Cancer Biology 101

this program is a presentation of uctv for educational and non-commercial use only [Music] good evening welcome to mini medical school and winning the war on cancer and my name is Thea toasty Margaret tempura sends her regrets she couldn't be here to introduce me so she said I had to introduce myself so that's all I'm gonna say I could just skip all the other stuff and I'm going to talk to you about cancer 101 if I say something that's not clear raise your hand let me know okay what we're gonna do is cover a really big field so I have to be selective in terms of what I talk about but what I'm going to try and do is give you a feeling for what cancer is and we're going to talk about how understanding cancer gives you opportunities for insight into what the disease is doing and of course that would lead to opportunities for intervention or prevention and that's the goal that we'd like to achieve this is the startling statistic that over 10,000 people per week die of cancer in the United States that's a lot of people and if we could lower that number that would be fantastic and so today what I'd like to do is I'd like to address three questions with you what makes a cancer cell different in your body how does a cancer cell become different and how can we control it if we could get to the bottom line that would be really fantastic so let's start what makes a cancer cell different first of all you've probably all seen pictures like this in your doctor's office can anybody tell me one thing that's different that looks different about this thing on the slide anything uneven number one another thing color another thing raised great one other thing excellent it doesn't have a round edge it has a created edge it's it's reaching all of those things are typical in terms of what these cells are doing so let's take a little bit of a look about what that is in terms of a cancer cell so the raised part of it it's growing when it's not supposed to and it's growing in a way that it's not supposed to most skin grows in a nice flat plane it moves spreads the last answer so you can see that it's it's invading the areas next to it if you were to run your finger over this lesion on the skin it would feel different it's raised and it's bumpy it's not supposed to be it doesn't go away so some things they come up like a pimple and then it goes back down it's a reaction to what your body is responding to this one stays that's not good it recruits food and that's this is this red color the blood vessels and this is to feed the cells that are growing and it looks different which is what we were talking about previously so cancer is not one disease it's actually hundreds of diseases and even in one cell type in the body so your body is composed of 206 cell types and even in one cell type you can have multiple types of cancer so there's hundreds of different types of cancer so to say cancer in the singular is not correct it's a it's a it's a whole constellation of diseases and that actually provides a real challenge in terms of trying to address this therapeutically because many times as you're going to see through this lecture and of course as you already know different people react differently different cancers react differently and so the trick is trying to figure out what it's going to do what to predict what how to predict things or how to Prochnow Sting's okay and so here I'm just mentioning a couple of the different pieces a couple of different organs in the body the lung the breast the skin and the colon this and pancreas make up the big five in terms of cancer the most frequently seen but as I said there's many other types now our first information about cancer came back several centuries ago and all we could do was look at what claim came out of the body or when dissections became available to actually look what was in the body and of course nowadays it's several hundred years later we have much better ways of doing this I'm not going to talk to you about imaging it's a whole new world it's very exciting somebody else might give you that lecture but I'm going to show you the difference between something that is not dangerous and something that is more dangerous so this is so your colon your colon is a tube down your body and this is split open and laid out and what is being shown here is this little tiny kidney beam type thing on a little stalk that's a polyp and that is actually nothing to worry about it's benign meaning that it is not malignant I'll talk about those words in just a moment but what it means is that you can snip it off and it's fine and there's no problem no foul you don't have to worry about it this on the other hand is something different this is called a carcinoma meaning that it's a cancer of the epithelial cells of the colon and you can see some things that are very different first of all there's no tiny little stalk that's allowing it to just sit up there it's really embedded in that tissue notice that there's a lot of redness this is that that recruiting of the blood vessels to feed the cancer that we were talking about before these are some of the hallmarks of what makes this malignant versus this other guy which is simply benign okay so what we're going to do now is take an example and go a little bit deeper because it's hard to talk so superficially about hundreds of types of cancers so what I'm going to do is today is use an example of breast cancer because a lot is known about it and one of the reasons that a lot is known about breast cancer is because of you guys it's because of the lay audience or it's because of kids I would say that probably 20 years ago not much was known about war certainly not as much as we know now was known about breast cancer but it became very clear that the advocate movement could raise money for research and it was first done here in San Francisco with AIDS and when that turned out to be successful two other very large movements swept across the country this was about 20 years ago one was for women's health trying to understand breast cancer and the other one was for prostate cancer and so a lot of money a lot of your tax dollars and philanthropy have gone into trying to understand this disease and it makes it a poster child for trying to understand what's happening with cancer so the breast