1 00:00:00,000 --> 00:00:05,000 The following content is provided by MIT OpenCourseWare under a creative 2 00:00:05,000 --> 00:00:11,000 commons license. Additional information about our 3 00:00:11,000 --> 00:00:17,000 license and MIT OpenCourseWare in general is available at OCW. 4 00:00:17,000 --> 00:00:23,000 IT.edu. Cancer is a disease that really needs no introduction. 5 00:00:23,000 --> 00:00:29,000 It's a very familiar disease. It's a very common disease. 6 00:00:29,000 --> 00:00:47,000 The American Cancer Society predicts 7 00:00:47,000 --> 00:00:51,000 that there will be 1. million new cases of cancer in this 8 00:00:51,000 --> 00:00:55,000 country, and that excludes the common forms of skin cancer, 9 00:00:55,000 --> 00:01:00,000 squamous cell cancer, and basal cell cancer. 10 00:01:00,000 --> 00:01:08,000 There's about another million of those. So, 1. 11 00:01:08,000 --> 00:01:16,000 non-cutaneous skin cancers in the US this year. Both wide numbers are 12 00:01:16,000 --> 00:01:24,000 probably 10 to 15 times as many. In 2006, more than 550,000 people 13 00:01:24,000 --> 00:01:37,000 in the US -- 14 00:01:37,000 --> 00:01:40,000 More than 550, 00 people in the US will die from 15 00:01:40,000 --> 00:01:50,000 this disease --= 16 00:01:50,000 --> 00:01:54,000 -- more than 1, 00 each day. So, 17 00:01:54,000 --> 00:01:58,000 in today's, cancer takes as many lives as died in the World Trade 18 00:01:58,000 --> 00:02:03,000 Center tragedy. It's a very common disease. 19 00:02:03,000 --> 00:02:09,000 It's estimated that in their lifetimes, one half of all males -- 20 00:02:09,000 --> 00:02:18,000 -- and a third of females will be 21 00:02:18,000 --> 00:02:22,000 diagnosed with cancer of one sort or another. So the likelihood is that 22 00:02:22,000 --> 00:02:26,000 the person sitting next to you, or you yourself will be faced with a 23 00:02:26,000 --> 00:02:30,000 diagnosis of cancer in your lifetime. 24 00:02:30,000 --> 00:02:44,000 And in this country, 25 00:02:44,000 --> 00:02:48,000 a quarter of all deaths are due to cancer. Soon, 26 00:02:48,000 --> 00:02:52,000 probably this year, cancer will be the leading cause of 27 00:02:52,000 --> 00:02:56,000 death in the United States. It will surpass heart disease as 28 00:02:56,000 --> 00:03:00,000 the number one killer. So, it's a major disease. 29 00:03:00,000 --> 00:03:03,000 And that sounds depressing. But by the end of this section on 30 00:03:03,000 --> 00:03:07,000 cancer, my hope is that you will actually feel optimistic about our 31 00:03:07,000 --> 00:03:11,000 prospects for dealing with the disease more effectively in the 32 00:03:11,000 --> 00:03:15,000 future, and I don't mean in the distant future. 33 00:03:15,000 --> 00:03:18,000 I actually think that within the next several years, 34 00:03:18,000 --> 00:03:22,000 we'll have new methods, new agents to control cancer much, 35 00:03:22,000 --> 00:03:26,000 much more effectively. We are already starting to see the first 36 00:03:26,000 --> 00:03:30,000 examples of these. And I'll tell you about them. 37 00:03:30,000 --> 00:03:34,000 And before long, we will have many more. 38 00:03:34,000 --> 00:03:38,000 So hopefully by the time you guys are at the age where cancer is the 39 00:03:38,000 --> 00:03:42,000 greatest risk, these numbers will actually change 40 00:03:42,000 --> 00:03:47,000 dramatically. OK, so although cancer is familiar based 41 00:03:47,000 --> 00:03:51,000 on its prevalence, it may not be so familiar. 42 00:03:51,000 --> 00:03:55,000 And I hope that is not so familiar in detail. So, 43 00:03:55,000 --> 00:03:59,000 I thought I would show you a couple of slides which really give you a 44 00:03:59,000 --> 00:04:04,000 picture of the disease. Lung cancer is a common type of 45 00:04:04,000 --> 00:04:08,000 cancer. We'll talk about it today. And it's diagnosed like many 46 00:04:08,000 --> 00:04:13,000 cancers are diagnosed through radiological methods, 47 00:04:13,000 --> 00:04:17,000 through imaging, in this case a chest x-ray or computed tomography, 48 00:04:17,000 --> 00:04:22,000 which is a serial chest x-ray basically. And 49 00:04:22,000 --> 00:04:26,000 you can see this mass in the lung. This is lung cancer at a fairly 50 00:04:26,000 --> 00:04:31,000 advanced stage. Cancer is a disease of too many 51 00:04:31,000 --> 00:04:35,000 cells. They often grow together in a mass, a lump, 52 00:04:35,000 --> 00:04:40,000 and so this is an example of cancer diagnosis, a solid tumor. 53 00:04:40,000 --> 00:04:43,000 You can also have cancers of the blood, leukemias, 54 00:04:43,000 --> 00:04:47,000 as well as blood cell lymphomas. And here, you can, again, see an 55 00:04:47,000 --> 00:04:51,000 overabundance of cells. Here's a normal blood smear with 56 00:04:51,000 --> 00:04:54,000 red blood cells, these smaller guys which have no 57 00:04:54,000 --> 00:04:58,000 nuclei, and some white blood cells which are larger and do have nuclei. 58 00:04:58,000 --> 00:05:02,000 And here, you can see a blood smear of a leukemia patient where there 59 00:05:02,000 --> 00:05:06,000 are way too many white blood cells, nucleated cells, and they also 60 00:05:06,000 --> 00:05:10,000 happen to look a little immature. They have been differentiated into 61 00:05:10,000 --> 00:05:14,000 their fully developed state. Too many cells, in this case, 62 00:05:14,000 --> 00:05:19,000 not in a lump but dispersed throughout the blood. 63 00:05:19,000 --> 00:05:23,000 And leukemias, and some lymphomas, are diagnosed by doing a blood test 64 00:05:23,000 --> 00:05:28,000 of this sort. Other cancers are detected through other imaging 65 00:05:28,000 --> 00:05:33,000 techniques like colonoscopy as shown here. 66 00:05:33,000 --> 00:05:36,000 Colonoscopies are now fairly common. They are recommended for all people 67 00:05:36,000 --> 00:05:40,000 beyond the age of 50 because colon tumors are actually rather common. 68 00:05:40,000 --> 00:05:44,000 And if they are caught early enough, there relatively easily treated. 69 00:05:44,000 --> 00:05:48,000 And here's the normal colon viewed from the inside. 70 00:05:48,000 --> 00:05:52,000 And here's an early colon tumor called a polyp. 71 00:05:52,000 --> 00:05:56,000 And I'll give you a little more nomenclature in a minute. 72 00:05:56,000 --> 00:06:00,000 But this is an early stage tumor, probably not a malignant tumor. 73 00:06:00,000 --> 00:06:03,000 If you saw this tumor, you might not actually remove it 74 00:06:03,000 --> 00:06:06,000 because it might not progress to a full-scale cancer. 