Cell Adhesion, Signaling and Cancer
Transcript of Part 1: Adhesion, Signaling and Cancer
00:00:03.10 Hello. My name is Mary Beckerle, and I'm a professor of biology and oncological sciences 00:00:07.27 at Hunstman Cancer Institute and the University of Utah. 00:00:10.23 It's really a pleasure to be with you today, 00:00:13.15 wherever you are, to talk with you about adhesion and signaling, 00:00:18.26 critical cell behaviors that control a variety of important cellular 00:00:26.00 processes, and in particular focus on the role of adhesion and signaling in cancer biology. 00:00:32.11 My presentation is going to be divided into three parts 00:00:36.14 and the first part I am going to provide a very brief introduction to 00:00:40.15 the cancer problem and our appreciation of the mechanisms 00:00:45.19 underlying the development of cancer, with particular emphasis 00:00:48.28 on the role of cell adhesion in tumor development. 00:00:51.26 In the second part I am going to tell you a short story from work in my own laboratory 00:00:57.12 about the discovery of a molecule that is found at sites of adhesion 00:01:00.29 and how we now appreciate that this protein may regulate 00:01:06.03 processes that are important 00:01:07.17 in a particular type of cancer, Ewing's sarcoma. 00:01:10.20 And finally I am going to tell you about 00:01:13.28 some very exciting new results, which implicate 00:01:17.19 specialized zones where cells attach to the extracellular matrix 00:01:22.05 and the ability of cells to sense physical forces. 00:01:25.25 And these physical forces, again, influence cell behavior in really important 00:01:32.23 ways, and we are just at a sort of new frontier in terms of 00:01:36.09 understanding how cells perceive and respond to mechanical cues. 00:01:40.27 So in part one of my talk, I am going to again give you 00:01:45.21 a brief introduction to the cancer problem. 00:01:48.23 I think everybody appreciates what a large problem 00:01:53.00 cancer is from a human health perspective. 00:01:55.04 All of us have been touched by cancer in one way or another, 00:01:57.14 either with someone we know, a family member or a friend, 00:02:01.17 encountering this illness. It is a major 00:02:06.03 global health problem with over 6 million deaths worldwide 00:02:11.29 from cancer on an annual basis. 00:02:14.25 In the United States alone we lose one person to cancer every minute of every day. 00:02:21.07 And there are over 3,800 people diagnosed with cancer each day. 00:02:26.03 You can see from these data that more than 20 million new 00:02:30.11 cancer diagnoses have occurred since 1990, which means 00:02:33.25 that many, many more people are living with this 00:02:36.23 disease. Worldwide it is anticipated that half of all men 00:02:41.26 and a third of all women will get cancer at some time in their lifetimes. 00:02:46.20 So this is clearly a major medical challenge worldwide, 00:02:51.19 and really research is the hope for the future 00:02:54.21 to impact cancer detection, diagnosis, treatment and ultimately prevention. 00:03:01.20 We already know that some cancers can be prevented. 00:03:06.03 Smoking, for example, accounts for at least 30% of all cancers, 00:03:09.22 and in the case of lung cancer, almost 90% of lung cancer deaths 00:03:14.00 can be attributed to smoking. 00:03:16.08 Similarly, excessive sun exposure, including the use of tanning booths, 00:03:21.23 and excessive sun exposure in the absence of sun protection 00:03:26.26 is clearly responsible for many types of skin cancer, including 00:03:30.23 a very lethal form of skin cancer called melanoma. 00:03:34.10 So just by changing our behavior, minimizing or eliminating smoking 00:03:40.27 and minimizing or eliminating exposure to sunlight in the absence of protection, 00:03:48.09 can have a huge impact on the occurrence of these devastating cancers. 00:03:52.27 Similarly we now have a behavioral intervention, a new vaccine against 00:03:57.27 human papilloma virus, which we believe will have a huge impact 00:04:03.18 in reducing mortality due to cervical cancer. 00:04:07.14 So science has already taught us a lot about how to prevent cancers. 