is a ductal system and that's what these different colors are I'm going to show you a different picture in a moment and they radiate out from the center and here's a different picture of it showing the chest wall and the ductal structures and if I take one of these and blow it up that's what it looks like and the cells that turn into cancer are the ones that line this circle they're called epithelial cells and what they do is they line this ductal structure here under a proper hormonal stimulation they make milk so the inner cells make the milk the outer cells contract so that the milk is expressed through the duct and of the nipple and so under proper hormonal stimulation the gland has a function in the body but sometimes you get cancer and when when a person gets when when a pathologist looks at how the tissue goes bad oftentimes it's represented like this as going through a continuum so here if you cut this right here this looks like a normal duct and you can see the cells properly aligned sitting next to each other and adhering to each other this is proper social interactions but notice that as you start to go towards the right this is called introductory high intraductal hyperplasia you can see that these cells start proliferating more there's more of them than there should be and they're sitting on top of their neighbors that's not so to happen and here not only do they do that but they start looking very unusual the word for that is pleomorphic okay the degree of pleomorphic the degree of cells that are there tells the pathologist how far down the road these these this tissue has gone towards malignancy now all four of these are called benign meaning it isn't what you call cancer the thing at the at the right is called malignant malignant is when the cells that are inside here breach this this circle this basement membrane and they go out to into other parts of the body the breaching can either be local in which it's called locally invasive disease or it can go to other parts of the body like the brain the bone the lungs etc in which case it's called metastasis but you do not have a malignant cell you do not have a cancer as a pathologist calls it until you have reached this basement membrane and so the hope is that when it's in this stage you can control it somewhat the good news is that it takes probably 15 to 20 years before it goes from this stage to this stage and so if we can understand what's happening here the hope is that we can stop it here before you actually see a disease that's what a lot of people are trying to do okay I want you to show you a picture of what it actually looks like to a pathologist I hope you can see back there is that is a the lighting pretty good for you to see okay so here's the schematic that I showed you previously and now here's what it looks like under a microscope so here's the normal breast tissue and like I say if this is the ductal structure and what we're doing is we're cutting it right there so you're seeing the little holes of the ducts and you can see they're lined by the cells a double layer of cells that are separated this is a normal tissue but look what happens here in this hyperplasia here's the outside circle of of cells but then they're cells in the center when there shouldn't be and here not only are the cells in the center but they also look very very different some of them have very tiny nuclei in the center which contains the the blueprint the DNA some have very large nuclei and they're they're different shapes this heterogeneity is a hallmark of cancer and the more heterogeneity oftentimes it means the worse the cancer is this on the right is a very rare picture it's this was captured by a resident here at UCSF and it's you're capturing the tumor cells in the process of breaching the basement membrane think about it you have this whole tube like a garden hose and they can get out anyplace and so actually cutting the slide exactly where they're escaping is a very rare thing and so this is really a beautiful slide that tells you that shows you what's happening as they spill out into the environment okay so this is what a pathologist sees and this is what a pathologist uses for diagnosis to tell you what's going to be happening now what are those cells doing well they've got some problems they're not behaving the way they should if you have a normal tissue as is seen here what happens is the ductal structure grows and then there's signals that tell it to stop that's why the breast or the prostate or the lung or any part of your body looks the way it does is a it's of a typical size the prostate is the size of a walnut not the size of a watermelon and that's because there are controls there's a conversation that happens between the the cells on the outside of these ductal structures these are called stromal cells and the conversation is with the cells that are on the inside and it's this molecular conversation that goes back and forth that tells the duct how to grow how much to grow when to grow and when to stop so when all that works properly you have a nice proper structure that can do what it's supposed to do but when some of those signals become damaged which is what happens in cancer cells then you have the this ugly response that that is not what's supposed to be so cancer cells have an improper response to signals so they can keep growing when they're not supposed to and that's why a physician can detect prostate cancer in a man because the the digital exam is to see whether the prostate has gotten enlarged or not and part of that is because the cancer cells and the prostate have abrogated their stop signals death signals usually cells are like a population they're born they do their function and then they fade away they're supposed to do that if the cells of your body didn't die you'd be in big trouble the digits your hands when you're in the womb this is a paddle and there's programmed death between the fingers that actually give you your digits so death is a good thing in the body it's put it makes it carves out your hands and your toes and several other things and allows for turnover in your colon and your hair and your skin all of those things but in cancer cells a lot of times the cells ignore those death signals and they stay around even if they're damaged or old or