lot of cytokines where they call a cytokine storm these are these are molecules that that are very very inflammatory and and to try to destroy the tumor what the resolved ins do is they tell the macrophage to do something different they promote what they call a phagocyte ptosis phenotype where the micro fish instead of going crazy and start releasing all these cytokines it starts to engulf and get rid of the debris so it reprograms the macrophages to a more what we call like a resolving direction okay so what we suggest in our experiment is that because we see that the mouth stretched mouth naturally produces resolved ins we showed that with inflammation we also now see that in the tumor which we this is what we think is that the resolved ins are actually acting the same way except instead of injecting them the mouth is actually making with themselves but there was something that was bothering us and that was that when we looked at the whole tumor also we did what we call the cytokine profile and we looked at other molecules for example interferon gamma and TNF alpha these are strong pro-inflammatory molecules and we saw that they were elevated this was not statistically significant but it's still concerned us because it still looked like the environment inside the tumor was mostly pro-inflammatory so we decided let's look at this some more we did a transcriptome analysis where we looked at the gene expression in the tumor and we saw the same thing it looked like every every profile that we saw that seemed to indicate that there was more in the direction of inflammation you're more in the red direction indicates inflammation more in the blue direction goes away especially in this interferon gamma we were very very interested in this interferon gamma why because interferon gamma remember at the beginning I was talking about immune therapy the body interferon gamma is one of the most important cytokines that t-cells use to kill cancer cells in immune therapy you try to increase that right you try to increase the body's ability to chew what we call cytotoxic T cell ability and what happens when it's cytotoxic t cell recognizes the cancer cell first of all it goes to the lymph node and then there's a something called il-2 which is a cytokine that promotes it to clone to multiply into a clone and then this clone starts to become cytotoxic and is able to then to create these molecules interferon gamma T and F and these are the very cytotoxic cytokines that are then able to go and kill the cancer cells the problem what happens is when with a lot of chronic infections and enter mission and infections like tuberculosis HIV hepatitis and also cancer you get what we call chronic antigen exposure the immune systems gets tired it gets exhausted and he stops doing this and there are blockers that happen on the surface of these t-cells and one of the very important ones it's called PD one and it shuts down the t-cell it prevents it from becoming excited toxin it's almost like saying enough already you know too much inflammation you're killing the whole body trying to get rid of this infection or this tumor let's just slow down this infection a little bit or this inflammation and that's tolerated right so this is a more tolerant response and so what happens is it's over the course of time when you have exhaustion you have increased this is over time this increase of these blocking pb1 Tim 3 these are the blocking receptors and then il-2 TNF these are all the inflammatory cytokines they decrease so the phenotype of an exhausted t-cell is you see the blocker and you don't see the cytokine okay so what happened we thought let's look let's see let's look at PD one in our tumors we thought okay if the if there's if the a if the if the the cytotoxic ability of the tumor is is helped by the stretching you should see a reduction in PD one right because PD one here blocks the cytokine response and that's what we saw we saw a reduction in the amount of PD one on the surface of t lymphocytes we also looked in the lymph node looking for this il-2 because il-2 is important that's what causes the clones to proliferate and we saw an increase and both of these results suggest that the stretching actually helped the cytotoxic immune response it helped the cell to the body to combat the tumor so how do we put this all together well on the one hand you have this increase in interferon gamma right which is the really sort of what we think is the key cytokine here that allows a greater cytotoxic activity in the tumor but at the same time you see the resolving acting to clean up the mess so we think that this is this is where we we don't we have not shown yet a mechanism that links these two we don't know whether there is a relationship there are some interesting papers that got published recently about a relationship between interferon-gamma and prose and resolution actually one in the lab of dr. Bruce levy right here at the Brigham where they've looked at this in asthma we don't know but we think that there may be you know these are very interesting areas that we want to pursue in terms of understanding what's going on so basically the take-home message really is that I think the important thing is that we really need to pay more attention to the effect of physical based treatments that can help us to understand not only the effect of mechanical forces on the