00:04:11.23 And it's also taught us that early detection of cancer 00:04:16.06 is really critical. We know that cancer acquires 00:04:20.16 more and more aggressive potential as time goes on. 00:04:24.04 and those more aggressive tumors are much more difficult 00:04:28.27 to treat, often widely disseminated throughout the body. 00:04:31.29 So screening strategies that can detect cancer early 00:04:36.04 before it has begun to spread can have a huge impact on the ultimate outcome. 00:04:40.29 So in many cases, in the case of breast, colon cancer, prostate cancer, 00:04:46.27 melanoma, skin cancer, and others, 00:04:49.12 screening processes are readily available, 00:04:51.18 and a huge human health burden could be readily eliminated 00:04:54.15 by individuals really adhering to screening guidelines 00:05:00.00 and taking advantage of these opportunities 00:05:02.11 to detect cancers very early before they become more lethal. 00:05:07.27 So really what is the base of cancer? How does cancer develop in the first place? 00:05:14.19 Well, we really have appreciated over that past 20 or 30 years that cancer is a cellular 00:05:20.26 disease that results from derangements in control pathways that regulate cell number. 00:05:28.26 Here you can see a nice illustration of how the human body 00:05:33.00 is comprised of functional units called cells, 00:05:37.09 trillions of cells in the body. And these cells are really organized in beautiful 00:05:43.11 patterns when they are grown in culture, and as you'll see, 00:05:46.29 are also very well organized in situ. 00:05:50.19 Here's an example of a section through 00:05:54.12 the stomach where you can really appreciate the highly ordered 00:06:00.06 structure of the tissue, 00:06:02.05 with the individual secretory cells relating to each other 00:06:05.16 with apical and basal aspects, with a nicely organized lumen, 00:06:11.25 with each of these secretory structures looking very similar to each other, 00:06:17.17 really illustrating that cells have information 00:06:21.11 that establish pattern and morphology, and that they are receiving signals 00:06:27.02 and controlling their architecture under normal conditions. 00:06:30.07 Things are very different in the case of tumors. 00:06:34.12 And here you can see a lovely illustration showing 00:06:37.15 the difference between normal mammary gland and a mammary tumor. 00:06:42.06 In the top panel you can see mammary gland with a milk duct 00:06:46.28 and, again, these cells are nicely organized with a lumen here and surrounding 00:06:52.09 stromal tissues, and look what happens in breast carcinoma. 00:06:57.16 We've completely lost the architecture of the tissue. 00:07:01.05 The cell number, if we were to analyze it, would be out of control, 00:07:04.27 but fundamentally the cells have lost their capacity 00:07:08.28 to recognize signals from their surroundings 00:07:12.18 and to acquire this highly ordered, differentiated phenotype. 00:07:18.20 The fundamental thing, the first thing that happens 00:07:23.04 in the establishment of tumors is of course derangement in the control of cell number. 00:07:29.20 And cells begin, as you can see in this diagram, 00:07:33.15 to grow out of control, and that then disturbs the architecture. 00:07:37.23 And this growth, or loss of growth control 00:07:42.16 can happen at a number of different levels illustrated schematically here. 00:07:47.20 And I'll just touch on a couple of them today. 00:07:50.09 You can...tumor cells can acquire an insensitivity to antigrowth signals, 00:07:58.15 to signals that normally constrain their 00:08:01.10 proliferation, and an example of that is the inability to recognize 00:08:06.14 that they're surrounded by other cells. 00:08:08.22 Their inability to really detect or respond 00:08:12.19 appropriately to environmental cues 00:08:15.04 that normally would slow their growth. 00:08:20.16 A second example is that they can become self-sufficient and not require positive growth 00:08:26.24 signals anymore. Normally cells divided only when there are growth factors 00:08:31.11 present that activate signaling pathways 00:08:33.23 that lead to proliferation and cell division. 00:08:36.05 In tumors, many times the cells have lost that need 00:08:42.00 to have exogenous growth signals, 00:08:45.14 and they're sort of constitutively activated for the proliferation pathways. 