decrepit and that's not what you want there are certain responses to aging where cells stop and in cancer cells they do not behave those signals they don't listen to them and so they keep proliferating even though the body says stop growth is different than then proliferation it's when the cell gets bigger okay so there are very so cancer cells don't know how to control the growth they get big they get small they're all disrupted differentiation this is a really interesting one if you look at your neighbor you'll see a person with hair and eyes and a nose etc so you've started from one cell and you've become this human being you've undergone multiple differentiations that make all the tissues cancer cells can't do that properly normal cells can cancer cells can't so you can even have some cancers of the germ cells or when they take them out of the people they have all the different types of tissues of the body it has hair coming out of it teeth coming out of it eyeballs liver bone it's called a teratoma or a teratoma our Sonoma and it means that it's gone abnormal so there's problems with differentiation I already showed you an example of recruitment for food I showed you that lesion that was on the skin it was red that was recruiting blood vessels to support the increased growth that we were seeing up here we already talked about movement that the cancer cells move places where they're not supposed to go either locally or metastatic Lee and this is really interesting it turns out that as I said before most of the cells of your body are born they do their thing and then they fade away but cancer cells enjoy immortality and so oftentimes they keep growing they keep living even when they're damaged and they they should be they should know to go to sleep so to speak normal cells don't do any of these things in other words they they are properly controlled for all of these processes and so there are things that are very distinctive about cancer cells that perhaps would give us targets for how to control these things we'll get to that in a moment what I've been telling you up until now is pretty much what has been looked at in cancer for the past two centuries but over the last ten years five years it's become much more appreciated that a cancer is really more than just the epithelial cells that go bad it's also the cells that are around it remember I emphasized to you I said that there was that molecular conversation that went back and forth about how to make a proper ductal structure well it turns out that you can actually have the cancer initiate in the epithelial cells or you can have it initiate in the cells around it called the stromal cells if you have an improper balance of either of those you've got the cancer process that's going on so if you want to control this you don't you shouldn't just control the epithelial cells you need to control the environment around it think about a neighborhood and think about children at risk in a neighborhood right if you have a good home environment chances are you're gonna do your homework and grow up to be a good person etc but if you grow up in a bad neighborhood there's a higher probability that you'll be exposed to drugs or gunshots or things like that so think about it microenvironment in the neighborhood so here is another picture of the tissue the normal tissue that I was showing you before and these little circles are the proper ductal structure this is exactly how it's supposed to look but look at what cancer looks like so not only are these little ductal structures all stretched out and disrupted say these cells are epithelial cells of these these so they're just screaming and crawling where they're not supposed to be but look at the stroma look at the cells around them so here's what a normal stroma looks like in between here it's very delicate here it sits very lightly stained look what happens here dark pink it's because these cells out here have deposited more collagen this really stiff stuff and it turns out that when you palpate when you feel a cancer a breast cancer or skin cancer or anything when you feel a cancer in your body this is what you're feeling it's not the actual cancer it's the cells around the cancer that are making this excess collagen it's called extracellular matrix okay another thing that's here are extra immune cells when the epithelial cells don't behave properly your body responds and there's a signal that goes out like to the cavalry and the white blood cells the macrophages many different types of immune cells come and try and repair the damage and often they don't succeed so it's it's a real chaotic mess of cells that typify what a cancer is it's not this beautiful typical architecture that defines a normal tissue okay so who are the players here I told you that the stromal cells are important and this is just a picture of what I told you before how there's the conversation between the stromal cells and the epithelial cells so I'm showing you this talking to that well it turns out that if you take the stromal cells from this cancer area and you put it next to either these normal cells or some cells that are just on their way to becoming cancer what happens is you get a huge tumor so in other words there are signals that are coming from these stromal cells here they're called carcinoma or cancer associated fibroblasts that actually turn on the the aberrant responses in the epithelial cells so the major thing that I'm trying to tell you here is that cancer is not just the epithelial cell going wrong it's the epithelial cell going wrong in the microenvironment and the reason that's important is because then that gives you a whole set of other targets that you can approach in terms of trying to control this disease if you take the normal stromal cells and put them with the normal cells what it does is it creates a little tiny piece of tissue and this can be done in a mouse you put it in a mouse and if the mouse is exposed to the proper hormones you can even get proper milk that's produced human milk if these are prostate cells you can get PSA produced this is called tissue reconstruction so you can take human tissue cells separate them put them back together again and get them to reconstruct the tissue if you take the fibroblasts from the cancer and put them with these cells