1 00:00:00,090 --> 00:00:02,490 The following content is provided under a Creative 2 00:00:02,490 --> 00:00:04,030 Commons license. 3 00:00:04,030 --> 00:00:06,360 Your support will help MIT OpenCourseWare 4 00:00:06,360 --> 00:00:10,720 continue to offer high quality educational resources for free. 5 00:00:10,720 --> 00:00:13,320 To make a donation or view additional materials 6 00:00:13,320 --> 00:00:17,280 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,280 --> 00:00:18,450 at ocw.mit.edu. 8 00:00:26,710 --> 00:00:27,420 TYLER JACKS: OK. 9 00:00:27,420 --> 00:00:30,930 So now we're going to change gears entirely, and talk 10 00:00:30,930 --> 00:00:31,650 about cancer. 11 00:00:31,650 --> 00:00:36,070 And to put you in the mood to talk about cancer, 12 00:00:36,070 --> 00:00:38,070 I'm going to show you a video, which we actually 13 00:00:38,070 --> 00:00:42,780 produced last year for the American Association for Cancer 14 00:00:42,780 --> 00:00:49,320 Research annual meeting, to open up that meeting, actually. 15 00:00:49,320 --> 00:00:50,910 Hopefully, there's sound. 16 00:00:50,910 --> 00:00:51,785 Guys, upstairs? 17 00:00:57,120 --> 00:00:59,120 [VIDEO PLAYBACK] 18 00:05:04,620 --> 00:05:07,120 [END PLAYBACK] 19 00:05:07,120 --> 00:05:09,500 TYLER JACKS: Hopefully, you're inspired. 20 00:05:09,500 --> 00:05:12,390 That video is on YouTube if you want to watch it again. 21 00:05:12,390 --> 00:05:13,740 It's got to 15,000 hits. 22 00:05:13,740 --> 00:05:18,030 It's not exactly viral, but still pretty good, pretty good 23 00:05:18,030 --> 00:05:20,580 for a cancer research video. 24 00:05:20,580 --> 00:05:22,650 And the video really was to kind of get 25 00:05:22,650 --> 00:05:25,200 people excited about both the progress that's been made 26 00:05:25,200 --> 00:05:26,550 and the opportunity that exists. 27 00:05:26,550 --> 00:05:28,091 But also some of the great challenges 28 00:05:28,091 --> 00:05:30,499 that we're referred to in some of those facts and figures 29 00:05:30,499 --> 00:05:31,290 that you saw there. 30 00:05:31,290 --> 00:05:33,040 So I want to review some of that with you, 31 00:05:33,040 --> 00:05:34,950 and give you a sense of what we're 32 00:05:34,950 --> 00:05:38,560 doing to improve our progress, accelerate our progress. 33 00:05:38,560 --> 00:05:40,140 And the bottom line is I'm actually 34 00:05:40,140 --> 00:05:42,420 extremely excited about the potential 35 00:05:42,420 --> 00:05:44,400 that we'll have over the next decade or two 36 00:05:44,400 --> 00:05:46,650 in really changing the course of some of those numbers 37 00:05:46,650 --> 00:05:49,520 that you saw there. 38 00:05:49,520 --> 00:05:53,180 But just to remind you of the severity of the problem, when 39 00:05:53,180 --> 00:05:55,700 we consider the statistics regarding cancer in the United 40 00:05:55,700 --> 00:06:04,550 States, in the United States over the next year, 41 00:06:04,550 --> 00:06:11,390 there'll be about 1.4 million new cases in the United States. 42 00:06:11,390 --> 00:06:22,540 That does not include common forms of skin cancer-- 43 00:06:27,630 --> 00:06:32,430 squamous cell skin cancer, basal cell skin cancer 44 00:06:32,430 --> 00:06:35,580 contribute another million cases. 45 00:06:35,580 --> 00:06:37,410 So it's a very, very common disease, 46 00:06:37,410 --> 00:06:39,270 very commonly diagnosed in this country, 47 00:06:39,270 --> 00:06:41,310 and indeed, around the world. 48 00:06:41,310 --> 00:06:47,445 Again, just considering the next year, 49 00:06:47,445 --> 00:06:48,820 it's estimated that there will be 50 00:06:48,820 --> 00:06:59,490 about 560,000 deaths in the United States due to cancer, 51 00:06:59,490 --> 00:07:01,649 and about 8 million in the world. 52 00:07:01,649 --> 00:07:03,190 And you might have seen the statistic 53 00:07:03,190 --> 00:07:05,680 that more people die in the world of cancer 54 00:07:05,680 --> 00:07:11,110 per year than of malaria, TB, or HIV aids combined. 55 00:07:11,110 --> 00:07:13,615 So very, very common, very, very deadly disease. 56 00:07:31,710 --> 00:07:36,200 In this country, the lifetime risk of developing cancer 57 00:07:36,200 --> 00:07:39,830 is 1 in 2 for men, 1 in 3 for women, 58 00:07:39,830 --> 00:07:41,510 based on current statistics. 59 00:07:41,510 --> 00:07:44,450 Again, hopefully by the time you guys are old 60 00:07:44,450 --> 00:07:47,300 and cancer typically is a disease of older people, 61 00:07:47,300 --> 00:07:49,160 these statistics will change. 62 00:07:49,160 --> 00:07:50,900 But that's what they are now. 63 00:07:50,900 --> 00:07:53,270 So if they don't change, then a large number 64 00:07:53,270 --> 00:07:56,630 of you sitting here will experience this diagnosis. 65 00:08:08,710 --> 00:08:13,510 And by current statistics, 1 in 4 deaths are due to cancer. 66 00:08:13,510 --> 00:08:17,080 Cancer has recently bypassed cardiovascular disease 67 00:08:17,080 --> 00:08:19,690 as the leading cause of death in the United States. 68 00:08:19,690 --> 00:08:23,260 Cardiovascular disease rates have dropped precipitously. 69 00:08:23,260 --> 00:08:25,930 Cancer rates have dropped less significantly, 70 00:08:25,930 --> 00:08:27,770 although they are coming down. 71 00:08:27,770 --> 00:08:29,890 Also, the population is aging. 72 00:08:29,890 --> 00:08:33,260 And cancer tends to be a disease of older people. 73 00:08:33,260 --> 00:08:35,590 So the demographics also increase 74 00:08:35,590 --> 00:08:38,080 the numbers of people who are dying from this disease. 75 00:08:38,080 --> 00:08:39,789 So a major problem. 76 00:08:39,789 --> 00:08:43,000 But also think of it as a major opportunity 77 00:08:43,000 --> 00:08:47,290 to do something really important if you 78 00:08:47,290 --> 00:08:49,390 choose to get into this field. 79 00:08:49,390 --> 00:08:51,940 So cancer, I think, is familiar to everybody 80 00:08:51,940 --> 00:08:54,520 on one level or another, but you might not 81 00:08:54,520 --> 00:08:56,830 have seen the disease up close. 82 00:08:56,830 --> 00:08:58,810 I hope that you haven't. 83 00:08:58,810 --> 00:09:01,990 But I want to teach you a little bit about what it looks like, 84 00:09:01,990 --> 00:09:04,930 and really what are some of the fundamental definitions. 