00:08:49.24 And finally some recent work just in the last 10 to 20 years 00:08:56.03 has revealed that all of the changes in cell number that occur 00:08:59.26 in cancers cannot be attributed just to regulation of proliferation, 00:09:03.22 but rather another very important mechanism 00:09:06.25 by which cell number is controlled is through a process called apoptosis 00:09:11.05 or programmed cell death. 00:09:13.20 And programmed cell death is a process that is used 00:09:17.18 during development, it is used during normal tissue and organ maintenance, and 00:09:23.10 if that process becomes curtailed in some way, cells that should normally die 00:09:29.26 will fail to die, and of course that can also give rise to enhanced cell number. 00:09:34.13 And this is also something that can cause cancer. 00:09:41.06 Fundamentally all of these behaviors of cells, 00:09:43.25 the ability of cells to get signals from their environment 00:09:47.18 the ability of cells to interact and to acquire this highly ordered architecture 00:09:53.24 within tissues is completely dependent on our genetic material, 00:09:58.27 which really controls cell behavior. 00:10:01.25 And here you can see the diagram of a cell 00:10:06.28 or an image of a cell where 00:10:08.08 the red illustrates the cytoskeleton, and here is the nucleus. 00:10:12.24 And the nucleus of course contains all of the genetic material: 23 pairs of chromosomes, 00:10:19.02 which represent or are comprised of the genetic material, 00:10:24.08 DNA, organized into units called genes. 00:10:29.06 And the human genome project has led to an appreciation 00:10:33.16 that humans have about 30,000 protein coding genes, 00:10:37.29 and you can see here that that effort has allowed us 00:10:42.03 to appreciate not only what those genes are 00:10:45.14 and what they encode, but also where they are located on each chromosome. 00:10:49.10 So here are the sex chromosomes, the X and Y chromosomes. 00:10:52.04 And here's a pattern that illustrates the distribution of the genes 00:10:58.12 on those two chromosomes. We now appreciate that it is alteration in genes, the 00:11:05.24 genetic material, that really is responsible for the early changes that lead to cancer. 00:11:10.19 Normal genetic material in a healthy individual leads to control of cell growth and cell death 00:11:20.08 and all of the behaviors of cells that I have described previously. 00:11:25.01 And we now understand that it is lesions in the genetic material, 00:11:29.25 the DNA, and mutations in those genes that alter those important regulatory pathways 00:11:36.16 and lead to excessive cell growth and ultimately to a tumor. 00:11:42.11 Excessive cell growth, or inadequate cell death and then the tumor. 00:11:46.07 These genetic changes can be inherited and passed from 00:11:50.25 parent to child or they can be acquired over time by exposure to chemical carcinogens 00:11:58.12 too much sunlight, etc. We now have a much deeper understanding 00:12:05.12 of some of the basic causes, the basic genetic causes, that give 00:12:10.20 rise to tumors and this understanding has come from a variety of approaches. 00:12:15.11 It has come from trying to recreate a cancer phenotype, looking at cells in culture, 00:12:22.06 and it has also come from direct analysis 00:12:25.28 of patients and their families where there is an inherited sensitivity 00:12:32.00 to the development of cancer. 00:12:33.26 And I'll just give you a couple of examples of this approach 00:12:37.03 and the powerful impact that this new genetic understanding 00:12:41.07 has on our ability to think about creative ways to address this clinical problem. 00:12:46.19 We know as I mentioned that some cancers run in families, 00:12:51.24 you've heard about friends or colleagues perhaps who have a high probability of colon cancer 00:12:58.21 in their family. And although this doesn't happen very frequently we now can 00:13:04.28 actually look at populations of individuals and identify these inherited patterns. 00:13:13.17 These high predisposition to particular types of cancer and one really unique resource 00:13:19.14 that allows us to do this is the Utah population database, 00:13:23.15 which has extensive pedigree information going back many generations 00:13:28.09 and over 20 million records linked to the pedigree information, so 00:13:33.01 we have a very, very clear picture of clinical information linked to the family structures. 