75 00:06:06,000 --> 00:06:09,000 But these days, because they're pretty easy to remove using very 76 00:06:09,000 --> 00:06:12,000 similar methods as this gentleman here with the colonoscopy, 77 00:06:12,000 --> 00:06:15,000 one would clip them out, and not risk the possibility that 78 00:06:15,000 --> 00:06:18,000 they could progress. If they do progress, 79 00:06:18,000 --> 00:06:21,000 they get larger. And more importantly, they begin to invade 80 00:06:21,000 --> 00:06:25,000 through the wall of the colon. And this is very dangerous because 81 00:06:25,000 --> 00:06:28,000 now the cancer cells can spread throughout the body, 82 00:06:28,000 --> 00:06:31,000 taking up residence elsewhere and causing even greater problems 83 00:06:31,000 --> 00:06:35,000 for the patient. So, this would require surgery. 84 00:06:35,000 --> 00:06:39,000 A section of the colon would be removed as is shown here. 85 00:06:39,000 --> 00:06:43,000 This is a section of colon where the colon cancer is highlighted by 86 00:06:43,000 --> 00:06:47,000 this circle. And this is a life sparing surgery. 87 00:06:47,000 --> 00:06:51,000 Individuals can live just fine. So if colon cancer is caught even 88 00:06:51,000 --> 00:06:55,000 at this stage, an advanced stage, 89 00:06:55,000 --> 00:06:59,000 but before it has spread to other parts of the body, 90 00:06:59,000 --> 00:07:04,000 it's relatively treatable, even curable by surgical methods. 91 00:07:04,000 --> 00:07:08,000 Now, this set of pictures gives you a sense that cancers progress. 92 00:07:08,000 --> 00:07:13,000 They progress from early-stage, relatively normal looking tissue 93 00:07:13,000 --> 00:07:17,000 through much more advanced cancers, including to the point of metastasis. 94 00:07:17,000 --> 00:07:22,000 And we are beginning to understand this process in some detail both in 95 00:07:22,000 --> 00:07:27,000 terms of what the cells look like, the tissues look like, but also what 96 00:07:27,000 --> 00:07:32,000 the genes look like that are driving these processes forward. 97 00:07:32,000 --> 00:07:35,000 And I'm now going to give you some examples, or introduce the concept, 98 00:07:35,000 --> 00:07:38,000 that cancer progression from normalcy to malignancy is associated 99 00:07:38,000 --> 00:07:42,000 with changes in genes. That's really going to be a major 100 00:07:42,000 --> 00:07:45,000 theme of today and in the following lectures. But 101 00:07:45,000 --> 00:07:49,000 histologically, the process looks like this in cartoon form. 102 00:07:49,000 --> 00:07:52,000 One starts with a normal looking tissue. All of your cells are 103 00:07:52,000 --> 00:07:56,000 organized in one way or another in tissues, where they have important 104 00:07:56,000 --> 00:07:59,000 interactions with their neighboring cells: so here, 105 00:07:59,000 --> 00:08:03,000 a series of, say, epithelial cells. 106 00:08:03,000 --> 00:08:06,000 Maybe these are the cells that line your gut. They are in normal 107 00:08:06,000 --> 00:08:10,000 juxtaposition with their neighbors. They are sitting atop what's called 108 00:08:10,000 --> 00:08:13,000 a basement membrane, proteins that are secreted by those 109 00:08:13,000 --> 00:08:17,000 cells and other cells to give the cell something literally to sit on 110 00:08:17,000 --> 00:08:21,000 it, attach to. And then there are other cells in 111 00:08:21,000 --> 00:08:24,000 their vicinity including the cells that give rise to these cells, 112 00:08:24,000 --> 00:08:28,000 the stem cells or precursor cells, of the tissue that will be called on 113 00:08:28,000 --> 00:08:32,000 to differentiate into these end stage cells when these cells are 114 00:08:32,000 --> 00:08:36,000 lost, sloughed off. At some frequency in all of us, 115 00:08:36,000 --> 00:08:40,000 alterations occur in these cells such that an abnormal cell arises. 116 00:08:40,000 --> 00:08:45,000 This is a cell which has acquired a change. I'll tell you now that it's 117 00:08:45,000 --> 00:08:50,000 a genetic change which allows that cell to do things that its neighbors 118 00:08:50,000 --> 00:08:54,000 can't do. And in particular, it allows those cells to grow, 119 00:08:54,000 --> 00:08:59,000 to divide inappropriately. Your tissues are very carefully 120 00:08:59,000 --> 00:09:04,000 orchestrated systems with the appropriate numbers of cells. 121 00:09:04,000 --> 00:09:08,000 And cancer is fundamentally a disease of too many cells. 122 00:09:08,000 --> 00:09:13,000 And so one of the first things to go wrong in the cancer development 123 00:09:13,000 --> 00:09:17,000 process is this orderly cell division is disrupted such that now, 124 00:09:17,000 --> 00:09:22,000 too many cells are produced. And this results in a phenomena known as 125 00:09:22,000 --> 00:09:27,000 hyperplasia, hyperplasia meaning too many cells. 126 00:09:27,000 --> 00:09:31,000 But importantly these cells look pretty normal. 127 00:09:31,000 --> 00:09:35,000 So to the pathologist, and I'll show you some pathology 128 00:09:35,000 --> 00:09:39,000 slides in a second, to the pathologist, they would say 129 00:09:39,000 --> 00:09:43,000 the abnormal cells in number have a normal morphology. 130 00:09:43,000 --> 00:09:47,000 Their shape looks right. Their internal structures look 131 00:09:47,000 --> 00:09:51,000 right. Their nuclei look right. This process can continue, and 132 00:09:51,000 --> 00:09:55,000 probably often does continue until there is a discernible mass at least 133 00:09:55,000 --> 00:10:00,000 when it comes to solid tumors, a discernible mass. 134 00:10:00,000 --> 00:10:03,000 And here we refer to this as an adenoma. And I'll show you these 135 00:10:03,000 --> 00:10:06,000 terms again in a minute on the board, in this case, an adenoma, 136 00:10:06,000 --> 00:10:10,000 a benign tumor. And you heard that were before, benign, 137 00:10:10,000 --> 00:10:13,000 as opposed to malignant. And a benign tumor is a tumor in 138 00:10:13,000 --> 00:10:17,000 the sense that there are too many cells. So it's a mass. 139 00:10:17,000 --> 00:10:20,000 But the cells look pretty normal. In a benign tumor, it's not 140 00:10:20,000 --> 00:10:24,000 considered to be life-threatening. The cells have not undergone 141 00:10:24,000 --> 00:10:27,000 sufficient changes that we know for sure that they're going to, 142 00:10:27,000 --> 00:10:31,000 for example, invade and spread throughout the body. 143 00:10:31,000 --> 00:10:35,000 And oftentimes, benign tumors are left alone because 144 00:10:35,000 --> 00:10:39,000 they don't have the potential to spread or to become more aggressive. 145 00:10:39,000 --> 00:10:44,000 But some of them do. And through additional changes within the cells, 146 00:10:44,000 --> 00:10:48,000 additional alterations take place such that now the cells really do 147 00:10:48,000 --> 00:10:53,000 look different from the neighbors. Their structures look different. 