85 00:09:04,930 --> 00:09:10,390 So lung cancer, a very commonly diagnosed cancer in this 86 00:09:10,390 --> 00:09:12,530 country-- we'll talk more about it in a minute-- 87 00:09:12,530 --> 00:09:16,709 is diagnosed either by a chest x-ray following symptoms, 88 00:09:16,709 --> 00:09:19,000 and you can see perhaps, although the light isn't great 89 00:09:19,000 --> 00:09:21,610 here, that there's a dark mass right here. 90 00:09:21,610 --> 00:09:25,750 And this dark mass indicates the presence of a tumor. 91 00:09:25,750 --> 00:09:27,820 A more refined diagnosis can be done 92 00:09:27,820 --> 00:09:32,140 by basically serial x-rays, commuted tomography. 93 00:09:32,140 --> 00:09:35,830 And you can see this very clearly defined mass growing 94 00:09:35,830 --> 00:09:37,150 in the lung of the individual. 95 00:09:37,150 --> 00:09:40,780 Cancer is an accumulation of cells, an abnormal number 96 00:09:40,780 --> 00:09:42,430 of cells within a tissue. 97 00:09:42,430 --> 00:09:47,040 And you can see that solid tumor here and here. 98 00:09:47,040 --> 00:09:50,400 You can also see cancers in the blood. 99 00:09:50,400 --> 00:09:52,710 Again, an abnormal number of cells 100 00:09:52,710 --> 00:09:55,150 within the blood, a leukemia. 101 00:09:55,150 --> 00:09:56,990 This is a normal blood smear. 102 00:09:56,990 --> 00:09:58,360 Here are red blood cells. 103 00:09:58,360 --> 00:10:01,170 And here is a normal number of white blood cells. 104 00:10:01,170 --> 00:10:02,500 These might be B-cells. 105 00:10:02,500 --> 00:10:05,640 These might be neutrophils. 106 00:10:05,640 --> 00:10:08,670 And you can see an accumulation of these nucleated white blood 107 00:10:08,670 --> 00:10:11,820 cells in this leukemic patient. 108 00:10:11,820 --> 00:10:14,970 Thousands, hundreds of thousands more of these cells 109 00:10:14,970 --> 00:10:16,970 than should be present within this blood sample. 110 00:10:19,970 --> 00:10:22,850 This is colon cancer. 111 00:10:22,850 --> 00:10:24,440 Colon cancer, as you probably know, 112 00:10:24,440 --> 00:10:27,920 can be detected by colonoscopy, a very important 113 00:10:27,920 --> 00:10:30,450 diagnostic test, preventative test. 114 00:10:30,450 --> 00:10:33,590 And we can actually see the lining of the colon. 115 00:10:33,590 --> 00:10:38,180 And this is a normal section of colonic epithelium. 116 00:10:38,180 --> 00:10:40,190 And here is a tumor developing. 117 00:10:40,190 --> 00:10:41,510 It's called a polyp. 118 00:10:41,510 --> 00:10:47,030 This is an early stage, precancerous tumor. 119 00:10:47,030 --> 00:10:50,040 We'll talk more about the details of that in a second. 120 00:10:50,040 --> 00:10:52,580 If this is diagnosed during endoscopy, 121 00:10:52,580 --> 00:10:55,610 they're actually removed right during the procedure. 122 00:10:55,610 --> 00:10:58,550 And this is very important to prevent those tumors 123 00:10:58,550 --> 00:11:01,430 from progressing further into true cancer. 124 00:11:01,430 --> 00:11:04,700 And actually, colon cancer rates have dropped significantly 125 00:11:04,700 --> 00:11:06,170 because of this test. 126 00:11:06,170 --> 00:11:09,380 When these lesions are discovered, they are removed. 127 00:11:09,380 --> 00:11:10,970 And therefore, they can't progress 128 00:11:10,970 --> 00:11:13,290 into true colon cancer. 129 00:11:13,290 --> 00:11:15,680 However, sometimes you see this. 130 00:11:15,680 --> 00:11:18,170 And this is a tumor that has progressed further. 131 00:11:18,170 --> 00:11:19,400 It's divided more. 132 00:11:19,400 --> 00:11:22,220 It's taken on additional abnormal properties 133 00:11:22,220 --> 00:11:25,730 and actually moved through the wall of the colon 134 00:11:25,730 --> 00:11:27,890 and is beginning to spread throughout the body. 135 00:11:27,890 --> 00:11:30,950 This is true cancer and much, much harder to treat. 136 00:11:30,950 --> 00:11:33,766 Not impossible, but much harder to treat. 137 00:11:33,766 --> 00:11:35,390 When this is discovered, you can't just 138 00:11:35,390 --> 00:11:37,370 remove the specific lesion. 139 00:11:37,370 --> 00:11:39,380 You have to have surgery. 140 00:11:39,380 --> 00:11:41,660 And a section of the colon is removed 141 00:11:41,660 --> 00:11:43,850 to take out the tumor in the hope 142 00:11:43,850 --> 00:11:46,440 that that will get rid of the disease entirely. 143 00:11:46,440 --> 00:11:48,110 But the concern is, in this situation, 144 00:11:48,110 --> 00:11:50,510 that the diseased cells might have moved out 145 00:11:50,510 --> 00:11:53,420 into the body in the process of metastasis, 146 00:11:53,420 --> 00:11:58,120 which will make the disease much more difficult to treat. 147 00:11:58,120 --> 00:11:58,620 OK. 148 00:11:58,620 --> 00:12:01,080 So I've given you some terminology there. 149 00:12:03,900 --> 00:12:06,295 Let me just explain some of it in greater detail. 150 00:12:11,279 --> 00:12:13,070 Actually, before I do that, let me show you 151 00:12:13,070 --> 00:12:14,810 one more, a couple of slides. 152 00:12:14,810 --> 00:12:18,020 So as indicated on that slide, cancer 153 00:12:18,020 --> 00:12:21,440 develops in stages from normal cells 154 00:12:21,440 --> 00:12:25,820 through the development of a benign, precancerous lesion, 155 00:12:25,820 --> 00:12:28,740 finally to the development of true cancer. 156 00:12:28,740 --> 00:12:32,400 And we can depict that graphically, as shown here. 157 00:12:32,400 --> 00:12:34,070 This is a normal tissue. 158 00:12:34,070 --> 00:12:35,540 Here are normal cells. 159 00:12:35,540 --> 00:12:39,140 These might be epithelial cells lining the intestine. 160 00:12:39,140 --> 00:12:42,020 Those cells sit on top of a basement membrane made 161 00:12:42,020 --> 00:12:45,770 of extracellular matrix proteins, which provide them 162 00:12:45,770 --> 00:12:47,750 structure and some function. 163 00:12:47,750 --> 00:12:49,850 There might be other cells present in this region, 164 00:12:49,850 --> 00:12:51,710 stem cells or progenitor cells, which 165 00:12:51,710 --> 00:12:54,260 will replenish those differentiated cells as they 166 00:12:54,260 --> 00:12:57,230 are sloughed off and die. 167 00:12:57,230 --> 00:12:59,810 These cells can acquire alterations-- 168 00:12:59,810 --> 00:13:02,510 and we'll discuss this in great detail today and next time-- 169 00:13:02,510 --> 00:13:05,300 alterations in their genes, which 170 00:13:05,300 --> 00:13:07,790 allow those cells to do things they shouldn't do, 171 00:13:07,790 --> 00:13:10,280 namely to proliferate abnormally. 