00:13:44.16 And with that approach one can identify families for example that have a high probability of 00:13:52.25 developing colon cancer, and then actually search through the DNA provided by individuals 00:14:00.11 in those families for the particular segment of DNA that tracks with the inherited 00:14:07.22 predisposition to colon cancer. And in that type of strategy 00:14:11.24 many human disease genes have been identified, 00:14:15.08 and these include the colon cancer gene, APC, as well as breast cancer genes, 00:14:21.02 BRCA1 and BRCA2, and the melanoma gene, p16. 00:14:25.15 It's actually extremely useful to have this genetic information 00:14:32.12 in terms of developing better strategies for detection, treatment, and ultimately 00:14:38.22 prevention of cancer. Let me just give you an example 00:14:41.05 from colon cancer, which I already mentioned was identified 00:14:46.01 in patients that have a predisposition to this familial form of cancer 00:14:52.15 using this Utah population database. 00:14:54.24 And it was also identified independently in sporadic tumors by other investigators as well. 00:15:02.04 But here you can see the highly organized structure, diagrammatically 00:15:07.15 of normal colon. And really the initiating step in colon cancer is 00:15:12.27 mutation of the APC gene. We know now that this is the cause of these inherited forms 00:15:18.27 of colon cancer, as well as is responsible for the initiation in the vast majority 00:15:23.24 of sporadic colon cancers as well. 00:15:26.28 It's, as I mentioned, over time these initiated cells 00:15:35.07 can develop additional changes, which can lead 00:15:38.25 to the beginnings of uncontrolled growth, and at that stage 00:15:42.07 in a human patient you would have what's called an adenomatous polyp, 00:15:47.08 a small growth of cell material associated with the wall of the 00:15:52.14 colon. But this tumor, this is not yet 00:15:55.10 a cancer, it is an adenoma. It is not invasive, and it is easily removed 00:16:00.00 surgically. Over time, however, you can see that the tumor can progress 00:16:04.12 acquire properties where it can invade and become a carcinoma 00:16:09.10 and with additional mutations even begin to spread or metastasize. 00:16:13.24 And of course at these stages these tumors are much more difficult to 00:16:17.17 treat. They are widely disseminated. They have invaded the wall of the bowel, 00:16:22.09 and this is then very, very challenging from a clinical perspective. 00:16:26.12 So knowing that you, for example, are in a family where colon cancer 00:16:32.05 is prominent and potentially inherited, you can go and have genetic testing, which 00:16:39.23 if you are then a carrier of the disease susceptibility gene, 00:16:43.27 the mutant form of APC, you will be guided 00:16:47.25 to much more robust screening strategies, 00:16:51.16 and that will allow the detection of the developing cancers 00:16:55.15 at this adenomatous polyp stage early enough that it 00:16:58.17 can be removed for a complete cure. 00:17:02.15 So knowing, and being able to screen and identify individuals 00:17:07.06 who are at high risk for colon cancer clearly 00:17:09.24 has an impact on their health, and in addition, 00:17:16.02 knowing that APC is the first...that mutations in APC represent 00:17:20.23 the first step in the development of this disease 00:17:23.00 we can then go back into the laboratory and really try and dissect 00:17:26.25 the pathways that are controlled by APC and use that information potentially to develop 00:17:34.18 therapeutic interventions. 00:17:37.12 And we know now a lot about the function of the APC protein, 00:17:41.05 and one really exciting new development has come 00:17:45.07 from the work of David Jones, which has clearly illustrated 00:17:49.27 that the APC is required for retinoic acid metabolism. 00:17:53.11 And he has been able in some preclinical studies to provide retinoic acid 00:17:58.13 derivatives to whole organisms and reverse the course 00:18:03.08 that would have occurred due to the APC mutation. 