148 00:10:53,000 --> 00:10:57,000 Their overall shape looks different. Their nuclei look different. Their 149 00:10:57,000 --> 00:11:02,000 interactions with the neighboring cells look different. 150 00:11:02,000 --> 00:11:06,000 And the structure of the tissue changes as well in the sense that 151 00:11:06,000 --> 00:11:11,000 now, new blood vessels have been recruited into this mass, 152 00:11:11,000 --> 00:11:15,000 which was important actually in feeding this growing tumor. 153 00:11:15,000 --> 00:11:20,000 This is true cancer. It's called in C2 cancer because it's present 154 00:11:20,000 --> 00:11:24,000 at the original site where the process started in C2 cancer. 155 00:11:24,000 --> 00:11:29,000 And it's called cancer based on these various characteristics: how 156 00:11:29,000 --> 00:11:33,000 much the cells are growing, dividing, and also what the cells 157 00:11:33,000 --> 00:11:38,000 look like, their shape and their nuclear shape. 158 00:11:38,000 --> 00:11:41,000 That's a problem. But it's a bigger problem because 159 00:11:41,000 --> 00:11:45,000 it facilitates and usually leads to the development of these tumors into 160 00:11:45,000 --> 00:11:49,000 an invasive state. So now, the cells are no longer 161 00:11:49,000 --> 00:11:53,000 staying where they started. They are starting to move out into 162 00:11:53,000 --> 00:11:57,000 the surrounding tissue. They break down, degrade the 163 00:11:57,000 --> 00:12:01,000 extracellular matrix, and actually start to migrate away 164 00:12:01,000 --> 00:12:05,000 from the primary tumor into the surrounding tissue, 165 00:12:05,000 --> 00:12:09,000 into the surrounding musculature, and ultimately into the blood 166 00:12:09,000 --> 00:12:13,000 vessels. It can move into the blood vessels. 167 00:12:13,000 --> 00:12:17,000 And once there, they can move throughout the body, 168 00:12:17,000 --> 00:12:21,000 and escape the blood vessels, and take up residence elsewhere in a 169 00:12:21,000 --> 00:12:25,000 process known as metastasis. This process happens at some 170 00:12:25,000 --> 00:12:29,000 frequency once started. If it reaches this point, 171 00:12:29,000 --> 00:12:33,000 it's a very bad situation. Most cancers that kill people, 172 00:12:33,000 --> 00:12:38,000 kill people because of this process of metastasis. 173 00:12:38,000 --> 00:12:42,000 90% of cancer deaths are attributable to metastasis. 174 00:12:42,000 --> 00:12:46,000 And although we know many of the things that happened over the course 175 00:12:46,000 --> 00:12:50,000 of these earlier stages, we actually know this process 176 00:12:50,000 --> 00:12:54,000 relatively less well. And obviously, we need to 177 00:12:54,000 --> 00:12:58,000 understand it better if we are going to control mortalities 178 00:12:58,000 --> 00:13:01,000 due to cancer. This shows you some histology. 179 00:13:01,000 --> 00:13:05,000 These are slices through tumors and other tissue that a pathologist 180 00:13:05,000 --> 00:13:09,000 would look at, and kind of emphasizes the points 181 00:13:09,000 --> 00:13:13,000 that I was making on an earlier slide in cartoon form. 182 00:13:13,000 --> 00:13:16,000 So, here you have a lung. And in it is some abnormal cells in 183 00:13:16,000 --> 00:13:20,000 the red circle here. There are too many cells compared 184 00:13:20,000 --> 00:13:24,000 to the surrounding tissue. You can see them in this kind of 185 00:13:24,000 --> 00:13:28,000 dark blue depiction. And you'll see it easier on your 186 00:13:28,000 --> 00:13:31,000 computer screens later. But again, these cells look 187 00:13:31,000 --> 00:13:35,000 relatively normal. There are just too many of them. 188 00:13:35,000 --> 00:13:39,000 So we call this hyperplasia. These can progress into small and benign 189 00:13:39,000 --> 00:13:42,000 tumors called, in this case, adenomas. 190 00:13:42,000 --> 00:13:46,000 And you can see on the histology that they are rather homogeneous in 191 00:13:46,000 --> 00:13:50,000 their structure. The cytoplasm looks pretty much the 192 00:13:50,000 --> 00:13:53,000 same. Cell to cell, the nuclei look pretty much the same 193 00:13:53,000 --> 00:13:57,000 cell to cell. And they actually look pretty similar to the normal 194 00:13:57,000 --> 00:14:01,000 cells that surround them. So this is not true cancer. 195 00:14:01,000 --> 00:14:04,000 This is a benign tumor. But it can progress to a true 196 00:14:04,000 --> 00:14:07,000 cancer, adenocarcinomas. And you can see from the high 197 00:14:07,000 --> 00:14:11,000 magnification view that this looks very different from this. 198 00:14:11,000 --> 00:14:14,000 The cells don't look the same one to the other, and their nuclei don't 199 00:14:14,000 --> 00:14:18,000 look the same either. And what you can't appreciate is 200 00:14:18,000 --> 00:14:21,000 that these cells are also dividing at a much greater rate compared to 201 00:14:21,000 --> 00:14:24,000 these cells. And so, this is true cancer. And this has 202 00:14:24,000 --> 00:14:28,000 the potential, then, to spread to metastatic 203 00:14:28,000 --> 00:14:32,000 disease. OK, so I've given you, 204 00:14:32,000 --> 00:14:37,000 there, all bunch of terminology. Let me tell you a bit more about it. 205 00:14:37,000 --> 00:14:52,000 Hyperplasia: too many cells. 206 00:14:52,000 --> 00:14:56,000 That's all it means. Hyper: too many. Plasia: growth, 207 00:14:56,000 --> 00:15:03,000 too much growth. 208 00:15:03,000 --> 00:15:11,000 Hyperplasias can result in benign tumors, which are non-aggressive -- 209 00:15:11,000 --> 00:15:17,000 -- nondestructive -- 210 00:15:17,000 --> 00:15:23,000 And they, at this moment at least, 211 00:15:23,000 --> 00:15:28,000 have not spread to nearby tissue, non-aggressive meaning that the 212 00:15:28,000 --> 00:15:34,000 cells look pretty normal. They don't look different from 213 00:15:34,000 --> 00:15:43,000 their normal neighbors. 214 00:15:43,000 --> 00:15:48,000 These can give rise to malignant tumors. And the word cancer is 215 00:15:48,000 --> 00:15:54,000 actually reserved for malignant tumors. If you have a tumor that's 216 00:15:54,000 --> 00:15:59,000 benign, you don't have cancer. Cancer refers to malignant tumors. 217 00:15:59,000 --> 00:16:05,000 And these are different in the sense that they are aggressive. 218 00:16:05,000 --> 00:16:08,000 The cells are much more active. They've changed their shape. 219 00:16:08,000 --> 00:16:15,000 They've changed their structures. 220 00:16:15,000 --> 00:16:18,000 They are destructive, that is, they secrete factors into 221 00:16:18,000 --> 00:16:22,000 the environment, which break down, 222 00:16:22,000 --> 00:16:29,000 for example, extracellular matrix. 