172 00:13:10,280 --> 00:13:12,380 So rather than having a single line of cells, 173 00:13:12,380 --> 00:13:14,840 we now have a little clump of cells. 174 00:13:14,840 --> 00:13:17,750 These cells might look identical to their neighbors, 175 00:13:17,750 --> 00:13:19,380 but there are too many of them. 176 00:13:19,380 --> 00:13:22,580 This is a process we call hyperplasia, too many cells, 177 00:13:22,580 --> 00:13:25,280 too much growth. 178 00:13:25,280 --> 00:13:29,390 Within this collection of cells, additional alterations 179 00:13:29,390 --> 00:13:33,590 may take place that allow those cells to divide more rapidly 180 00:13:33,590 --> 00:13:35,780 and to do even more abnormal things, 181 00:13:35,780 --> 00:13:38,270 to pile up on one or another, which they shouldn't normally 182 00:13:38,270 --> 00:13:39,350 do. 183 00:13:39,350 --> 00:13:43,190 This is the development of one of those early stage tumors. 184 00:13:43,190 --> 00:13:45,530 I showed you a polyp in the colon. 185 00:13:45,530 --> 00:13:47,930 That's a stage of cancer, in the case of colon cancer, 186 00:13:47,930 --> 00:13:48,950 called an adenoma. 187 00:13:48,950 --> 00:13:51,120 That's a benign tumor. 188 00:13:51,120 --> 00:13:52,580 It's not yet cancer. 189 00:13:52,580 --> 00:13:54,920 It's actually not yet life threatening. 190 00:13:54,920 --> 00:13:57,590 But it's detectable because it's a mass of cells 191 00:13:57,590 --> 00:13:59,180 that shouldn't be there. 192 00:13:59,180 --> 00:14:01,850 Within that collection of cells, still further alterations 193 00:14:01,850 --> 00:14:03,170 can take place. 194 00:14:03,170 --> 00:14:05,240 And now the cells do additional things 195 00:14:05,240 --> 00:14:08,040 that are wrong and potentially dangerous. 196 00:14:08,040 --> 00:14:11,120 One, they're recruiting a blood supply. 197 00:14:11,120 --> 00:14:13,790 They're recruiting blood vessels into the tumor 198 00:14:13,790 --> 00:14:17,510 to nourish the tumor and bring factors that the tumor 199 00:14:17,510 --> 00:14:20,880 cells need for their survival. 200 00:14:20,880 --> 00:14:22,560 In addition, the cells are starting 201 00:14:22,560 --> 00:14:25,710 to degrade that extracellular matrix. 202 00:14:25,710 --> 00:14:29,370 They're starting to acquire the ability to move away 203 00:14:29,370 --> 00:14:30,870 from their normal site. 204 00:14:30,870 --> 00:14:34,320 Most cells in your body know where they're supposed to be, 205 00:14:34,320 --> 00:14:35,760 and they stay there. 206 00:14:35,760 --> 00:14:39,870 Cancer cells acquire the ability to leave their primary site 207 00:14:39,870 --> 00:14:42,340 and to disseminate throughout the body, 208 00:14:42,340 --> 00:14:44,640 creating secondary tumors. 209 00:14:44,640 --> 00:14:47,940 This happens when the cells access the blood vessels. 210 00:14:47,940 --> 00:14:50,790 They can then travel within the blood system 211 00:14:50,790 --> 00:14:54,870 and then take up residence in some secondary site. 212 00:14:54,870 --> 00:14:57,860 And this we call metastasis. 213 00:14:57,860 --> 00:15:00,260 Metastatic tumors are tumors that 214 00:15:00,260 --> 00:15:03,080 are derived from the primary cancer-- 215 00:15:03,080 --> 00:15:05,040 and this is true cancer here-- 216 00:15:05,040 --> 00:15:07,100 derived from the primary cancer, that 217 00:15:07,100 --> 00:15:10,310 have now created a secondary tumor somewhere else. 218 00:15:10,310 --> 00:15:14,070 And this is actually the most lethal phase of cancer. 219 00:15:14,070 --> 00:15:16,420 Of the 560 cancer-- 220 00:15:16,420 --> 00:15:19,000 560,000 cancer deaths that will occur 221 00:15:19,000 --> 00:15:23,290 in this country this year, 500,000 of them 222 00:15:23,290 --> 00:15:25,545 are due to this phase of the disease. 223 00:15:25,545 --> 00:15:26,920 It's actually not a phase that we 224 00:15:26,920 --> 00:15:29,290 understand terribly well today, but clearly 225 00:15:29,290 --> 00:15:30,610 a very important one. 226 00:15:30,610 --> 00:15:33,370 So cancer arises from normal cells 227 00:15:33,370 --> 00:15:34,960 through the sequential acquisition 228 00:15:34,960 --> 00:15:37,480 of alterations that allow those cells to do things 229 00:15:37,480 --> 00:15:39,940 they should not normally do, including 230 00:15:39,940 --> 00:15:44,140 invade and metastasize. 231 00:15:44,140 --> 00:15:46,460 This is what it looks like in real life. 232 00:15:46,460 --> 00:15:47,140 This is a tumor. 233 00:15:47,140 --> 00:15:50,560 It's actually a tumor from a mouse created in my lab. 234 00:15:50,560 --> 00:15:52,280 It's lung cancer. 235 00:15:52,280 --> 00:15:56,080 This lacy appearance is the normal lung epithelium. 236 00:15:56,080 --> 00:15:57,970 There's a lot of air spaces in the lung 237 00:15:57,970 --> 00:16:01,621 to allow you to get gas exchange in the lung. 238 00:16:01,621 --> 00:16:03,370 And you can see in this region right here, 239 00:16:03,370 --> 00:16:08,440 there's a bit of a thickening of those epithelial structures. 240 00:16:08,440 --> 00:16:12,460 Too many cells, that's this area we call hyperplasia. 241 00:16:12,460 --> 00:16:17,870 Over time, these will give way to solid growths. 242 00:16:17,870 --> 00:16:20,506 The cells within those solid growths look pretty normal. 243 00:16:20,506 --> 00:16:22,130 And you might be able to see that here. 244 00:16:22,130 --> 00:16:24,090 The cells are pretty well organized. 245 00:16:24,090 --> 00:16:25,650 They are all lined up. 246 00:16:25,650 --> 00:16:27,320 There's just too many of them. 247 00:16:27,320 --> 00:16:30,960 That's a benign tumor, an adenoma. 248 00:16:30,960 --> 00:16:36,660 Over time, these will give rise to true cancers, carcinomas. 249 00:16:36,660 --> 00:16:39,750 And these have the ability to spread locally 250 00:16:39,750 --> 00:16:41,080 and throughout the body. 251 00:16:41,080 --> 00:16:43,440 In addition, the cells look even more abnormal. 252 00:16:43,440 --> 00:16:47,400 They don't look like the cells that gave rise to them. 253 00:16:47,400 --> 00:16:48,190 OK. 254 00:16:48,190 --> 00:16:51,577 Now let me give you some more details of the terminology 255 00:16:51,577 --> 00:16:52,660 that I've just been using. 256 00:16:57,150 --> 00:17:05,745 Hyperplasia is increased cell number. 257 00:17:09,700 --> 00:17:14,980 But the architecture of the cells is otherwise normal. 258 00:17:14,980 --> 00:17:16,210 They look like normal cells. 259 00:17:20,819 --> 00:17:25,950 If progression occurs, a benign tumor might arise. 