body not naturally but how can we apply this and design treatments that can apply the right amount of the force how much how long how often these are all important things I mean we are not right now in any position whatsoever to recommend any type of specific stretching or you know people to do for treating cancer obviously right this is just an animal model however cancer patients are already doing yoga they're already stretching cuz it feels good because it helps them sleep because it helps them you know with their dealing with some of their complaints like pain or or fatigue so I would say keep doing that I mean that's the important thing is that is that these are treatments that are already in effect for lifestyle reasons for well-being and so I think our job in the lab is to now try to understand the biology that may link this to the cancer biology and so I want to acknowledge all of the people who have contributed to this work this work actually started the University of Vermont way back with dr. Artie Shukla which we had the first very first attempt to to try stretching in a cancer model and here at the Brigham and also importantly our collaboration at the Dana Farber Cancer Institute with dr. gene Zhao Johan Burke host and kim yo-jong who they really are helped us with the cancer model of the breast cancer cells thank you very much thank you helene that was silicon um what's the evidence that there might be some systemic effects from the stretching if in the experimental model you put the tumor elsewhere in the back very good question it's very difficult to do that in an animal right because the animals you see it's very hard to stretch only one part of the animal i mean we have models right now of inflammation where we try to do that where we only stretch one part of the animal and put the inflammatory lesion somewhere else but you have to anesthetize the animal for that and for these models you can't do that because you would have to anesthetize the poor mouse every day for a month you know that just wouldn't work so this this whole question of local versus the stomach has been very intriguing to us we're gonna try to look at that slightly in a sort of a different way in humans we I have one of our new postdoc in the lab who is going to be looking at that in a model of inflammation in in the forearm so if you have a kind a little bit of inflammation in one arm and then you stretch that arm but you don't stretch the you know you you only stretch the arm versus stretching the other arm you know you could see if there's some systemic effect if you have inflammation on one arm and you stretch the other arm and you still get the anti-inflammatory effect that would suggest that it's it is systemic there's also the whole issue of stress when their mouth is held by their tail and it is stressed there's no question about that we have a control another experiment in the animal where we stretch the mouse passively under anesthesia compared with anesthesia and alone and we still see anti-inflammatory effects there which suggests that it's not the stress may be may play a role but it's not the only thing so these are this is a very good question we're gonna chip away at it we know it's it's it's going to be a long time before we you understand that thank you for the lecture work on the pulmonary division gal Deva my question is to two questions if you don't mind one why everything is around inflammation and I think there is inflammation there is fibrosis there is also a book ptosis and there is a great paper by dr. luis calso that mentioned a lot of intermediary mechanism so I think we're narrowing too much on inflammation and probably that helps us to measure other things that probably can be also the answer and response of what you are presenting that's one common question the second part is on the latest slide there is a middle wonder you have measurements and timing so is the question about treatment - cancer - the treatment with stretching something that is randomly you need to do it all the time or you do it after is their timing part important as well - very good question yeah as far as why focus so much in inflammation for we this is kind of where we started from in our lab as inflammation we moved into cancer but totally agree with you we really need to look at the whole sort of metabolome you know and and really obviously the questions of timing excellent point we only start we started stretching the animals right after injecting the cancer cells but we inject a very small amount of cells so you could almost think about it as a almost like a preventive protocol it would be very interesting I think to wait until the tumors have developed a fair amount and taken hold and then start stretching we haven't done that we could also train the animals to stretch for you know several months and then inject the cancer cells so a lot of different experiments that we can and should do hopefully once we get a grant to do that so yeah the timing I think will be will be key also we want to look at metastasis one experiment that I didn't mention what back when I was at University of Vermont we did an experiment where we injected mesothelioma cells instead of the breast cancer cells in the same location it's very interesting what happened the only reason I did that is because I had a lab right next door they were studying his athelia but