223 00:16:29,000 --> 00:16:34,000 And they have the potential to spread. They've begun to invade 224 00:16:34,000 --> 00:16:39,000 into the local environment, and can't access the blood supply. 225 00:16:39,000 --> 00:16:44,000 OK, there are cancers in many of your organs in many different cell 226 00:16:44,000 --> 00:16:49,000 types within those organs. In the cancers in different places 227 00:16:49,000 --> 00:16:54,000 in your body are referred to by different terms. 228 00:16:54,000 --> 00:17:01,000 For epithelial tissues, 229 00:17:01,000 --> 00:17:09,000 skin, intestines, breast, brain, lung, epithelial tissues, 230 00:17:09,000 --> 00:17:18,000 we call the tumors carcinomas. 231 00:17:18,000 --> 00:17:23,000 Carcinomas, and depending on the particular cells that are affected, 232 00:17:23,000 --> 00:17:29,000 whether they are glandular cells or secretory cells, 233 00:17:29,000 --> 00:17:35,000 we can give them additional names, for example, an adenocarcinoma. 234 00:17:35,000 --> 00:17:40,000 And that's a cancer that looks like the glands that give rise to the 235 00:17:40,000 --> 00:17:46,000 tumor in adenocarcinoma. And there could be adenocarcinomas 236 00:17:46,000 --> 00:17:52,000 in the different places that I mentioned previously. 237 00:17:52,000 --> 00:17:58,000 And there are benign versions of this tumors. And for 238 00:17:58,000 --> 00:18:04,000 adenocarcinomas, the benign version the adenoma. 239 00:18:04,000 --> 00:18:13,000 You can get tumors of connective 240 00:18:13,000 --> 00:18:18,000 tissues, and these are referred to as sarcomas. And there could be 241 00:18:18,000 --> 00:18:24,000 different sarcomas depending on where they are found, 242 00:18:24,000 --> 00:18:29,000 for example, various types of myosarcomas would be found in what 243 00:18:29,000 --> 00:18:35,000 type of tissue? These are muscle tumors, 244 00:18:35,000 --> 00:18:41,000 rhabdomyosarcomas, leiomyosarcomas. Another example are chondrosarcomas 245 00:18:41,000 --> 00:18:51,000 -- 246 00:18:51,000 --> 00:18:54,000 -- which are tumors of cartilage. In this class of tumors, which are 247 00:18:54,000 --> 00:18:58,000 called soft tissue tumors, were in the news just today as a 248 00:18:58,000 --> 00:19:02,000 matter of fact, front page of the Boston Globe if 249 00:19:02,000 --> 00:19:06,000 you happen to see it. There is a site, a former dye 250 00:19:06,000 --> 00:19:10,000 factory that was dumping pollutants into ponds and Ashland. 251 00:19:10,000 --> 00:19:14,000 And they've just determined that the exposure to those dyes greatly 252 00:19:14,000 --> 00:19:18,000 increased the risk of children to later develop soft tissue sarcomas. 253 00:19:18,000 --> 00:19:23,000 Several children then turning into 20, 30 year olds developed tumors of 254 00:19:23,000 --> 00:19:27,000 this type which fits to the theme of the lecture in terms of exposures 255 00:19:27,000 --> 00:19:36,000 leading to cancers. 256 00:19:36,000 --> 00:19:42,000 Tumors of the blood system are referred to by different 257 00:19:42,000 --> 00:19:55,000 names, leukemias -- 258 00:19:55,000 --> 00:20:00,000 -- in which the tumor cells are in the blood, B cell leukemias, 259 00:20:00,000 --> 00:20:06,000 T cell leukemias, erythroleukemias, myeloid leukemias where the cells 260 00:20:06,000 --> 00:20:12,000 are in the bloodstream like the one I showed you before, 261 00:20:12,000 --> 00:20:17,000 and lymphomas where the tumors are in the lymph organs like the spleen 262 00:20:17,000 --> 00:20:23,000 or the thymus or the lymph nodes. So, that gives you some terminology. 263 00:20:23,000 --> 00:20:29,000 And I'll be referring to some of this terminology as we go through 264 00:20:29,000 --> 00:20:35,000 the remaining lectures. And it's just useful to know as you 265 00:20:35,000 --> 00:20:52,000 learn about and hear about cancers. 266 00:20:52,000 --> 00:20:56,000 Now, cancer research, over the last several decades has 267 00:20:56,000 --> 00:21:01,000 been dedicated to try to understand this process of normalcy to 268 00:21:01,000 --> 00:21:06,000 malignancy. How does that happen? And the conclusion from all of this 269 00:21:06,000 --> 00:21:10,000 work, which I will review for you is that cancer is a genetic disease. 270 00:21:10,000 --> 00:21:15,000 What do I mean by that? What do I mean by cancer is a genetic disease? 271 00:21:15,000 --> 00:21:20,000 Does anybody want to hazard a guess? What do we normally think of when 272 00:21:20,000 --> 00:21:24,000 we talk about genetic diseases? Heritable diseases, predispositions 273 00:21:24,000 --> 00:21:29,000 to disease, we talked about several of them previously in the class like 274 00:21:29,000 --> 00:21:34,000 cystic fibrosis and many others. Cancer can be a genetic disease in 275 00:21:34,000 --> 00:21:38,000 that sense. There can be inherited predispositions to certain cancers. 276 00:21:38,000 --> 00:21:42,000 And I'll mention some in later lectures. But in fact, 277 00:21:42,000 --> 00:21:46,000 all cancers are genetic diseases. All cancers arise through 278 00:21:46,000 --> 00:21:50,000 alterations in your genes. Those alterations in most cases are 279 00:21:50,000 --> 00:21:54,000 not inherited from one of your parents but are acquired through 280 00:21:54,000 --> 00:21:58,000 your lifetimes through mistakes or exposures to things that 281 00:21:58,000 --> 00:22:03,000 cause such changes. Why do we believe this so strongly? 282 00:22:03,000 --> 00:22:09,000 Well, firstly, and this has been known for some time, 283 00:22:09,000 --> 00:22:15,000 cancer cells don't look normal chromosomally. 284 00:22:15,000 --> 00:22:21,000 If you look at the chromosomes of normal cells, they're all the same. 285 00:22:21,000 --> 00:22:27,000 All have 46 chromosomes. The chromosomes have proper structures 286 00:22:27,000 --> 00:22:34,000 but when you look at cancer cells, that's not true. 287 00:22:34,000 --> 00:22:37,000 For most cancers, in contrast to the normal karyotype, 288 00:22:37,000 --> 00:22:40,000 the normal chromosomal number in architecture, and this is an image 289 00:22:40,000 --> 00:22:44,000 which highlights the different chromosomes by different colors. 290 00:22:44,000 --> 00:22:47,000 This technique allows us to distinguish one chromosome from the 291 00:22:47,000 --> 00:22:51,000 other based on the color that it stains with these dyes that are used 292 00:22:51,000 --> 00:22:54,000 here. Anyway, this is a normal cell, 293 00:22:54,000 --> 00:22:58,000 46 chromosomes. And here's a cancer cell. And it's different 294 00:22:58,000 --> 00:23:01,000 in many ways. There are way too many chromosomes. 