260 00:17:25,950 --> 00:17:28,710 This is not yet cancer. 261 00:17:28,710 --> 00:17:34,330 These tumors are so-called not aggressive. 262 00:17:34,330 --> 00:17:37,510 They basically stay where they started. 263 00:17:37,510 --> 00:17:39,565 They don't destroy the local tissue. 264 00:17:45,100 --> 00:17:46,530 And they don't leave the site. 265 00:17:51,620 --> 00:17:54,960 And if they are detected, for example in a colonoscopy, 266 00:17:54,960 --> 00:17:56,680 they can be removed. 267 00:17:56,680 --> 00:18:00,720 If they're detected in the lung when they're at this stage, 268 00:18:00,720 --> 00:18:04,980 they can be removed surgically and the patient will be fine. 269 00:18:04,980 --> 00:18:14,030 However, they can progress into a malignant tumor. 270 00:18:17,960 --> 00:18:19,850 And this is where we use the term cancer. 271 00:18:19,850 --> 00:18:22,790 Cancer actually refers not to just any tumor, 272 00:18:22,790 --> 00:18:24,950 but a malignant tumor. 273 00:18:24,950 --> 00:18:30,820 And these, by contrast, are aggressive. 274 00:18:30,820 --> 00:18:33,430 The cells are dividing more rapidly. 275 00:18:33,430 --> 00:18:39,620 They're also causing changes within the local tissue 276 00:18:39,620 --> 00:18:41,390 such that they're locally destructive 277 00:18:41,390 --> 00:18:42,365 to the local tissue. 278 00:18:49,070 --> 00:18:51,620 And they have the potential to spread, 279 00:18:51,620 --> 00:18:56,300 to get outside of their local area, access the blood vessels, 280 00:18:56,300 --> 00:18:59,140 and move to a distant site. 281 00:18:59,140 --> 00:19:06,060 And that leads to this final phase 282 00:19:06,060 --> 00:19:20,080 of metastasis, which is the tumor growing 283 00:19:20,080 --> 00:19:22,260 at a distant site. 284 00:19:22,260 --> 00:19:24,930 And that can be one site or it can be many sites. 285 00:19:24,930 --> 00:19:27,720 And again, it's the combined effects 286 00:19:27,720 --> 00:19:32,390 of the metastatic tumors that tends to kill cancer patients. 287 00:19:32,390 --> 00:19:36,770 Now cancers can arise in virtually all organs, 288 00:19:36,770 --> 00:19:38,570 all tissues. 289 00:19:38,570 --> 00:19:40,610 Cancer is an umbrella term that actually 290 00:19:40,610 --> 00:19:46,310 refers to many different diseases of abnormal growth. 291 00:19:46,310 --> 00:19:56,780 The most common tumors in humans affect epithelial tissues, 292 00:19:56,780 --> 00:19:58,580 epithelial tissues. 293 00:19:58,580 --> 00:20:00,560 And these epithelial tissues will give rise 294 00:20:00,560 --> 00:20:03,350 to a cancer type called carcinomas. 295 00:20:07,950 --> 00:20:10,440 Carcinomas are cancers of epithelial tissues. 296 00:20:15,360 --> 00:20:23,280 Breast cancer, lung cancer pancreas cancer-- 297 00:20:23,280 --> 00:20:27,520 these are all cancers of epithelial tissues. 298 00:20:27,520 --> 00:20:38,910 The precursor lesions are called adenomas, in many cases. 299 00:20:38,910 --> 00:20:39,785 And these are benign. 300 00:20:50,290 --> 00:20:53,050 We can also have cancers of connective tissues, 301 00:20:53,050 --> 00:20:55,040 and these are called, collectively, 302 00:20:55,040 --> 00:20:59,130 sarcomas, sarcomas. 303 00:20:59,130 --> 00:21:02,400 Muscle tumors, myosarcomas. 304 00:21:02,400 --> 00:21:06,750 Fibroblast derived tumors, fibrosarcomas. 305 00:21:06,750 --> 00:21:13,040 Cartilage derived tumors, these tumors are rarer in humans, 306 00:21:13,040 --> 00:21:14,780 but they occur. 307 00:21:14,780 --> 00:21:18,110 And when they occur, they can be quite problematic, as well. 308 00:21:18,110 --> 00:21:20,330 And they go through similar stages of progression, 309 00:21:20,330 --> 00:21:22,550 as I've been describing for the other tumor types. 310 00:21:29,610 --> 00:21:44,940 And we can have tumors of blood cells, leukemias, too 311 00:21:44,940 --> 00:21:46,950 many cells in the blood. 312 00:21:46,950 --> 00:21:50,959 And I showed you a blood smear of a leukemic patient. 313 00:21:50,959 --> 00:21:53,250 The blood smear indicates that there are too many cells 314 00:21:53,250 --> 00:21:55,280 circulating. 315 00:21:55,280 --> 00:22:02,520 That contrasts to lymphomas, which 316 00:22:02,520 --> 00:22:04,120 is also a blood cell tumor. 317 00:22:19,570 --> 00:22:24,510 But here the tumor cells are confined to lymph organs, 318 00:22:24,510 --> 00:22:28,530 like the thymus or the spleen or lymph nodes. 319 00:22:28,530 --> 00:22:31,260 So there actually aren't too many cells circulating, 320 00:22:31,260 --> 00:22:36,180 but there are too many of these cells in these structures, 321 00:22:36,180 --> 00:22:38,100 which likewise can cause problems 322 00:22:38,100 --> 00:22:42,030 within those local structures, and surrounding tissues 323 00:22:42,030 --> 00:22:42,940 as well. 324 00:22:42,940 --> 00:22:43,440 OK. 325 00:22:43,440 --> 00:22:45,000 So some terminology. 326 00:22:45,000 --> 00:22:48,660 Cancers affect all tissues, or virtually all tissues. 327 00:22:48,660 --> 00:22:52,790 There are probably 200, 250 different types of cancer 328 00:22:52,790 --> 00:22:54,540 when we think about all the different cell 329 00:22:54,540 --> 00:22:57,990 types in your body that can undergo these changes 330 00:22:57,990 --> 00:23:02,450 and result in one or another type of cancer. 331 00:23:02,450 --> 00:23:02,950 All right. 332 00:23:02,950 --> 00:23:05,840 So cancers arise from normal cells. 333 00:23:05,840 --> 00:23:08,240 They develop in stages. 334 00:23:08,240 --> 00:23:10,940 What causes them to change over time? 335 00:23:10,940 --> 00:23:14,810 What gives them the ability to divide inappropriately, 336 00:23:14,810 --> 00:23:17,520 to grow abnormally? 337 00:23:17,520 --> 00:23:21,300 The answer to this question is that alterations take place 338 00:23:21,300 --> 00:23:25,660 in the DNA of the developing cancer cells. 339 00:23:25,660 --> 00:23:28,440 And in this respect, cancer is a genetic disease. 340 00:23:39,560 --> 00:23:41,270 And I'm going to use this term in quotes 341 00:23:41,270 --> 00:23:43,144 because when we talk about a genetic disease, 342 00:23:43,144 --> 00:23:45,770 we tend to talk about inherited diseases. 343 00:23:45,770 --> 00:23:48,560 You inherit a disease allele from one of your parents. 344 00:23:48,560 --> 00:23:50,450 You develop a disease. 