they had the model and said all that's try injecting them so when you inject mesothelioma cells subcutaneously most of the tumors if you only look at them for a month they they stay where they are but a small proportion of them metastasizes to the perineum because they're very invasive much more aggressive tumor than the tumor then this cancer cells we used here and we saw exactly the same difference between stretch and no stretch in the music theory cell except a tiny tiny proportion of that metastasized and there were slightly more of them in the stretch than the non stretch group this was not statistically significant the the metastasis but it worried us and not that we didn't publish it we waited to repeat it in a different model but now I really want to go back to a metastatic model and make sure that this stretching does not actually enhance metastasis because that would be bad so there are a lot of questions obviously Thank You Helen great work as a former t-cell immunologist I'm curious you you should I'm really struck by that the shift in phenotype in the cd8 positive T cells I'm curious if you actually looked at change differences in absolute numbers of T cells in the tumor and also not just the cd8 s but looked at other populations we looked at macrophages as well we looked at the only type of cell we did not look at NK cells and there were too small the numbers were too small these tumors a limiting factor there was only these tumors were literally like 1 to 2 millimeters so when your timing would did the flow cytometry we had to pick and choose so we were not able to look at every single marker that we would have liked but there was a very interesting paper that was published recently on the effect of exercise on NK cells that it boosts and also decreased tumors these were mice that were freerunning and exercise wheels that I should have mentioned that at the beginning we we think there may be very much of a parallel between what goes along with stretching or what goes on with exercise the thing is that when you look at animal models of exercise and cancer most of them involve levels of exercise that are quite vigorous and aerobic you know and a lot of them make animals run on a treadmill and cancer patients a lot of times can't do that it's too it's too exhausting and so that's why we thought well stretching might be nice because you know it's easier to do and it's not as aerobic ly intensive but yeah so I think there's a lot of it's interesting parallels with with that so we'll definitely have to look at these other populations as well so this is a great great great talk and and it's a great model for for treating cancer ultimately that that would be the obvious implication I'm my mind goes to prevention yes and I was intrigued by that sub-threshold injection I'm wondering can you do a sub sub-threshold injection where you might be able to show that that controlled it would turn into a tumor whereas in a stretching model you might actually eliminate it I totally agree I mean and of course we know that a substantial fraction of cancer in the population is preventable so this would be significant I mean the whole idea that cancer little many cancers happen all the time I mean you know that our body your immune system is is programmed and able to deal with it it's just once in a while it doesn't and I think that's that's the idea is that is that could you by staying healthy by doing a certain number of things we already know that exercise diet those things help prevent but we don't really know exactly why and so this could be a part of it I was really amused by the mouse that relaxed into the stretch and do the whole aspect of the relaxation response and how it might influence this the combat the stress factors there yeah well we don't we think the mice relaxed and the way we can you know again we're we're interpreting what we see and we're not sure but you know at first when we teach them they they kind of squirm they struggle they poop they you know they do things but after they've been trained and this is what every one of my you know students and technicians tells me is that they can tell when the miles has had enough they start squirming and they let them go they don't force them to stretch for the total amount and there once the mouse kind of learns they just they seem to relax it's very like a new yoga student was a big Wiggly and yeah yeah exactly so I don't know what it is you know and it'll be very interesting to look at their brains when this is going I have to ask this six differences oh thank you so these are female mice these are actually you know usually we use male mice I'm very proud to say I should have mentioned it you know yeah every one of these experiments needs to be obviously looked at we're we're very interested obviously looking at our inflammatory model in male and female mice we have a name of our grant we're going to do that in rats we're gonna start that probably a middle of next year so yeah it's very important obviously it could be completely different dose all right thank you very much [Applause]

Channel: Osher Center for Integrative Medicine

Views: 13,659

Rating: 4.9801979 out of 5

Keywords: connective tissue, Helene Langevin, Stretching, Cancer, Tumor Growth, inflammation, mouse model, research

Id: micXX__6L8g

Length: 55min 14sec (3314 seconds)

Published: Mon Jun 11 2018