00:18:07.18 And so again, knowledge of the fundamental genetic change that occurs in a tumor 00:18:14.08 the initiating change, can allow us to, 1: identify individuals who are at high risk 00:18:19.23 for developing a tumor, and 2: with cellular and molecular analysis 00:18:25.07 of the role of that normal protein product 00:18:30.29 help us to identify strategies that will lead to changes in the outcome for patients. 00:18:40.19 Now another thing that has, I think, really been striking 00:18:43.24 from the genetic analysis of tumors both 00:18:46.19 in a classical genetic sense and also in a molecular genetic sense 00:18:50.07 is that different genes are turned on in different tumors. 00:18:54.18 I think in 1971 when Richard Nixon announced the war on cancer 00:18:58.16 scientists, as well as the public, 00:19:01.04 were very optimistic that we were going to identify a single gene or a handful 00:19:06.08 of genes, or a single cause or a handful of causes 00:19:09.12 for cancer, and that we would then be able to identify some sort of silver bullet 00:19:14.08 that would allow us to eliminate this disease. But we now really appreciate that 00:19:20.07 cancer is hundreds of diseases. It is a much more complex challenge. 00:19:24.23 I have already given you an example of several cancer mutations 00:19:28.16 that can cause different kinds of cancers, 00:19:30.14 and we now have the capacity to actually look at all 30,000 human genes 00:19:36.15 for their expression simultaneously 00:19:38.08 using microarray strategies, and when we do this... in this image here 00:19:44.12 we are looking at 1,800 genes running from the top to the bottom 00:19:48.01 of this panel and 140 or so different types of tumors running from left to right. 00:19:54.24 And what you can see when you analyze this 00:19:58.02 with the green genes being... green spots 00:20:00.16 representing genes that are turned off 00:20:03.09 and the red spots representing genes that are turned on, 00:20:06.06 is that these patterns of gene expression actually segregate into groups. 00:20:12.12 And many times you can see that, for example here, 00:20:14.26 all of these prostate cancer samples have very, very similar patterns 00:20:20.24 of expression and that...but on the other hand, 00:20:25.08 if you look down here in breast cancers you can see that 00:20:28.21 even though these in the box here are all breast cancers, genes expressed in breast cancers, 00:20:34.16 you can see that they are not all green and they are not all red, 00:20:37.10 illustrating that there is a great deal of heterogeneity even within a particular type of tumor. 00:20:43.10 And this is really one of the major challenges 00:20:46.27 I think for cancer biologists and clinical care providers 00:20:50.28 that we are facing currently. It is very 00:20:53.17 common for two women with breast cancer to have the same diagnosis, 00:20:57.16 the same treatment, and 00:20:59.04 have very, very different outcomes. 00:21:00.29 One person may succumb to their cancer 00:21:02.21 within a few months, another may live for ten years, 00:21:06.02 and we really now can appreciate 00:21:09.08 because of this kind of detailed molecular understanding 00:21:12.02 molecular fingerprinting analysis, that we really need 00:21:16.04 to have a more high resolution view of the tumor itself, 00:21:20.27 in order to define the most appropriate treatment for that tumor. 00:21:25.26 So I think a really major revolution in our thinking 00:21:30.28 about cancer biology is this appreciation of 00:21:35.03 the diversity both of tumor populations and of patient populations and this has 00:21:41.28 really come specifically through advances in genetics, 00:21:46.04 molecular genetics, and the approaches that I have described today. 00:21:50.05 We used to think that all tumors were the same 00:21:53.00 and a tumor in any individual context was the same, we now 00:21:57.16 appreciate that there are many, many 00:21:59.11 differences in tumors, even tumors of the same tissue type, 00:22:04.20 can be extremely different in terms of their properties, 00:22:09.00 and therefore extremely different in terms of their responses to therapeutic intervention. 