instead of getting a proper tissue what you get is this horrible tumor notice the redness that's the the growth of the blood vessels to feed it again so what this is saying is that these stromal cells are really important okay and the signals that they send to the epithelial cells are they say increase your growth decrease your cell death stimulate the blood vessels in the area so that they grow more provide more food more nutrients change your cell-cell contacts losing it see their which means that what I showed you previously the cells are not properly aligned they're now scattered in different places and it even says increase the rate of mutation so these are are really important in terms of the signals and of course the idea is that if you can interrupt these signals perhaps you could stop the carcinogenic process cold in its tracks this what I've been telling you is summarized here coming from both directions what it says is that there's normal tissue architecture and every once in a while you have a cell that can go wrong but unless unless the stroma also contributes to this it pretty much stays where it's supposed to be it's only when you have the stromal cells contributing with the with a messed up epithelial cells that you start to get the cancer that's such a problem therapeutically so how does this happen how does a cell or tissue become a cancer whether it's a stromal cell or an epithelial cell so we've been studying that for quite a while we know that the body is exposed to many different insults and that it tries to deal with it and so in the 1700s it was recognized that there was a population of boys that got scrotal cancer much much more frequently than anybody else that was the first link between damage and cancer so the Chimney Sweeps the little boys that could go down the chimneys and sweep them out they had a very high rate of cancer because they didn't wash as often as they should and the suit is a carcinogen on the skin and it resulted in cancer and of course you're all familiar with the second big example which is cigarette smokers and here's an example of a lung from a smoker you can see a lot of the residual from the cigarette smoke that's deposited in the lung if this was a lung of a baby this would all be beautiful pink pliable tissue it would be like a delicate little pink sponge when this comes out of an individual and adult that's been smoking if you squeeze the bottom of it it can crumble it's it's black and it's crumbly and that's that's what it does to the tissue so cigarette smoke can do that and there's other carcinogens of course that can do the same thing to other parts of the body and you're all familiar with sun exposure talking about what happens with the skin so the first clue was that damage to the body in many different ways can exacerbate this cancer frequency okay so how do you take that apart well there was an experiment done in the turn of the last century it was 1903 and there were three Japanese investigators that took cigarettes and they extracted what came out of the smoke and they distilled it down into a liquid and then they painted on the back of mice to ask if there was some cancer-causing property in that smoke and they got cancer they got cancer and that was the first identification of Ben's pyrene chemicals that can exacerbate cancer that can start this whole process so the cigarette extract and after a period of time you get cancer so people started looking at what other chemicals were in the environment or what other physical things were in the environment they would turn up the frequency of cancer x-rays etc what I'm showing you here is another example of how we learned about cancer genes and that's the familial syndromes that go with cancer so this is an individual this is actually benign polyps none of these have turned cancerous yet but this individual has a mutation in one of the genes that stops cancer so when you take the break away you get more growth and this is what happens and if these cells accumulate more mutations some of these can turn cancerous this is neurofibromatosis it's a familial predisposition to cancer so environmental agents gave us clues family history gave us clues and then we working with cells in the in the laboratory gave us clues and what I'm showing you here are some human breast cells growing in culture these particular culture conditions were developed by Martha Stamper across the bay but growing these cells in culture and seeing how they respond to these agents that I've been telling you about gives us insights in terms of what's happening so I told you that in culture you can mimic proper tissue formation so here's this ductal structure and I told you if you put these cells together properly in the animal you can mimic ductal structure and you can even get this to form milk so the idea is if you expose these cells to carcinogenic insults can you turn this into cancer and study how it happens and how you can stop it and this work has been going on for several decades so 40 years of work have suggested to us have told us have taught us that the cells of the body are exposed to many many insults some of the injury comes from the inside of your body simply making the DNA reproducing it metabolizing the food that you eat heat it's a process that can sometimes damage molecules all of those things stress the cells but your body is very robust it has ways of dealing with it it has many repair mechanisms on many different levels and we know that these are very important in terms of preventing cancer because if any of these repair mechanisms or if any of these stress responses are compromised in any way as I'm showing you here what happens is the incidence of cancer goes up dramatically so that was a good clue we knew that this kind of thing is very important and you can start to study these cells in culture and identify the cells that have broken these pathways and actually start to see them to grow but I'm not going to talk about that much more so what I was trying to say here is what makes a cancer cell different it's their ability their inability to react properly under whole set of conditions and so they behave abnormally normal cells respond properly full-blown malignant cells are broken in all of these these pathways and precursors are simply abnormal