295 00:23:01,000 --> 00:23:05,000 So it's a defect in chromosome number. But it's also a defect in 296 00:23:05,000 --> 00:23:09,000 chromosome structure. And you can see in the boxes a 297 00:23:09,000 --> 00:23:13,000 couple of alterations here. There is a chromosome 7, which is 298 00:23:13,000 --> 00:23:17,000 lacking a little bit of its end. So it's got a truncation. I think 299 00:23:17,000 --> 00:23:21,000 that's a seven. Actually, maybe that's not. 300 00:23:21,000 --> 00:23:25,000 Many that's chromosome 24. Anyway, it doesn't matter. And here, you 301 00:23:25,000 --> 00:23:29,000 can see, it looks like an ice cream cone: a little bit of paint on the 302 00:23:29,000 --> 00:23:33,000 bottom, a little bit of green on the top. 303 00:23:33,000 --> 00:23:36,000 This is a new kind of chromosome that has been fused by two different 304 00:23:36,000 --> 00:23:39,000 chromosomes coming together. So this is a translocation. And 305 00:23:39,000 --> 00:23:43,000 here's another translocation here. So, chromosomes and cancer cells 306 00:23:43,000 --> 00:23:46,000 are often abnormal in their structure. They can have 307 00:23:46,000 --> 00:23:49,000 translocations. They can have deletions. 308 00:23:49,000 --> 00:23:53,000 They can have other kinds of rearrangements. 309 00:23:53,000 --> 00:23:56,000 And so, based on this, we know that cancer has defects in 310 00:23:56,000 --> 00:24:00,000 its genomes, and ultimately we know in its genes. 311 00:24:00,000 --> 00:24:05,000 We also know that agents that cause cancer -- 312 00:24:05,000 --> 00:24:11,000 -- and we refer to these 313 00:24:11,000 --> 00:24:20,000 as carcinogens -- 314 00:24:20,000 --> 00:24:29,000 -- cancer-causing agents, carcinogens are most often mutagens -- 315 00:24:29,000 --> 00:24:49,000 -- agents that cause mutations. 316 00:24:49,000 --> 00:24:53,000 Carcinogens are mostly mutagens. And therefore, it's likely that the 317 00:24:53,000 --> 00:24:57,000 reason they are carcinogens is because they lead to mutations in 318 00:24:57,000 --> 00:25:02,000 cellular genes. We believe that very strongly, 319 00:25:02,000 --> 00:25:07,000 and it's based on work from many groups over long periods of time 320 00:25:07,000 --> 00:25:11,000 that have established this kind of correlation. To sort of prove the 321 00:25:11,000 --> 00:25:16,000 point, many, many agents, many, many things that have been 322 00:25:16,000 --> 00:25:21,000 suspected to be cancer-causing have been tested to see whether they are 323 00:25:21,000 --> 00:25:26,000 mutation causing, to see whether carcinogens are 324 00:25:26,000 --> 00:25:31,000 mutagens. And they are tested using assays -- 325 00:25:31,000 --> 00:25:41,000 -- like carcinogenicity assays where 326 00:25:41,000 --> 00:25:46,000 the compound in question or the agent, might be a physical agent 327 00:25:46,000 --> 00:25:51,000 like radiation, is tested to see whether it will 328 00:25:51,000 --> 00:25:56,000 promote tumor formation. And this is typically done in 329 00:25:56,000 --> 00:26:01,000 laboratory animals. So, you expose, say, 330 00:26:01,000 --> 00:26:06,000 a mouse or a rate to the agents in question, and you ask the question, 331 00:26:06,000 --> 00:26:12,000 over time, does that promote the formation of a discernible tumor? 332 00:26:12,000 --> 00:26:16,000 If yes, then the agent is a carcinogen. OK, 333 00:26:16,000 --> 00:26:20,000 and then you ask the question, is the agent a mutagen -- 334 00:26:20,000 --> 00:26:30,000 -- using mutagenicity assays. 335 00:26:30,000 --> 00:26:34,000 And these are typically done in bacteria because they can be done 336 00:26:34,000 --> 00:26:38,000 very, very rapidly. We can ask whether the agent is 337 00:26:38,000 --> 00:26:42,000 able to cause mutations in bacterial cells. And the standard assay that 338 00:26:42,000 --> 00:26:46,000 has been developed, and is still in use, 339 00:26:46,000 --> 00:26:50,000 is to take this agent, drop it into a broth carrying 340 00:26:50,000 --> 00:26:54,000 bacteria, and not just any bacteria, but bacteria that have mutation in a 341 00:26:54,000 --> 00:26:58,000 gene required for histidine synthesis. 342 00:26:58,000 --> 00:27:07,000 They can't make their own histidine, 343 00:27:07,000 --> 00:27:11,000 the amino acid histidine. And so, for them to grow, 344 00:27:11,000 --> 00:27:16,000 they require histidine in the medium here, or in the medium on the plate, 345 00:27:16,000 --> 00:27:21,000 the auger plate that you grow them. If you were to take some of these 346 00:27:21,000 --> 00:27:25,000 histidine minus bacteria, and plate them on a tissue culture 347 00:27:25,000 --> 00:27:30,000 plate, or rather a bacterial plate, that lacked histidine would any of 348 00:27:30,000 --> 00:27:35,000 them grow? No, because they can make their own. 349 00:27:35,000 --> 00:27:39,000 You have been given them any. So they can't grow into colonies. 350 00:27:39,000 --> 00:27:43,000 You would get zero colonies if you did that. This is due to a mutation 351 00:27:43,000 --> 00:27:48,000 in a single gene. If you can create another mutation 352 00:27:48,000 --> 00:27:52,000 at that site and revert the abnormal gene into a normal gene, 353 00:27:52,000 --> 00:27:57,000 now the cells can make their own histidine. So, 354 00:27:57,000 --> 00:28:01,000 if you can mutate these cells back to becoming competent to make 355 00:28:01,000 --> 00:28:05,000 histidine, then if you plate these cells on a histidine minus plate, 356 00:28:05,000 --> 00:28:10,000 you might get colonies. You would get some colonies. 357 00:28:10,000 --> 00:28:14,000 For every bacterial cell that acquired a mutation at the right 358 00:28:14,000 --> 00:28:18,000 site, fixing the histidine synthesis gene, now that cell would be able to 359 00:28:18,000 --> 00:28:22,000 grow into a colony. And actually, the potency of the 360 00:28:22,000 --> 00:28:26,000 mutagen determines how many colonies you get. So, you can have weakly 361 00:28:26,000 --> 00:28:30,000 acting mutagens or strongly acting mutagens. And 362 00:28:30,000 --> 00:28:34,000 as I mentioned, most agents that pass this test will also 363 00:28:34,000 --> 00:28:43,000 pass this test, OK? 364 00:28:43,000 --> 00:29:00,000 However -- 365 00:29:00,000 --> 00:29:04,000 -- some known carcinogens fail that test. They clearly are carcinogens. 366 00:29:04,000 --> 00:29:09,000 You paint them on the back of a mouse or feed it to an animal: the 367 00:29:09,000 --> 00:29:13,000 animal will develop cancer. And yet, when you do the bacterial 368 00:29:13,000 --> 00:29:18,000 reversion test, they don't show up as being mutagens. 