00:22:12.27 And we also appreciate that the tumors within the context of an individual 00:22:19.00 the same, even the same type of tumor within the context of a 00:22:21.29 different individual can be very different as well. 00:22:24.25 And we've had a presentation in this series from 00:22:29.23 Brian Druker which addresses that exact issue. 00:22:33.20 So, I think that again this revolution in molecular genetics that we've seen 00:22:43.14 occurring just very recently really gives us 00:22:46.28 increased genetic understanding of the causation of cancer, 00:22:50.07 makes us appreciate how diverse the mechanisms are that can cause cancer, 00:22:56.21 but gives us a lot of hope that with that information 00:23:00.12 we can be empowered to use new strategies to address this really major health issue. 00:23:07.11 We can, as I've described, begin to 00:23:11.03 identify individuals who are at high risk for developing certain types of cancers 00:23:16.00 particularly in the inherited forms of cancers, 00:23:18.24 but maybe over time the sporadic ones as well, and then with that predictive power 00:23:25.24 develop guidelines for more aggressive screening and early detection. 00:23:30.26 And then the goal would be of course to then prevent those tumors from ever 00:23:34.20 developing or at least screen and catch them early before 00:23:38.15 they are very dangerous. 00:23:39.09 And really this all leads to this view of a more personalized approach 00:23:44.00 both in terms of identifying individuals at risk, as well as, 00:23:48.24 using molecular strategies for high resolution diagnosis of tumors, so that 00:23:54.22 the tumors can be matched in a very rigorous and appropriate way 00:23:59.09 to therapeutic intervention. 00:24:02.12 and moreover, that the individual themselves can be identified 00:24:10.06 for individuals that may be at risk for adverse events 00:24:15.09 from various chemotherapeutic interventions, etc. 00:24:18.25 So I think we are moving into a new era 00:24:22.04 in cancer biology that has great promise for the future. 00:24:27.12 We do have to face the fact that this is a very complex situation, and that 00:24:34.15 the processes of control of cell growth and cell death 00:24:38.17 are regulated by many, many biochemical pathways. 00:24:42.05 This diagram illustrates just some of the pathways 00:24:45.29 that are involved in controlling the circuits that regulate cell growth 00:24:51.17 and cell death and can contribute to cancer. 00:24:53.22 All of the proteins marked in red here, 00:24:56.17 here is APC, here, over here is p16 that I told you was responsible for melanoma, 00:25:03.06 and you can see that all of the elements that are marked in red 00:25:07.19 have already been identified as having a role in cancer development. 00:25:11.19 And so there are many, many ways that cancer can develop, 00:25:13.23 and therefore there are going to have to be many, many ways 00:25:15.28 to try to tackle the individual cases of cancer. 00:25:21.15 The first human oncogene that was identified is the Ras protein, 00:25:28.27 and this was identified in a screen for 00:25:33.08 cDNAs that could cause cellular transformation in a cell-based assay. 00:25:38.17 And it was very, very striking at the time that 00:25:42.25 this gene...a single amino acid change in the Ras... 00:25:47.17 that gave rise to a single amino acid change in the Ras protein 00:25:51.00 could be responsible for the establishment of bladder carcinoma. 00:25:55.02 And we now have a very deep appreciation of exactly what pathways are 00:26:01.17 regulated by Ras. So here you can see the Ras protein is part of a critical signaling pathway 00:26:11.17 that starts with growth factor exposure and ends with regulation of cell cycle control. 00:26:20.22 And we now understand that manipulation of this pathway, 00:26:26.06 either by direct mutation of the gene that encodes Ras, 00:26:29.13 or also of any of the components in this pathway 00:26:33.24 can lead to tumors. 00:26:37.08 So for example in glioblastomas, we have an increase in the growth factor PDGF, 00:26:48.03 which seems to play a really important role in the development of that type of tumor. 00:26:52.19 Similarly, an increase in TGF alpha expression is prominent in certain sarcomas. 00:26:59.25 So you can see that you can control the activity of 00:27:03.12 this pathway at the level of production of growth factors. 