in some of them but on there they're on their way to in activating all of these and the idea that's emerged is that these little areas of cells then grow out and acquire mutations and go on to become malignant so what I wanted to do is to take you to a place that is exciting these days it's if things are moving forward in a really good manner and here I was showing you that some studies can actually start to see that the cells the little areas of cells that are not yet tumors but someday will become tumors so if a pathologist looks at this tissue it looks completely normal but notice that this little area stains Brown this the brown stain here is the turning on of a stress signal so for some reason these this little group of cells are stressed while the other ones aren't and it turns out that when you start to see the cancers emerge in the tissue they always come out of these little patches of cells so that is a step forward because if we can address these cells perhaps we can do something about them so if we see these little patches of cells in normal tissue and they have many of the characteristics that we see in tumors in full-fledged tumors one might hypothesize that these are precursors to tumors and it's turning out that that's probably the case because you can see these patches of cells as I told you in areas of pre malignant lesions and these people are at an increased risk for cancer so so far everything is going hand-in-hand okay the other point that I wanted to make about this is that our body is doing things all the time this is a really interesting study that not a lot of people are familiar with it's a whole set of studies I should say and what it is is it asks what is the reservoir of undetected disease in the body okay so all of you are sitting here in the audience many of you have not been diagnosed with cancer but I can tell you that probably yeah well every single one of you are sitting there and in your bodies are these little tiny areas that are just at the beginning or already cancer they're all they're being held in check by the stromal cells the reason I can tell you that is because of these types of studies they're called autopsy studies so what they did is 100 autopsies come to the morgue the people died from car accidents suicides heart attacks nothing to do with cancer okay and what the investigators wanted to know is what is the frequency of cancer in those people that have not been diagnosed with cancer so in this particular study they looked at the breast but in other studies they looked at the prostate or the bladder or the lungs or the colon or any other part of the body that you want to talk about this particular study they looked at the breast and what they did a little the little squares that I drew up here is they they did a mastectomy they cut the breast off of the corpse and they did what's called Eagan sub sectioning in both directions bread slicing in this direction and in that direction so it makes little blocks of tissue and then the pathologist can look at every single block and see does it look normal or does it look abnormal and what they found was really interesting to remember these people are not diagnosed with cancer at all what they found is that almost a third of them had hyperplasia those little areas where we have increased numbers of cells that I showed you over 1/4 of people had atypical hyperplasia so not only do they have more of the cells but they look abnormal there playa tropic and and created the atypical hyperplasia was always in the people that had hyperplasia and if you hear eighteen percent somewhere around eighteen percent of the people had ductal carcinoma in situ that was that step just before it reaches the basement membrane okay and there were even a small number of people that had invasive cancer but it was so small that it hadn't been detected yet so that's quite a few people just walking around and if you as I say if you look at the pancreas if you look at the colon the prostate the lung this is happening in all of those tissues as well so what it does is it gives you a feeling for what's happening your body these little cells are rising they're responding to stress if you're lucky they resolve and they go away what's hope holding these things in check it's probably the stromal signals if you take a tumor cell and put it into a compromised Mouse it doesn't have an immune system and the stroma is not the way it should be it forms this big ugly tumor it can kill the mouse very rapidly if you take the same tumor cells and now you put it in a proper place in the mouse where it has immune function or where the stromal cells are sending the right signals what happens is a tumor doesn't form at all so what that's saying is that the stroma is actually controlling a lot of what's happening with the cancer and if we can if we can build up those signals we can help prevent the cancer or slow it from progressing that's the idea that people are working with okay so this is many tissue types how can we control it or how can we predict it so I was just telling you about how we might approach controlling it but the story that I wanted to tell you here is how can we predict who's going to get cancer and who's not going to get cancer and do something about it this is a very old study it's from the 60s and you can't do this anymore because it would be unethical if somebody's diagnosed with cancer they get treatment here what we're showing you is what happens when people are untreated this was historical people from rural areas etc what you can see is for untreated breast cancer you have a lot of mortality but with treatment and treatment progresses as we go through the decades this line hopefully is moving up up up and up that's the whole idea of trying to go forward so and what people have thought is that if we can find the cancer earlier and earlier we can make that line go up faster and so the big problem in cancer research is that by the time we find the cancer it's usually out here so death is here when the cancer is so large that it compromises the body but by the time you can see it with a mammogram or radiology or by the time you can feel it it's already to this size and this is about 10 or 15 years after it first starts so if we can understand these early events perhaps we can stop