369 00:29:18,000 --> 00:29:25,000 Why is that so? Anybody? Yes? 370 00:29:25,000 --> 00:29:28,000 They could be so mutagenic that they block the development of the 371 00:29:28,000 --> 00:29:32,000 bacteria at all. That's actually a very interesting 372 00:29:32,000 --> 00:29:36,000 idea, not what I was thinking of. But it's a good idea. They are 373 00:29:36,000 --> 00:29:40,000 super mutagens. So they fail the test for that 374 00:29:40,000 --> 00:29:44,000 reason. Anything else? What's different between this test 375 00:29:44,000 --> 00:29:48,000 of this mutagenicity, and what actually happens in the 376 00:29:48,000 --> 00:29:52,000 body? Anybody? Yes? That's good. 377 00:29:52,000 --> 00:29:56,000 And I'll actually come back to that. There is another good suggestion, 378 00:29:56,000 --> 00:30:00,000 but I'll come back to that answer in a second. 379 00:30:00,000 --> 00:30:05,000 The difference is metabolism. Your body metabolizes things that 380 00:30:05,000 --> 00:30:10,000 you get exposed to that you eat, or that you inhale, or that you 381 00:30:10,000 --> 00:30:16,000 inject yourselves with. It metabolizes it oftentimes to 382 00:30:16,000 --> 00:30:21,000 detoxify it or to make it more water-soluble so that you can 383 00:30:21,000 --> 00:30:27,000 excrete it. There is a lot of metabolism breaking down or changing 384 00:30:27,000 --> 00:30:32,000 the things that you get exposed to. And so, it's been observed that 385 00:30:32,000 --> 00:30:37,000 there are certain compounds which are not themselves mutagens but are 386 00:30:37,000 --> 00:30:42,000 pro-mutagens. They have the capacity to turn into mutagens. 387 00:30:42,000 --> 00:30:47,000 And in the process of metabolic enzymes, they become mutagens. 388 00:30:47,000 --> 00:30:52,000 And there are very important carcinogens that fall into this 389 00:30:52,000 --> 00:30:57,000 category. And one of them is shown here. This is a polycyclic 390 00:30:57,000 --> 00:31:02,000 hydrocarbon called benzoate pyrene. It's a very important ingredient in 391 00:31:02,000 --> 00:31:06,000 cigarette smoke as well as in barbecued beef. 392 00:31:06,000 --> 00:31:10,000 It's a very potent carcinogen. It passes this test with flying 393 00:31:10,000 --> 00:31:14,000 colors. But if you do the bacterial reversion test, 394 00:31:14,000 --> 00:31:19,000 you don't see anything. And the reason is that in the body, 395 00:31:19,000 --> 00:31:23,000 many of these double bonds had to be broken and replaced ultimately by 396 00:31:23,000 --> 00:31:27,000 hydroxyl groups to make this compound more water-soluble so that 397 00:31:27,000 --> 00:31:32,000 it can be excreted. And an intermediate step in the 398 00:31:32,000 --> 00:31:36,000 detoxification, the hydroxylation, 399 00:31:36,000 --> 00:31:41,000 is the formation of epoxide. And these epoxides are actually 400 00:31:41,000 --> 00:31:45,000 highly reactive to DNA. And these molecules, these 401 00:31:45,000 --> 00:31:50,000 intermediates, are highly mutagenic. 402 00:31:50,000 --> 00:31:55,000 And so, when you make these in your body, thinking you're doing a good 403 00:31:55,000 --> 00:31:59,000 thing, you're actually doing a bad thing by creating a mutagen. 404 00:31:59,000 --> 00:32:04,000 And it's this that's the mutagenic agent. And so, 405 00:32:04,000 --> 00:32:08,000 now the simple bacterial reversion test has been replaced by something 406 00:32:08,000 --> 00:32:13,000 called the Ames test named after Bruce Ames from Berkeley in which 407 00:32:13,000 --> 00:32:18,000 the compound in question is not just given directly to the bacteria. 408 00:32:18,000 --> 00:32:23,000 Its first passed through an extract of the liver, usually rat liver, 409 00:32:23,000 --> 00:32:28,000 and it's in the liver where these detoxifying enzymes do their job, 410 00:32:28,000 --> 00:32:33,000 these cytochrome P450's that are referred to here are present in 411 00:32:33,000 --> 00:32:39,000 abundance in your liver. And so if mutagens are going to be 412 00:32:39,000 --> 00:32:45,000 formed, they should be formed in this in vitro extract. 413 00:32:45,000 --> 00:32:52,000 And then, one takes the product of that and performs the bacterial 414 00:32:52,000 --> 00:32:58,000 mutation or reversion test. OK, and now the things that were 415 00:32:58,000 --> 00:33:04,000 carcinogens but not seen to be mutagens can be seen to be mutagens 416 00:33:04,000 --> 00:33:13,000 again. OK, but -- 417 00:33:13,000 --> 00:33:30,000 -- still -- 418 00:33:30,000 --> 00:33:36,000 There are still some truly non-mutagenic carcinogens. 419 00:33:36,000 --> 00:33:42,000 And two examples are alcohol and asbestos. 420 00:33:42,000 --> 00:33:48,000 These do not pass any mutagenicity 421 00:33:48,000 --> 00:33:52,000 tests that I'm aware of. But both of them are clearly linked 422 00:33:52,000 --> 00:33:56,000 to cancer development: alcohol in the case of liver, 423 00:33:56,000 --> 00:34:00,000 cancer, and head and neck cancer, and asbestos in the case of 424 00:34:00,000 --> 00:34:04,000 mesothelioma, the lining of the lung. 425 00:34:04,000 --> 00:34:08,000 So these are not mutagens. So how did they promote cancer 426 00:34:08,000 --> 00:34:12,000 formation? Based on the mechanism that was suggested over here. 427 00:34:12,000 --> 00:34:17,000 These agents cause irritation in tissues -- 428 00:34:17,000 --> 00:34:29,000 -- which results in tissue 429 00:34:29,000 --> 00:34:38,000 destruction, loss of cells -- 430 00:34:38,000 --> 00:34:44,000 -- and their replacement of those cells, cell replenishment. 431 00:34:44,000 --> 00:34:50,000 So, it recruits a lot of cells to begin to divide when they normally 432 00:34:50,000 --> 00:34:56,000 wouldn't. So it results in increased proliferation, 433 00:34:56,000 --> 00:35:02,000 and the increased potential for mutation because - 434 00:35:02,000 --> 00:35:07,000 when cells divide. When they duplicate their DNA, 435 00:35:07,000 --> 00:35:11,000 there is an inherent risk of making mistakes. It's not an error-free 436 00:35:11,000 --> 00:35:16,000 process. So the more cell division there is, the more opportunity there 437 00:35:16,000 --> 00:35:20,000 is for error, and therefore, the increased risk of acquiring 438 00:35:20,000 --> 00:35:25,000 mutations and becoming ultimately a cancer. OK, I want to take a couple 439 00:35:25,000 --> 00:35:29,000 of minutes talking about one really important environmental carcinogen, 440 00:35:29,000 --> 00:35:34,000 something that we get exposed to. And that is cigarette smoke. 