345 00:23:50,450 --> 00:23:54,740 In this case, cancer can arise as a consequence 346 00:23:54,740 --> 00:23:56,270 of an inherited mutation. 347 00:23:56,270 --> 00:23:58,680 We'll talk about that in a subsequent lecture. 348 00:23:58,680 --> 00:24:01,610 But what I'm referring to here is genetic alterations 349 00:24:01,610 --> 00:24:04,940 that take place within you, within your cells. 350 00:24:04,940 --> 00:24:09,380 And this accumulates over time, over decades in some cases, 351 00:24:09,380 --> 00:24:13,660 and allows the cells to progress through these various stages. 352 00:24:13,660 --> 00:24:17,470 The case that cancer develops through the acquisition 353 00:24:17,470 --> 00:24:22,860 of mutations in genes has been building for about a century. 354 00:24:22,860 --> 00:24:25,560 We've been suspecting that cancer was a genetic disease 355 00:24:25,560 --> 00:24:26,760 for a very long time. 356 00:24:26,760 --> 00:24:28,980 And now we know it's true because we've 357 00:24:28,980 --> 00:24:33,480 seen the alterations in the genes of cancer cells. 358 00:24:33,480 --> 00:24:36,030 And we'll come to those specific alterations 359 00:24:36,030 --> 00:24:36,990 in subsequent lectures. 360 00:24:36,990 --> 00:24:39,323 But I want to give you the background that led us there. 361 00:24:46,920 --> 00:24:53,570 The first and the oldest was the observation going back 362 00:24:53,570 --> 00:24:58,640 almost 100 years that cancer cells have abnormal number 363 00:24:58,640 --> 00:25:01,760 and structure of chromosomes. 364 00:25:01,760 --> 00:25:07,800 As you know, your cells have 46 chromosomes, 23 pairs. 365 00:25:07,800 --> 00:25:11,150 And most of your cells look like the cells on the left, 366 00:25:11,150 --> 00:25:15,440 where there's a pair of chromosome 1, 2, 3, 367 00:25:15,440 --> 00:25:16,970 and so forth. 368 00:25:16,970 --> 00:25:20,060 These chromosomes are painted with a specific chromosome 369 00:25:20,060 --> 00:25:23,330 specific paint so we can distinguish which one is which, 370 00:25:23,330 --> 00:25:26,880 and this is a so-called normal karyotype. 371 00:25:26,880 --> 00:25:29,470 Cancer cells can look like this. 372 00:25:29,470 --> 00:25:31,830 And you can see that they're different in many respects 373 00:25:31,830 --> 00:25:32,980 from normal cells. 374 00:25:32,980 --> 00:25:36,220 A, there's way too many chromosomes. 375 00:25:36,220 --> 00:25:38,460 This is a condition we call aneuploidy. 376 00:25:44,620 --> 00:25:47,620 Aneuploidy, as opposed to being diploid, 377 00:25:47,620 --> 00:25:52,210 the cells are aneuploid, an abnormal number of chromosomes. 378 00:25:52,210 --> 00:25:56,620 Moreover, you can see in some of the highlighted areas 379 00:25:56,620 --> 00:25:59,044 that the chromosome structure is abnormal. 380 00:25:59,044 --> 00:26:01,210 We have this chromosome here, which has a little bit 381 00:26:01,210 --> 00:26:04,960 of the pale blue chromosome-- which may be chromosome 4, 382 00:26:04,960 --> 00:26:06,272 I can't read it-- 383 00:26:06,272 --> 00:26:08,230 and a little bit of this pink chromosome, which 384 00:26:08,230 --> 00:26:09,810 is one of these guys here. 385 00:26:09,810 --> 00:26:13,630 A translocation has taken place so that the structure 386 00:26:13,630 --> 00:26:16,010 of the chromosome is abnormal. 387 00:26:16,010 --> 00:26:19,480 So we have aneuploidy, defects in chromosome number, 388 00:26:19,480 --> 00:26:23,580 but also defects in chromosome structure, like translocations. 389 00:26:26,410 --> 00:26:29,980 We also have deletions-- not easy to see in this slide-- 390 00:26:29,980 --> 00:26:36,030 where chromosomes have incurred big losses of genetic material. 391 00:26:36,030 --> 00:26:36,610 OK? 392 00:26:36,610 --> 00:26:38,169 Chromosome abnormalities in cancer 393 00:26:38,169 --> 00:26:39,960 have been known about for a very long time. 394 00:26:42,710 --> 00:26:44,750 A second and very important observation, 395 00:26:44,750 --> 00:26:47,480 which occurred sometime in the '40s-- 396 00:26:47,480 --> 00:26:50,270 maybe '30s, '40s, and '50s-- 397 00:26:50,270 --> 00:26:56,690 and built up over time since then, 398 00:26:56,690 --> 00:27:07,600 is that carcinogens, carcinogens, which 399 00:27:07,600 --> 00:27:20,440 are cancer causing agents, are almost always mutagens, which 400 00:27:20,440 --> 00:27:22,505 are mutation causing agents. 401 00:27:29,520 --> 00:27:31,530 So something that can cause cancer in, 402 00:27:31,530 --> 00:27:34,260 for example, a laboratory animal, 403 00:27:34,260 --> 00:27:38,370 can be shown to alter the DNA and cause mutations. 404 00:27:38,370 --> 00:27:41,250 That would suggest that the carcinogen 405 00:27:41,250 --> 00:27:45,590 is acting through the alterations in the DNA. 406 00:27:45,590 --> 00:27:51,020 And this observation was made much more convincing 407 00:27:51,020 --> 00:27:52,760 through the work of an investigator 408 00:27:52,760 --> 00:27:57,120 by the name of Bruce Ames, who developed the so-called Ames 409 00:27:57,120 --> 00:27:57,620 test. 410 00:28:00,764 --> 00:28:02,180 And I want to tell you about that. 411 00:28:02,180 --> 00:28:09,110 But actually, before I do, let me just show you graphically 412 00:28:09,110 --> 00:28:16,670 how the agent can be tested for its carcinogenic capabilities 413 00:28:16,670 --> 00:28:20,070 and its mutagenic capabilities. 414 00:28:20,070 --> 00:28:25,870 The carcinogen is tested by treating an animal-- 415 00:28:25,870 --> 00:28:28,290 a mouse or a rat-- 416 00:28:28,290 --> 00:28:30,060 injecting the animal with the carcinogen 417 00:28:30,060 --> 00:28:32,790 or painting the carcinogen or the potential carcinogen 418 00:28:32,790 --> 00:28:34,740 on the skin of the animal, and then 419 00:28:34,740 --> 00:28:38,400 waiting a certain amount of time and asking the question 420 00:28:38,400 --> 00:28:40,050 whether the animal developed a tumor. 421 00:28:40,050 --> 00:28:42,729 And you can do this with different doses of the agent, 422 00:28:42,729 --> 00:28:44,520 with large numbers of animals, and actually 423 00:28:44,520 --> 00:28:46,650 get quantitative data that tells you 424 00:28:46,650 --> 00:28:49,710 the potency of this potential carcinogen. 425 00:28:49,710 --> 00:28:53,490 So that's the carcinogenesis assay. 426 00:28:53,490 --> 00:28:58,910 To test whether something is a mutagen, you can take the agent 427 00:28:58,910 --> 00:29:03,320 and treat cells and ask whether you can cause mutations 428 00:29:03,320 --> 00:29:04,520 in those cells. 