this and actually cut this curve right here that's the whole idea this long lag period provides us with an area of time where we can assess the risk in individual people where we can hopefully prevent it through the administration of of drugs or diet etc it gives us clues for early detection when is this going to flip over and go in up that that slope and it gives us also therapeutic targets there okay so how can we address this problem in terms of the heterogeneity of these little tiny pre malignancies that are on all of our body sometimes they go forward sometimes they don't sometimes they resolve sometimes they become cancer well what people are doing right now is they're taking a tumor and they're doing they're looking at the DNA and the mutations that are in the DNA and they're trying to predict is this tumor going to metastasize is it going to respond to therapy there are now fda-approved tests that allow you to look at the tumour and predict what's going to happen but what I'm going to tell you about is a story that happens back back here it happens in the cells that are not yet a cancer they may look pre malignant so they're on their way but they have not yet become a cancer and what's been found is that you can actually let me go forward you can actually start to identify which ones will become cancer and which ones won't so let's go back to this idea that the body when it's stressed deals with the stress and if it does it improperly you get cancer well what you know is that people are different at each of these levels they're different in how they're exposed to insults some people smoke some people don't some people get a lot of Sun others don't some people are very effective in repairing the damage that's done to their their body other people aren't they're defective because of the genes that they carry some people age quite rapidly others look young even when they're 70 all of these processes are heterogeneous in each individual and that's why if you look at something like this you can have a person that smokes three packs a day and does not get lung cancer and you can get people that smoke one pack a day but do it's because of these differences in terms of these repair processes how they deal with things so this is going to give us an idea of how the tissue responds and what's going to predict cancer this is just showing lung cancer the radiograph okay so when I started to tell you is that one can start to look at the tissue here and assess what's happening in the tissue and predict whether it's going to become cancer so studies of the very early events in human tissue provides insights into the mechanism the road to malignancy and that's what I'm going to show you right now I've shown you this picture before normal cells going through hyperplasia going through atypical hyperplasia going through ductal carcinoma in situ all of these being benign and this being malignancy all right now a lot of the screening that's done in our clinics today and I know that Margaret tempera talked to you a lot about screening last time is done to try and catch cancers at a very early stage DCIS is what I'm going to talk about right now it used to be a very rare diagnosis because the cancer is so small and the stroma hasn't really become that abnormal yet that you can't feel it and so it was a very rare diagnosis until mammography came along now you can see into the breast without without actually feeling it and this became a very common diagnosis and this now represents 20% of all diagnoses and it went from a rare disease to a very frequent one it's over 62,000 per year in the US and this simply shows you the diagnosis of DCIS per hundred thousand women as a function of years and what you can see is right here mammography was introduced into the United States and started to become popularized and so you can see that the frequency of DCIS skyrocketed it's continuing to go up for several reasons first of all this is over a 500% increase this is mammography now we're bringing on board MRI which is even more sensitive that can find them when they're even smaller okay so you might say that that's good but we'll get to that in a moment the other reason why DCIS is going up quite rapidly is because our population is aging so the demographics here I think are really quite startling so this is the year 2000 and the blue the darker the blue the more aged the population so here this is this blue color means that about at the most 20% of the population of Florida is over the age of 65 and notice that everybody else is pale notice in 2015 how now Florida it's 30% of the population is over 65 and look at all these other states that are darker blue and now look at the United States and 2025 all these dark blue states it means that every single one of these states 20 to 30 percent of the population is going to be over 65 okay these pre malignancies go up with frequency with age so we're talking about breast cancer here we're talking about DCIS but in prostate cancer it's called pin and how you measure it there's with PSA in colon cancers many of you have probably had colonoscopies you go in with an endoscope and you look for polyps okay so all of these are examples of pre malignancies all of them go up with age but the dirty secret is only about one in ten will become a cancer so you're finding more and more and more of these pre malignancies but only one out of ten is going to become a cancer so this is a really important clinical problem here's what happens with DCIS when you don't do anything about fifty percent of the women nothing happens over the next 10 to 20 years of their lives for 25 percent of the women they get a subsequent DCIS that's not a big deal because it's not life-threatening and about 25 percent of the women will go on and get invasive cancer that's what happens if you do nothing what happens if a woman is diagnosed with DCIS down here the black dots and she gets a mastectomy well the curve goes down quite dramatically but still 5% of the women will get invasive breast cancer that tells us that some of the cancer cells are escaping even at that very earliest stage okay what the lines in the middle represent are what happens the orange one is if you get a lumpectomy so it's a partial mastectomy and the one of the blue and the red indicate when you