441 00:35:34,000 --> 00:35:39,000 I mentioned that benzoate pyrene is one of the important ingredients in 442 00:35:39,000 --> 00:35:44,000 cigarette smoke, but it's actually not the only 443 00:35:44,000 --> 00:35:49,000 mutagen. There are actually hundreds of mutagens in cigarette 444 00:35:49,000 --> 00:35:55,000 smoke. And this is the most important environmental carcinogen 445 00:35:55,000 --> 00:36:00,000 that we have in our environments. And it results in a large number of 446 00:36:00,000 --> 00:36:05,000 deaths per year. Tobacco smoke is responsible for a 447 00:36:05,000 --> 00:36:10,000 high percentage of the 175, 00 people who die from lung cancer 448 00:36:10,000 --> 00:34:48,000 in this country each year. About 150 were either smokers 449 00:34:48,000 --> 00:36:27,000 or former smokers. 450 00:36:27,000 --> 00:36:31,000 And the association between lung cancer and cigarette smoking is 451 00:36:31,000 --> 00:36:35,000 really striking. If you look here, 452 00:36:35,000 --> 00:36:40,000 the green line represents cigarette consumption in males from the 453 00:36:40,000 --> 00:36:44,000 beginning of the century, the 1900s, through 1960. And you 454 00:36:44,000 --> 00:36:49,000 can see it rapidly increased through availability and social acceptance 455 00:36:49,000 --> 00:36:53,000 and social trends. Smoking was really rampant in the 456 00:36:53,000 --> 00:36:58,000 society. And shortly thereafter, with about a 20 year lag, you could 457 00:36:58,000 --> 00:37:02,000 see that lung cancer risk increased dramatically as well, 458 00:37:02,000 --> 00:37:07,000 which is directly attributable to the cigarette smoke exposure. 459 00:37:07,000 --> 00:37:10,000 It took time because cancers don't develop right away. 460 00:37:10,000 --> 00:37:13,000 They develop over years, and so you need to get exposed to 461 00:37:13,000 --> 00:37:17,000 stuff over a long period of time. But eventually the lung cancer 462 00:37:17,000 --> 00:37:20,000 started to rise. And you could see the shape of the 463 00:37:20,000 --> 00:37:24,000 curves are virtually identical. You can also see that the smoking 464 00:37:24,000 --> 00:37:27,000 rate has dropped off a little bit in men, and actually has dropped off a 465 00:37:27,000 --> 00:37:31,000 little bit starting about 15 to 20 years ago with respect to 466 00:37:31,000 --> 00:37:35,000 lung cancers as well. So smoking cessation has an effect. 467 00:37:35,000 --> 00:37:39,000 If you reduce the exposure, you can reduce your risk. 468 00:37:39,000 --> 00:37:44,000 That's true of men. Women have not caught up yet. 469 00:37:44,000 --> 00:37:48,000 Women started smoking later than men, about 20 years later, 470 00:37:48,000 --> 00:37:53,000 and their lung cancer rates followed, then, their increases in cigarette 471 00:37:53,000 --> 00:37:57,000 smoking with about a 20 year lag, and you can see now that lung cancer 472 00:37:57,000 --> 00:38:02,000 among women is still rising. And it recently passed breast cancer 473 00:38:02,000 --> 00:38:08,000 as the most common type of cancer deaths among women. 474 00:38:08,000 --> 00:38:13,000 So lung cancer is a major disease and is directly related to smoking 475 00:38:13,000 --> 00:38:19,000 and smoking history. Surprisingly, given that fact -- 476 00:38:19,000 --> 00:38:32,000 -- still 47 million Americans smoke, 477 00:38:32,000 --> 00:38:38,000 in recent polls something like 26% of men and 22% of women, 478 00:38:38,000 --> 00:38:44,000 a remarkably high number. And if you go to other countries, 479 00:38:44,000 --> 00:38:50,000 the numbers are worse. So the message clearly has not been 480 00:38:50,000 --> 00:38:56,000 adequately delivered. But what is even more surprising to 481 00:38:56,000 --> 00:39:02,000 me was the results of a survey done in 2002 where high school students 482 00:39:02,000 --> 00:39:13,000 are asked whether they smoked. 483 00:39:13,000 --> 00:39:18,000 What do you think? What percentage of American high 484 00:39:18,000 --> 00:39:23,000 school students smoke? Anybody? It was 28%; more than one 485 00:39:23,000 --> 00:39:28,000 in four smoke. And I've heard recently that the 486 00:39:28,000 --> 00:39:33,000 number is increasing since 2002. So, this very, 487 00:39:33,000 --> 00:39:38,000 very detrimental agent which one controls oneself is clearly not 488 00:39:38,000 --> 00:39:42,000 going away and will lead to, unfortunately, the deaths of many of 489 00:39:42,000 --> 00:39:47,000 these individuals because of lung cancer. And by the way, 490 00:39:47,000 --> 00:39:52,000 it's not just lung cancer that smoking is a problem for: emphysema, 491 00:39:52,000 --> 00:39:56,000 heart disease, and other diseases as well. I read a statistic which was 492 00:39:56,000 --> 00:40:01,000 really shocking to me. Of that however many billions of 493 00:40:01,000 --> 00:40:06,000 people are present on the planet today, the 500 million of them will 494 00:40:06,000 --> 00:40:11,000 die early because of complications of cigarette smoking. 495 00:40:11,000 --> 00:40:16,000 500 million people will live less than their full lifespans because of 496 00:40:16,000 --> 00:40:22,000 cigarette smoke. So, if you learn nothing else from 497 00:40:22,000 --> 00:40:28,000 this class, if you currently smoke, stop. And if you don't smoke, don't 498 00:40:28,000 --> 00:40:33,000 start. OK, that was my little sermon. 499 00:40:33,000 --> 00:40:39,000 Hopefully it had some effect. And it provides a segue into -- 500 00:40:39,000 --> 00:40:48,000 -- the sources of the mutations that 501 00:40:48,000 --> 00:40:53,000 occur in genes during cancer progression. We've just been 502 00:40:53,000 --> 00:40:58,000 discussing exogenous, or environmental mutagens, 503 00:40:58,000 --> 00:41:03,000 cigarette smoke being one, some lead exposure being another, 504 00:41:03,000 --> 00:41:08,000 dietary carcinogens I mentioned, environmental pollutants like the 505 00:41:08,000 --> 00:41:14,000 dyes in the ponds and ash land. They are common. They do certainly 506 00:41:14,000 --> 00:41:19,000 have an effect, but there are probably somewhat 507 00:41:19,000 --> 00:41:24,000 overblown except for some light and tobacco smoke, 508 00:41:24,000 --> 00:41:29,000 and then these rare instances of high exposure to very, 509 00:41:29,000 --> 00:41:38,000 very toxic things. 510 00:41:38,000 --> 00:41:42,000 A more common problem are replication errors, 511 00:41:42,000 --> 00:41:46,000 mistakes that your cells make in duplicating their DNA. 512 00:41:46,000 --> 00:41:50,000 They put in the wrong base or they skip a base, or other errors take 513 00:41:50,000 --> 00:41:58,000 place during DNA duplication. 514 00:41:58,000 --> 00:42:03,000 Your DNA can break inside of your cells as it gets moved around from 515 00:42:03,000 --> 00:42:08,000 place to place or because of an exposure to certain things from the 516 00:42:08,000 --> 00:42:13,000 outside. And then this can lead to translocations or deletions or other 517 00:42:13,000 --> 00:42:18,000 rearrangements. And I'll tell you later about how 518 00:42:18,000 --> 00:42:24,000 those can lead to cancer-causing mutations. 