429 00:29:04,520 --> 00:29:07,340 You could do this in lots of different types of cells. 430 00:29:07,340 --> 00:29:09,530 But the easiest types of cells to do it in 431 00:29:09,530 --> 00:29:14,720 are bacterial cells, for example, salmonella bacteria 432 00:29:14,720 --> 00:29:16,550 or E. coli. 433 00:29:16,550 --> 00:29:18,530 And the way this assay is done is 434 00:29:18,530 --> 00:29:22,190 to use cells that are defective in the production 435 00:29:22,190 --> 00:29:25,830 of an amino acid, let's say histidine. 436 00:29:25,830 --> 00:29:29,300 So the cells have mutations in a biosynthetic enzyme-- 437 00:29:29,300 --> 00:29:31,840 and I'll tell you more about this in a second-- 438 00:29:31,840 --> 00:29:34,730 that is required for the cells to make histidine. 439 00:29:34,730 --> 00:29:38,470 Now these cells can live if you provide histidine to them 440 00:29:38,470 --> 00:29:41,510 exogenously, for example, on the Petri dish. 441 00:29:41,510 --> 00:29:46,280 But if you take those cells and you plate them 442 00:29:46,280 --> 00:29:49,880 on a Petri dish that is lacking histidine, none of the cells 443 00:29:49,880 --> 00:29:57,380 will be able to grow because they require 444 00:29:57,380 --> 00:30:00,060 exogenous histidine to live. 445 00:30:00,060 --> 00:30:04,090 However, if you take that mutagen 446 00:30:04,090 --> 00:30:08,480 and you add it to these histidine minus cells, 447 00:30:08,480 --> 00:30:11,780 the mutagen might correct the mutation 448 00:30:11,780 --> 00:30:13,700 in the histidine biosynthesis gene, 449 00:30:13,700 --> 00:30:15,410 thereby converting it to a wild type 450 00:30:15,410 --> 00:30:18,680 form at some low frequency. 451 00:30:18,680 --> 00:30:22,760 Such that if you plate these now mutagen-treated cells 452 00:30:22,760 --> 00:30:26,420 on a histidine minus plate, you might 453 00:30:26,420 --> 00:30:28,080 get a few colonies growing. 454 00:30:30,980 --> 00:30:33,170 And these would be histidine plus, 455 00:30:33,170 --> 00:30:37,510 capable of producing histidine themselves, revertants. 456 00:30:43,110 --> 00:30:46,620 They've reverted the mutation to now a wild type form. 457 00:30:46,620 --> 00:30:47,730 OK? 458 00:30:47,730 --> 00:30:50,520 And it was this that was the basis of the Ames test, 459 00:30:50,520 --> 00:30:57,790 to test the mutagenicity of potential compounds. 460 00:30:57,790 --> 00:31:04,660 Now we actually use different versions of his minus bacteria, 461 00:31:04,660 --> 00:31:08,320 because different mutagens cause different types of mutations. 462 00:31:08,320 --> 00:31:10,570 And if you use just one mutant bacteria, 463 00:31:10,570 --> 00:31:14,200 you might miss certain potential mutagens. 464 00:31:14,200 --> 00:31:21,280 So for example, if we have a specific mutant, which 465 00:31:21,280 --> 00:31:35,300 is in a gene required for the conversion of histidinol, 466 00:31:35,300 --> 00:31:40,010 in an enzyme that is called histidinol dihydrogenase, 467 00:31:40,010 --> 00:31:48,940 this enzyme is required to produce histidine 468 00:31:48,940 --> 00:31:50,650 in the final step of the synthesis. 469 00:31:56,000 --> 00:32:12,950 The wild type enzyme would have a particular sequence, 470 00:32:12,950 --> 00:32:16,370 which would encode a particular pair of amino acids, 471 00:32:16,370 --> 00:32:19,650 glutamine and serine. 472 00:32:19,650 --> 00:32:22,500 And it is this collection of histidine minus bacteria, 473 00:32:22,500 --> 00:32:24,720 this collection of histidine minus bacteria 474 00:32:24,720 --> 00:32:27,960 that we use in this assay, we might 475 00:32:27,960 --> 00:32:40,160 have one mutant, which has an alteration, which 476 00:32:40,160 --> 00:32:42,950 converts that C to a T. 477 00:32:42,950 --> 00:32:44,480 This creates a termination codon. 478 00:32:46,990 --> 00:32:49,804 So this is why that bacterium can't make histidine, 479 00:32:49,804 --> 00:32:51,220 because it can't make that enzyme. 480 00:32:51,220 --> 00:32:52,761 It has a stop codon on that position. 481 00:32:57,090 --> 00:32:59,430 A second mutant might have a different stop codon. 482 00:33:06,080 --> 00:33:08,060 This is determination codon. 483 00:33:08,060 --> 00:33:14,650 Here, this C has been converted to a G, 484 00:33:14,650 --> 00:33:15,820 creating the stop codon. 485 00:33:15,820 --> 00:33:19,810 And a third mutant might have an abnormal number 486 00:33:19,810 --> 00:33:27,530 of bases in this region, an insertion of an A residue, 487 00:33:27,530 --> 00:33:29,740 which would cause a frame shift. 488 00:33:34,690 --> 00:33:36,700 These are three different mutants, 489 00:33:36,700 --> 00:33:39,370 which would require three different types of alterations 490 00:33:39,370 --> 00:33:42,290 in the DNA to convert back to the wild type. 491 00:33:42,290 --> 00:33:45,190 Here, this pyrimidine would have to be converted 492 00:33:45,190 --> 00:33:46,870 to a different pyrimidine. 493 00:33:46,870 --> 00:33:51,250 Here, this purine would have to be converted to a pyrimidine. 494 00:33:51,250 --> 00:33:53,290 And here this abnormal number of bases 495 00:33:53,290 --> 00:33:57,970 would have to be corrected to the correct number. 496 00:33:57,970 --> 00:34:00,760 This would allow one to find agents 497 00:34:00,760 --> 00:34:05,650 which function as point mutagens, which 498 00:34:05,650 --> 00:34:07,000 is a class of mutagens. 499 00:34:07,000 --> 00:34:09,469 They create point mutations. 500 00:34:09,469 --> 00:34:11,679 And this type of bacteria would allow 501 00:34:11,679 --> 00:34:14,010 you to find what are called frame shift mutagens. 502 00:34:19,800 --> 00:34:21,750 So these bacteria are mixed together. 503 00:34:21,750 --> 00:34:23,310 The mutagen is added. 504 00:34:23,310 --> 00:34:25,230 And then you count the number of cells that 505 00:34:25,230 --> 00:34:27,690 survive on the his minus plate. 506 00:34:27,690 --> 00:34:29,480 That's the original Ames test. 507 00:34:33,440 --> 00:34:39,110 As Ames and others continue to do this kind of testing, 508 00:34:39,110 --> 00:34:57,110 they discovered, to their surprise, 509 00:34:57,110 --> 00:35:00,240 that some clearly established carcinogens 510 00:35:00,240 --> 00:35:02,710 failed the Ames test. 511 00:35:02,710 --> 00:35:04,840 They cause lots of tumors in animals, 512 00:35:04,840 --> 00:35:06,910 but they didn't revert any bacteria 513 00:35:06,910 --> 00:35:09,310 in that bacterial assay. 