get a lumpectomy plus radiation plus hormone treatment in other words the frequency of getting an invasive cancer goes down but you're treating the whole population for the little tiny fraction that's actually at risk so it's difficult to say which woman should get treated and which woman should not get treated here's a different way of putting this so let's say that you have a tenderness or a shadow on a mammogram the doctor would say go get a biopsy the pathologist takes the biopsy and there's three things that can happen one the woman is diagnosed with invasive cancer she gets treatment standard treatment number two she can get diagnosed with DCIS we'll talk about that in a moment or number three she can be diagnosed with something called benign breast disease this is a million women per year in the United States get diagnosed with benign breast disease it shouldn't be called disease it's just benign breast observations it's those funny little things that I showed you in in that cartoon about how a normal cell becomes a cancer cell it's it's composed of cells that are proliferating but they look normal and cells that are proliferating but they look abnormal the atypia okay so this is what's happening when you get a biopsy and what I showed you before is that if a person is diagnosed with this and they simply get a lumpectomy seventy percent of the people nothing happens to them 15 percent of the people they get a subsequent DCIS 15 percent of people get a subsequent invasive cancer so those are the people we want to find we want to find out how to separate out the green people from the yellow people and particularly these yellow people that are going to get invasive cancer and the reason that that's a problem is because right now people that are identified with pre malignant lesions are offered everything from a full mastectomy down to watchful waiting okay so 20 years ago if a woman who's diagnosed with DCIS virtually 99% of them was suggested that you have a complete mastectomy but when I told you is only one out of ten of them is actually going to get cancer that means there's a lot of over treatment but I also told you that even if you do a complete mastectomy there's a 5% chance that you're going to get cancer and so those women are getting undertreated because not only should they have a lump of the mastectomy they should have systemic therapy to stop things so the problem this is called stratification if you can match the treatment to the probability of the aggressiveness of the disease you've got a match and that's what our medicines are starting to do today so let me watch let me show you what happens here okay so we want to identify which ones are in the green and which ones are in that yellow how do we decide people have been trying to do this for 50 years and so the first thing they did is they tried to look at the lesions and what you can see is that it's hard to see it here you can ask how big is it does that make a difference the answer was no how undifferentiated is it that doesn't make a difference how much death how much growth how much how what are the margins look like none of that stratified none of that predicted which one's going to be the cancer and which one's not going to be the cancer and people have been trying to they've looked at many things they've been trying to do this for several decades okay the epidemiologists tried to answer this as well is that the people that smoke is that the people that drink alcohol is that the people that weigh more no none of these markers stratified risk and the molecular biologists tried also can we look at some of these molecular markers and will it tell us which ones are going to get cancer and which ones won't the answer was no no biological marker showed a significant correlation with the future event the recurrence okay so the idea is that you need a proper cohort and and you need proper biomarkers to be able to identify these people all right so this is some work that was started here at UCSF and it was a collaboration with my laboratory and that of Carla Carla Kowski and it was a whole team of people that tried to address this question now what Carla had been doing is collecting biopsy's from people that had been diagnosed with DCIS so these women had been diagnosed with DCIS 20 30 years ago between the mid 80s and the mid 90s many different hospitals many different counties and the blocks just stay there in the hospital and so what she did is she went and she collected the blocks she contacted the women to find out who had nothing happened to them which ones had a subsequent DCIS and which ones developed invasive cancer so this is called outcome she had 20 years of outcome data for these individuals and she has over 1,500 right now she's a she's starting to approach a thousand this is such a valuable cohort because usually these tissue samples are thrown away and I think that there's there's information there is information in these tissue samples so Carla had this cohort and she tried all of those markers that I told you about previously the clinical factors the histopathological factors the molecular markers nothing nothing stratified risk so what we decided to do is to take some of the insights that had been gained from studying breast cells in culture and ask can that give us a clue as to who will and who won't in other words separate out this 15 percent from the from the rest of the people okay and so here's where we come back to the story that I've been telling you we know the cells respond to stress and we know that when you compromise this they go on to form tumors so this allowed us to make a hypothesis if you look at the biopsy and you see that the cells have activated these barriers to cancer wouldn't you predict that those people would not go forward and get invasive cancer wouldn't that be a good hypothesis so that hypothesis was tested the idea was that markers indicating the activation of one of these barriers and here we chose senescence the marker to say that that's been turned on is an upregulation of a particular protein called p16 so the hypothesis is that if the biopsy shows the increase in P 16 perhaps these women would not get future cancer because their barrier would be erected and so what we found is that if cells are expressing P 16 and there's no