519 00:42:24,000 --> 00:42:38,000 Defects in chromosome segregation, 520 00:42:38,000 --> 00:42:43,000 dividing the number of chromosomes properly between cells, 521 00:42:43,000 --> 00:42:48,000 is another problem. And I shown you an example of that. 522 00:42:48,000 --> 00:42:52,000 Here you can see that the number of chromosomes is also wrong in 523 00:42:52,000 --> 00:42:57,000 addition to their structure. So, defects in chromosome 524 00:42:57,000 --> 00:43:02,000 segregation are a problem in cancer. Defects in DNA repair processes can 525 00:43:02,000 --> 00:43:25,000 then facilitate further mutations. 526 00:43:25,000 --> 00:43:29,000 And various metabolic processes can produce mutagens insider cells like 527 00:43:29,000 --> 00:43:33,000 super oxide molecules which are very reactive and very mutagenic. 528 00:43:33,000 --> 00:43:36,000 Your cells have ways of detoxifying, but they're not always perfect. You 529 00:43:36,000 --> 00:43:40,000 can also take antioxidants to try to reduce your risk of getting this 530 00:43:40,000 --> 00:43:44,000 kind of exposure. But nevertheless, 531 00:43:44,000 --> 00:43:48,000 these endogenously produced mutagens are another common source of 532 00:43:48,000 --> 00:43:52,000 mutations in cancer. So, we get exposed to things. 533 00:43:52,000 --> 00:43:56,000 We produce things, we make mistakes, and in our cells, 534 00:43:56,000 --> 00:44:00,000 alterations occur in cellular genes which drive this process forward. 535 00:44:00,000 --> 00:44:04,000 And overall, therefore, we observe a clonal evolution of 536 00:44:04,000 --> 00:44:08,000 more and more abnormal cells in the development of cancer. 537 00:44:08,000 --> 00:44:13,000 And that's captured here. Clonal evolution from a normal cell, 538 00:44:13,000 --> 00:44:17,000 a cell that acquires a single mutation, this cell now has 539 00:44:17,000 --> 00:44:21,000 increased capacity to divide. So it divides more. More of its 540 00:44:21,000 --> 00:44:26,000 progeny are produced. We are maybe in the stage of 541 00:44:26,000 --> 00:44:30,000 hyperplasia here. And within this increased mass of 542 00:44:30,000 --> 00:44:35,000 cells, another mutation occurs. Now the cell has even greater 543 00:44:35,000 --> 00:44:39,000 capacity to divide or begin to act abnormally relative to its neighbors. 544 00:44:39,000 --> 00:44:43,000 It begins to grow. And within this increased 545 00:44:43,000 --> 00:44:48,000 collection of cells, yet another mutation occurs. 546 00:44:48,000 --> 00:44:52,000 There is a clonal evolution of more and more abnormal cells. 547 00:44:52,000 --> 00:44:57,000 And we know that cancers, in fact, have acquired many, 548 00:44:57,000 --> 00:45:01,000 many changes in their DNA as evidenced by the chromosomes, 549 00:45:01,000 --> 00:45:05,000 but also as evidenced by our knowledge of the sequence of key 550 00:45:05,000 --> 00:45:11,000 genes that are affected in cancer. Now, as we'll discuss, 551 00:45:11,000 --> 00:45:17,000 many of these genes affect proliferation -- 552 00:45:17,000 --> 00:45:29,000 -- and cell death. 553 00:45:29,000 --> 00:45:33,000 Again, cancer is a disease of cell number, too many cells. 554 00:45:33,000 --> 00:45:37,000 And this process is normally very carefully balanced inside of your 555 00:45:37,000 --> 00:45:41,000 bodies inside of your tissues. There is an equal balance between 556 00:45:41,000 --> 00:45:48,000 proliferation -- 557 00:45:48,000 --> 00:45:52,000 -- and cell death so that in normal homeostasis -- 558 00:45:52,000 --> 00:46:00,000 -- you have the appropriate members 559 00:46:00,000 --> 00:46:04,000 of cells produced as die off, and so that ultimately you are in 560 00:46:04,000 --> 00:46:09,000 balance. But in cancer, the balance is shifted. It's 561 00:46:09,000 --> 00:46:13,000 shifted in the direction of proliferation, 562 00:46:13,000 --> 00:46:18,000 and away from cell death. And the consequences of that are 563 00:46:18,000 --> 00:46:22,000 that you've now produced too many cells for the tissue, 564 00:46:22,000 --> 00:46:27,000 too many cells in the gut, too many cells in the blood. 565 00:46:27,000 --> 00:46:31,000 And these cells, then, accumulate and acquire additional changes that 566 00:46:31,000 --> 00:46:36,000 imbue them with those qualities that advanced malignancies have. 567 00:46:36,000 --> 00:46:40,000 Increased proliferation is one thing, but importantly it's not the only 568 00:46:40,000 --> 00:46:45,000 thing. Increased proliferation and cell death are important qualities 569 00:46:45,000 --> 00:46:49,000 for sure. But also as I mentioned, cancer cells develop in other ways 570 00:46:49,000 --> 00:46:54,000 that are important in the development of malignancies. 571 00:46:54,000 --> 00:46:58,000 Today, for example, a recruit a blood supply. They secrete factors 572 00:46:58,000 --> 00:47:03,000 that cause the blood vessels to grow into them, to feed the tumor. 573 00:47:03,000 --> 00:47:07,000 They increased their motility. Cancer cells move around. They 574 00:47:07,000 --> 00:47:11,000 move into tissue. They move into the bloodstream. 575 00:47:11,000 --> 00:47:15,000 They move back out again. And that's what this intravasation term 576 00:47:15,000 --> 00:47:19,000 means, moving into the blood supply, and other characteristics as well, 577 00:47:19,000 --> 00:47:23,000 how they remodel the extracellular matrix, or how they avoid the immune 578 00:47:23,000 --> 00:47:27,000 system, all sorts of things that cancer cells require in order to 579 00:47:27,000 --> 00:47:31,000 survive to get bigger, to thrive, are acquired through 580 00:47:31,000 --> 00:47:35,000 alterations in cellular genes. Now, the final thing, 581 00:47:35,000 --> 00:47:39,000 and I'll close with this and pick it up again next time, 582 00:47:39,000 --> 00:47:44,000 the final thing that convinces us that cancer is a disease of your 583 00:47:44,000 --> 00:47:48,000 genes is that we've now sequenced the genes of cancer cells and have 584 00:47:48,000 --> 00:47:53,000 found alterations. Like in this gene here that you've 585 00:47:53,000 --> 00:47:57,000 been exposed to, the RAS gene, in which in normal 586 00:47:57,000 --> 00:48:02,000 cells we see one sequence and in cancer cells we see a different 587 00:48:02,000 --> 00:48:06,000 sequence, and we can understand that as a change in the activity of this 588 00:48:06,000 --> 00:48:11,000 important signaling protein that causes cells to divide 589 00:48:11,000 --> 00:48:14,000 inappropriately. And I'll stop there.