514 00:35:09,310 --> 00:35:12,070 So can anybody think why that is? 515 00:35:12,070 --> 00:35:15,420 Why might an agent, which can clearly cause cancer, 516 00:35:15,420 --> 00:35:16,510 fail that test? 517 00:35:20,950 --> 00:35:23,530 Well, one answer-- and the most common answer-- 518 00:35:23,530 --> 00:35:31,990 is that the agent itself is not itself a mutation. 519 00:35:31,990 --> 00:35:40,880 But it can be converted in the body 520 00:35:40,880 --> 00:35:42,770 through the process of metabolism. 521 00:35:42,770 --> 00:35:45,590 As your body tries to convert that agent into something, 522 00:35:45,590 --> 00:35:47,570 for example, that it can excrete, 523 00:35:47,570 --> 00:35:50,360 it alters it chemically and converts it 524 00:35:50,360 --> 00:35:55,580 from a promutagenic form into a mutagenic form. 525 00:35:55,580 --> 00:35:59,780 And in this form, it can cause mutations in your DNA, 526 00:35:59,780 --> 00:36:03,060 and in theory, in the bacterial cases as well. 527 00:36:03,060 --> 00:36:07,550 And here's an example of a promutagen called 528 00:36:07,550 --> 00:36:13,360 benzo(a)pyrene, a very important mutation in cigarette smoke. 529 00:36:13,360 --> 00:36:15,580 This is converted, through various steps 530 00:36:15,580 --> 00:36:21,760 inside your liver, to a form that is much more mutagenic. 531 00:36:21,760 --> 00:36:25,420 These epoxides are much more mutagenic 532 00:36:25,420 --> 00:36:27,910 compared to the original compound, 533 00:36:27,910 --> 00:36:31,450 much more reactive, much more reactive to DNA. 534 00:36:31,450 --> 00:36:35,820 And in these forms, the compound will actually covalently 535 00:36:35,820 --> 00:36:40,260 attach to the bases of DNA and cause mutations. 536 00:36:40,260 --> 00:36:40,890 OK? 537 00:36:40,890 --> 00:36:44,430 So in this sense, your body is actually part of the problem. 538 00:36:44,430 --> 00:36:46,860 It's trying to get rid of this bad stuff, 539 00:36:46,860 --> 00:36:49,220 but in the process of doing that, it's making it worse. 540 00:36:53,210 --> 00:36:55,790 Recognizing that this was an issue for actually 541 00:36:55,790 --> 00:37:01,460 quite a few potential mutagens, Ames and others 542 00:37:01,460 --> 00:37:03,496 modified the Ames test. 543 00:37:03,496 --> 00:37:05,120 It's now called the Modified Ames test. 544 00:37:08,020 --> 00:37:10,390 In which case, you take the compound of interest, 545 00:37:10,390 --> 00:37:25,540 the potential mutagen, you mix it with some extract from liver 546 00:37:25,540 --> 00:37:28,810 to allow this metabolism to occur. 547 00:37:28,810 --> 00:37:33,730 And then you take those, the metabolized compound, 548 00:37:33,730 --> 00:37:45,760 and you do the bacterial, the bacterial mutagenesis 549 00:37:45,760 --> 00:37:47,510 test that I just reviewed for you. 550 00:37:47,510 --> 00:37:48,220 OK? 551 00:37:48,220 --> 00:37:50,830 And now you find that many of these things that failed 552 00:37:50,830 --> 00:37:52,870 initially, score positively. 553 00:37:55,511 --> 00:37:56,010 OK. 554 00:37:56,010 --> 00:37:59,940 So stuff that we get exposed to, like benzo(a)pyrene, 555 00:37:59,940 --> 00:38:01,800 and other agents in the environment, 556 00:38:01,800 --> 00:38:05,580 can cause mutations, and these can also cause cancer. 557 00:38:08,140 --> 00:38:15,160 I just want to take a few seconds 558 00:38:15,160 --> 00:38:20,550 to rail against tobacco smoke and cigarette smoking. 559 00:38:20,550 --> 00:38:23,850 Lung cancer is the most common form of cancer in this country. 560 00:38:23,850 --> 00:38:29,190 175,000 deaths due to lung cancer each year. 561 00:38:29,190 --> 00:38:33,720 About 150,000 of those deaths are due to smoking. 562 00:38:33,720 --> 00:38:36,120 It's the most common form of cancer, 563 00:38:36,120 --> 00:38:39,090 and among the most preventable forms of cancer, 564 00:38:39,090 --> 00:38:43,830 through to the failure to expose the body to carcinogens 565 00:38:43,830 --> 00:38:45,150 in cigarette smoke. 566 00:38:45,150 --> 00:38:48,490 Not only is there benzo(a)pyrene in cigarette smoke, 567 00:38:48,490 --> 00:38:54,960 but there's about 1,000 other carcinogens in cigarette smoke. 568 00:38:54,960 --> 00:38:58,020 Cigarette smoking is still very common in this country, 569 00:38:58,020 --> 00:38:59,610 remarkably common in this country. 570 00:38:59,610 --> 00:39:04,290 About 46 million adults still smoke in this country. 571 00:39:04,290 --> 00:39:06,360 A remarkable number of high school students 572 00:39:06,360 --> 00:39:08,220 still smoke in this country. 573 00:39:08,220 --> 00:39:11,820 And it's because of this that lung cancer rates are still 574 00:39:11,820 --> 00:39:13,830 very, very high. 575 00:39:13,830 --> 00:39:16,110 Moreover, smoking causes all sorts 576 00:39:16,110 --> 00:39:21,390 of other diseases-- emphysema, kidney diseases, 577 00:39:21,390 --> 00:39:23,370 cardiovascular diseases. 578 00:39:23,370 --> 00:39:27,102 It's now estimated that among the however many billions 579 00:39:27,102 --> 00:39:28,560 of people are on the planet today-- 580 00:39:28,560 --> 00:39:31,860 what's that number, 6 billion people on the planet today? 581 00:39:31,860 --> 00:39:34,650 Something like 650 million of them 582 00:39:34,650 --> 00:39:38,250 will die due to the exposure to cigarette smoke. 583 00:39:38,250 --> 00:39:44,130 So my little lesson here is that if you're currently smoking, 584 00:39:44,130 --> 00:39:45,690 stop. 585 00:39:45,690 --> 00:39:48,540 If you're not smoking, don't start. 586 00:39:48,540 --> 00:39:50,940 It's the easiest way to protect yourself 587 00:39:50,940 --> 00:39:54,701 against many, many dangerous future problems. 588 00:39:54,701 --> 00:39:55,200 All right. 589 00:39:55,200 --> 00:39:58,650 So cigarette smoke is something we do to ourselves. 590 00:39:58,650 --> 00:40:02,880 We expose ourselves to mutagens that cause cancer 591 00:40:02,880 --> 00:40:05,880 cells to develop in your lungs and in other parts 592 00:40:05,880 --> 00:40:08,330 of your body. 593 00:40:08,330 --> 00:40:18,140 There are other so-called exogenous mutagens, 594 00:40:18,140 --> 00:40:19,970 things that we get exposed to. 595 00:40:23,680 --> 00:40:28,440 Sunlight, for example, sunlight, the UV rays in sunlight, 596 00:40:28,440 --> 00:40:32,220 can cause damage to your DNA, causing skin cancer 597 00:40:32,220 --> 00:40:33,090 and melanoma. 