proliferation remember that I said that's the proper response damage stop that means that that would be a good signal but if the cells are experiencing insults but they continue to grow that means that they've broken their mechanism they've bypassed senescence now you're in trouble so can this predict who'll get cancer and who won't the answer was a huge yes okay so the green line up here represents the number of women excuse me it represents this marker expression in the biopsies of the women and you can see that they do not progress to cancer so these biopsies had high P 16 and low proliferation it means they stopped the way they were supposed to very few of these women got cancer look at this marker though these biopsies Express the markers that said that this pathway was broken this is high P 16 plus proliferation and what you can see is that every single one of these women have now developed cancer and furthermore when you ask what type of cancer these women developed it's the most lethal the most metastatic type of cancer it is so what this signal what these markers are identifying is a baby cancer before it actually becomes a malignancy it's identifying which pre malignancies are going to go forward to become a tumor and which ones are not it's separating out the green from the yellow just like we wanted to do this simply says that it that the upregulation of p16 identifies the most lethal type of cancer there is and you can use this same type of an approach to find other markers which is what this is are there additional biological clues that provide marker and so when you start to look at this a little bit more you identify another marker this is a stress marker and again when when it's activated and there's proliferation it's very bad and that's because this marker turns on the blood vessel growth it turns on epithelial proliferation it turns on the movement of cells and it stops the cells from dying so when this gene is turned on it's not a good thing because the kit helps the cancer grow and you can see that when there is high expression of this gene in the presence of proliferation many of the women go forward to form cancer so it's this type of biology layer upon layer that you add together in context and what you can do is put that together and now come up with a signature biopsies that express these markers have less than a 3% chance of forming a future tumor the reason that's so exciting is that any woman sitting here in the audience if you are aren't at you know unusual risk because of family or previous cancer she has a 6% chance of forming a tumor so this actually identifies women that are a very very low risk of getting future cancers this marker these markers on the other hand identify women that have a 98% chance of having a future invasive event so this is this is pretty powerful this allows stratification so now you can tell which women are in that green area and which women are in that yellow area and so if somebody now gets diagnosed with DCIS they can start to choose which options they want in terms of therapy so what I've tried to tell you is that there's biological clues from studying these tissues that provide prognostic markers predictive markers for what DCIS is going to do whether it's simply going to sit there or going forward to invasive disease and it's the response to stress that stratifies the risk for what's going to be happening so that gives us insights into what's happening with sir the implications are that women at high risk of a subsequent invasive disease may want to consider a full mastectomy and systemic treatment whereas women that have the signature that says they have a low probability perhaps they want to watch and wait and see what happens rather than to have a full mastectomy each person is individual each person has their own risk aversion just like with playing the stock market but this gives you more information to make a decision and what it says is that the different types of cancers that we can detect after the tumor forms actually goes earlier it goes to the pre malignancy and it suggests that they are the same flavor as they begin and go forward like this and that so this is a very bad cancer at the basal-like you want to treat it aggressively luminal a is a very innocuous one women can live with luminal a breast cancer for decades and and really not have a problem and so it's really nice to be able to distinguish between the two okay so the pilot study that I was just telling you about was published before that can become a clinical test you want to repeat it in a large study that has been repeated and it reproduced beautifully and then the final cherry on the icing is that you want to do it prospectively in other words you want to do it not in a cohort that was already collected but you want to start collecting now and say I can predict and then demonstrate you can predict and this so this perspective study has just been initiated okay so what I've tried to tell you is that one can go even earlier and that future directions in breast cancer we can perhaps start to assess who's going to be at risk and who's not when they're diagnosed with these pre malignancies and if we understand the biology that's here perhaps we can actually start looking at this with non-invasive imaging and seeing which which pre malignancies glow with the bad markers and which glow with the good markers in other words try and design smart probe for non-invasive imaging so you don't have to go in with a knife before you can make these determinations and it may allow us to identify targets of vulnerability so that we can selectively eliminate these cells and prevent the cancer all together that's the hope so people are trying to go forward and and there's movement forward which is nice these are the people that were involved in some of the work that I told you that in the second half of the talk and it's it takes a whole team of people working together to be able to do this type of research and I'll be happy to answer any questions you have about what I've discussed this evening thank you [Applause] [Music] [Music]

Channel: University of California Television (UCTV)

Views: 93,726

Keywords: cancer, cell function, cancer cell. tumor

Id: QymKG8mXm6g

Length: 59min 34sec (3574 seconds)

Published: Thu Jan 05 2012