00:27:07.08 In addition tumors may have altered growth factor receptor profiles or activities 00:27:13.18 that are responsible for the development of a particular tumor type. 00:27:20.01 One really common example is the EGF receptor, 00:27:23.13 which can either be upregulated by activating mutations 00:27:27.26 or upregulated by increased copy number, 00:27:31.12 and this is another way to, of course, activate this critical pathway which controls 00:27:38.00 cell growth and confer to cells self-sufficiency with respect to growth 00:27:42.08 signals. We've already discussed the activation of Ras itself. 00:27:47.20 Activating mutations in Ras can turn this 00:27:50.22 pathway on, out of control, and lead to uncontrolled cell proliferation. 00:27:56.18 And interestingly there are also other co-factors that can 00:28:01.18 be altered to give rise to uncontrolled growth 00:28:06.11 and uncontrolled activation of this pathway. 00:28:08.07 And one example of this is the integrins which are receptors for the extracellular matrix. 00:28:14.29 These integrins are transmembrane heterodimeric cell surface receptors, 00:28:20.14 and they were identified initially in an antibody 00:28:23.19 screen in which investigators were looking for 00:28:28.07 monoclonal antibodies that when applied to cells would 00:28:31.20 cause them to lose their ability to attach to extracellular matrix. 00:28:35.23 And those antibodies ultimately allowed the identification 00:28:40.03 of this very important family of cell surface proteins. 00:28:46.08 These integrins are critical for adhesion to extracellular matrix, 00:28:51.02 as well as transmembrane signaling, and they are concentrated 00:28:54.12 in cells at specific zones called focal adhesions, 00:28:58.17 which are specialized areas of the plasma membrane 00:29:01.23 that are important for adhesion to extracellular matrix. 00:29:08.27 You can see an example of one of these focal adhesions by electron microscopy 00:29:15.05 in this image and what we appreciate is that these areas 00:29:20.13 actually of enriched, enriched in integrins 00:29:24.09 where the cells attach to the extracellular matrix 00:29:26.11 are areas where the extracellular environment 00:29:29.08 is really aligned and integrated with the 00:29:33.00 intracellular environment, in particular the cytoskeleton. 00:29:36.02 So these receptors actually form a link between the extracellular matrix and 00:29:41.00 the cytoskeleton, and there are a variety of proteins that are present 00:29:46.04 clustered with the integrins at these sites which facilitate the linkage 00:29:50.04 of the integrins on the membrane to the actin cytoskeleton. 00:29:53.22 And although I don't have time to discuss this now, 00:29:55.29 this linkage is actually quite critical for the function 00:29:59.15 of the integrins both in terms of adhesion as well as in terms of signaling. 00:30:05.10 So we now know from studies of integrins 00:30:09.05 that these are signaling receptors not passive 00:30:12.13 adhesion receptors, but really active 00:30:15.29 classical receptors that respond to extracellular cues 00:30:19.18 and transmit information bi-directionally across the 00:30:22.28 plasma membrane to regulate both the ability of the cells to 00:30:26.24 adhere as well as their ability to migrate, which is, of course, critical for metastasis 00:30:33.27 in tumors, as well as to proliferate and to survive. 00:30:38.15 So why would these adhesion receptors have an impact on cell growth? 00:30:45.25 We have talked about the fact that growth factors are a critical signal 00:30:50.04 that regulates cell proliferation, particularly via the Ras signaling pathway. 00:30:54.22 And why would these cell adhesion receptors have an impact on cell growth? 00:31:00.17 Well, it turns out that integrin dependent adhesion 00:31:04.03 is actually required for a normal growth factor response. 00:31:07.25 And this became evident in a really lovely experiment 00:31:10.28 from Martin Schwartz's lab in the late 1990s where he 00:31:15.02 looked at the response of cells to exposure to growth factor. 