598 00:40:43,710 --> 00:40:48,370 Dietary carcinogens, barbecued beef, 599 00:40:48,370 --> 00:40:52,690 has certain dietary carcinogens in the category, actually, 600 00:40:52,690 --> 00:40:56,380 of benzo(a)pyrene, that can cause damage to your DNA 601 00:40:56,380 --> 00:40:58,480 and induce colon cancer. 602 00:40:58,480 --> 00:41:01,990 Not at high numbers, not saying you shouldn't eat barbecue. 603 00:41:01,990 --> 00:41:03,970 But still, this is an example of stuff 604 00:41:03,970 --> 00:41:06,480 we get exposed to that increases our cancer risk. 605 00:41:16,150 --> 00:41:18,710 Replication errors. 606 00:41:18,710 --> 00:41:21,810 Your cells are good at copying the DNA. 607 00:41:21,810 --> 00:41:23,280 They're very good at it. 608 00:41:23,280 --> 00:41:26,100 They have proofreading functions that make them better at it. 609 00:41:26,100 --> 00:41:27,630 But they're not perfect. 610 00:41:27,630 --> 00:41:30,660 So every time your cells divide, you actually 611 00:41:30,660 --> 00:41:34,240 run the risk of making a mistake. 612 00:41:34,240 --> 00:41:36,370 And replication errors are a common source 613 00:41:36,370 --> 00:41:37,560 of mutations in cancer. 614 00:41:45,120 --> 00:41:47,520 As your cells are moving DNA around, 615 00:41:47,520 --> 00:41:49,890 they also sometimes break it. 616 00:41:49,890 --> 00:41:52,800 And these DNA breaks are sometimes sealed properly, 617 00:41:52,800 --> 00:41:53,850 but sometimes not. 618 00:41:53,850 --> 00:41:55,170 And deletions can occur. 619 00:41:55,170 --> 00:41:57,520 And translocations can occur. 620 00:41:57,520 --> 00:42:01,800 And another endogenous process that leads to mutations, 621 00:42:01,800 --> 00:42:03,270 including in cancer cells. 622 00:42:13,140 --> 00:42:15,210 Defects in DNA repair. 623 00:42:15,210 --> 00:42:17,730 You have lots of enzymes that are looking at your DNA 624 00:42:17,730 --> 00:42:20,370 at all times for adducts that have formed, 625 00:42:20,370 --> 00:42:21,930 and other alterations. 626 00:42:21,930 --> 00:42:26,010 And those enzymes remove those damaged bases and fix them. 627 00:42:26,010 --> 00:42:28,020 But sometimes they fail. 628 00:42:28,020 --> 00:42:31,500 Sometimes they actually get mutated in cancer cells, 629 00:42:31,500 --> 00:42:34,220 raising the risk still further. 630 00:42:34,220 --> 00:42:37,590 So defects in DNA damage and DNA damage repair enzymes. 631 00:42:53,200 --> 00:42:55,890 Your cells also produce endogenous mutagens. 632 00:42:59,460 --> 00:43:07,140 Various reactive oxygen species are produced, for example, 633 00:43:07,140 --> 00:43:09,060 in the process of metabolism. 634 00:43:09,060 --> 00:43:10,730 And these reactive oxygen species, 635 00:43:10,730 --> 00:43:14,000 like superoxide, hydrogen peroxide, 636 00:43:14,000 --> 00:43:17,690 can interact with the DNA and cause mutations. 637 00:43:17,690 --> 00:43:21,530 This is why antioxidants are useful in preventing cancer 638 00:43:21,530 --> 00:43:23,220 in some settings. 639 00:43:23,220 --> 00:43:23,750 OK? 640 00:43:23,750 --> 00:43:26,780 So various things that we get exposed to 641 00:43:26,780 --> 00:43:30,710 or we expose ourselves to cause mutations in DNA. 642 00:43:30,710 --> 00:43:34,245 And this results, ultimately, in the development of cancers. 643 00:43:37,090 --> 00:43:38,560 The last thing I'll mention to you 644 00:43:38,560 --> 00:43:42,040 is that this doesn't happen overnight. 645 00:43:42,040 --> 00:43:46,000 It's not that a single alteration in a single gene 646 00:43:46,000 --> 00:43:49,210 is sufficient to derive tumor development. 647 00:43:49,210 --> 00:43:58,440 Instead, it's a process that occurs over time 648 00:43:58,440 --> 00:44:01,510 and requires alterations to many genes. 649 00:44:01,510 --> 00:44:04,290 So if you imagine a cell, a normal cell, 650 00:44:04,290 --> 00:44:07,710 which divides to produce two daughters with the same DNA 651 00:44:07,710 --> 00:44:13,170 content, at some frequency, this cell might acquire a mutation. 652 00:44:13,170 --> 00:44:15,630 Maybe it got exposed to cigarette smoke. 653 00:44:15,630 --> 00:44:17,550 Maybe it got exposed to superoxide. 654 00:44:17,550 --> 00:44:19,270 Maybe it made a mistake. 655 00:44:19,270 --> 00:44:22,410 And this mutation then confers upon that cell 656 00:44:22,410 --> 00:44:27,030 the ability to divide especially well. 657 00:44:27,030 --> 00:44:31,290 And now all of its daughter cells carry that same mutation. 658 00:44:31,290 --> 00:44:36,480 And as that cell divides further and produces 659 00:44:36,480 --> 00:44:43,050 daughter cells of its own, perhaps one of those cells-- 660 00:44:43,050 --> 00:44:45,900 and this might not be in the very next cell division, 661 00:44:45,900 --> 00:44:47,940 it might be five years later-- 662 00:44:47,940 --> 00:44:52,070 one of those cells acquires a second mutation. 663 00:44:52,070 --> 00:44:55,460 And that mutation gives that cell 664 00:44:55,460 --> 00:45:00,410 the ability to divide even more rapidly, 665 00:45:00,410 --> 00:45:02,810 or survive even better. 666 00:45:02,810 --> 00:45:05,210 And again, all of its descendant cells 667 00:45:05,210 --> 00:45:09,330 will have that same abnormal genotype. 668 00:45:09,330 --> 00:45:11,790 And maybe within that clone of cells, 669 00:45:11,790 --> 00:45:14,130 a third mutation takes place. 670 00:45:14,130 --> 00:45:15,900 And on and on we go. 671 00:45:15,900 --> 00:45:18,270 We now think that we need somewhere between 5 672 00:45:18,270 --> 00:45:22,320 and 10 mutations in cellular genes 673 00:45:22,320 --> 00:45:24,180 to allow the cells to progress all 674 00:45:24,180 --> 00:45:26,340 the way to that full blown cancer 675 00:45:26,340 --> 00:45:28,740 that I showed you in pictures before. 676 00:45:28,740 --> 00:45:38,760 So this process continues until we have true malignancy. 677 00:45:38,760 --> 00:45:44,130 And this process of developing clones with increasing ability 678 00:45:44,130 --> 00:45:58,890 to develop into cancer, we call the clonal evolution theory, 679 00:45:58,890 --> 00:46:03,850 the clonal evolution of increasingly abnormal clones, 680 00:46:03,850 --> 00:46:07,580 which eventually will develop into a cancer. 681 00:46:07,580 --> 00:46:09,230 And next time we'll talk about what 682 00:46:09,230 --> 00:46:14,530 are the genes that are mutated in these developing cancers.