00:31:20.18 And he could follow this by looking at the activation of one of the MAP kinases 00:31:27.07 in the signaling pathway, and here you can see 00:31:31.09 lots of activated ERK signaling, and over here, not very much. 00:31:38.29 And what he did was to take cells either in suspension or 00:31:43.14 attached and expose them to growth factor, and what you can see down here is that 00:31:48.10 the cells exposed to growth factor that were attached 00:31:53.07 launched a really robust signaling response, 00:31:57.08 activation of this MAP kinase signaling pathway, 00:32:00.10 whereas the same cells devoid of integrin engagement 00:32:05.22 and held in suspension, when they were exposed to growth factor 00:32:10.23 a very, very minimal signaling response 00:32:13.25 occurred. So this was really one of the first indications that 00:32:17.10 it's not as simple as a growth factor receptor on the surface of a cell, 00:32:22.00 that in fact there is a lot of cross talk and cells are monitoring also 00:32:25.23 whether they have integrins engaged and whether they are attached 00:32:28.29 in order to divide. And we now know that the integrins 00:32:32.28 actually talk to this canonical growth factor signaling pathway 00:32:37.02 at a number of different levels to regulate 00:32:41.02 its activity. They can be directly linked to the growth factor receptor. 00:32:46.20 They can regulate some of the MAP kinases, 00:32:50.13 and they can even act at the end of this pathway to control 00:32:53.26 whether one of the final activating proteins in the pathway can get 00:33:00.11 into the nucleus efficiently to act to regulate cell proliferation. 00:33:05.02 So again, this was a very exciting observation that integrins 00:33:10.01 are really critical for growth factor signaling and play 00:33:13.23 a role in controlling cell growth, 00:33:16.12 and then of course, led to the idea that perhaps if we could control 00:33:20.29 the integrins and their signaling behavior, we might be able to control 00:33:26.12 cell growth. And since these molecules are on the cell surface 00:33:29.08 they are easily accessible to agents that 00:33:32.22 can be provided on the outside of cells, 00:33:36.14 which makes them a good potential therapeutic target. 00:33:40.12 And so here is a preclinical study in which anti-integrin antibodies 00:33:45.28 were used to explore the impact on proliferation of ovarian tumor cells. 00:33:51.26 And here you can see in the open bar, 00:33:55.16 we are looking at ovarian tumor cells with a control antibody, 00:33:59.29 and that has no effect on growth, and the cells 00:34:02.04 continue to grow even at high antibody concentrations. 00:34:05.09 However, with the filled bar you can see 00:34:09.09 that as you increase the amount of anti-integrin specific antibody, the proliferation 00:34:16.18 of these ovarian tumor cells in culture diminishes 00:34:20.14 really dramatically. So this has given a lot of hope to the idea that 00:34:24.19 one might be able to control tumor cell growth 00:34:29.04 by manipulating integrin either directly, 00:34:33.29 or manipulating some of its downstream effectors, 00:34:37.26 which we now know are quite complex. 00:34:40.28 But I think that there's a lot of promise here, and we already have now 00:34:45.07 several integrin inhibitors in clinical trials, both antibodies as well as small peptides 00:34:52.23 for a variety of cancer applications. 00:34:55.27 So I am going to just briefly summarize then this broad introduction, 00:35:02.09 which I hope I have convinced you that cancer is a 00:35:05.16 genetic disease. That it is a quite complex disease where many genes 00:35:10.07 can be mutated to give rise to cancer because there are 00:35:12.29 so many pathways, so many critical cellular biochemical pathways that 00:35:17.20 control cell growth and cell death. 00:35:20.27 And among those, somewhat surprisingly, are the pathways 00:35:26.15 that are involved in cell adhesion. And really 00:35:30.06 I think that we are now at an inflection point in our 00:35:34.02 ability to utilize the wealth of information we have 00:35:38.22 about human genetics, cellular pathways, to have an impact 00:35:42.22 on the establishment of new therapies 00:35:45.23 that can ultimately impact human health by 00:35:48.25 affecting cancer development or establishment 00:35:55.13 or progression. Thank you.