WEBVTT 1 00:00:00.600 --> 00:00:03.090 Hi all, in this lecture, 2 00:00:03.090 --> 00:00:04.350 we'll continue our discussions 3 00:00:04.350 --> 00:00:06.060 of the epidemiology of lung cancer 4 00:00:06.060 --> 00:00:09.870 by discussing risk factors in tobacco carcinogenesis. 5 00:00:09.870 --> 00:00:13.290 Our two main goals are to describe tobacco carcinogenesis 6 00:00:13.290 --> 00:00:16.800 and to review studies of other lung cancer risk factors. 7 00:00:16.800 --> 00:00:20.100 So to begin with, tobacco smoke contains 8 00:00:20.100 --> 00:00:22.440 several carcinogenic chemicals. 9 00:00:22.440 --> 00:00:24.180 These are divided into three main classes, 10 00:00:24.180 --> 00:00:26.550 the polycyclic aromatic hydrocarbons, 11 00:00:26.550 --> 00:00:30.000 nitrous amines, and heterocyclic amines. 12 00:00:30.000 --> 00:00:31.530 These chemicals are taken up by the body 13 00:00:31.530 --> 00:00:34.290 and cause DNA mutations and damage, 14 00:00:34.290 --> 00:00:39.290 which leads to the cell division 15 00:00:39.690 --> 00:00:42.723 that is responsible for lung cancers. 16 00:00:43.830 --> 00:00:45.275 Tobacco smoke is a complex mixture 17 00:00:45.275 --> 00:00:48.630 of more than 5,000 gases and compounds, 18 00:00:48.630 --> 00:00:49.985 which has made it difficult to determine 19 00:00:49.985 --> 00:00:53.280 exactly what these carcinogens are, 20 00:00:53.280 --> 00:00:57.060 though many different epidemiologic studies 21 00:00:57.060 --> 00:01:00.000 have elucidated these three main classes 22 00:01:00.000 --> 00:01:02.973 as the ones responsible for cancers. 23 00:01:05.430 --> 00:01:09.270 So in addition to these three carcinogen classes, 24 00:01:09.270 --> 00:01:11.220 there's other chemical compounds that are present 25 00:01:11.220 --> 00:01:13.890 that are highly inflammatory to lung tissues. 26 00:01:13.890 --> 00:01:18.390 One of the primary ones is tobacco residue, or tar. 27 00:01:18.390 --> 00:01:20.700 It's the common name given to the particular matter 28 00:01:20.700 --> 00:01:25.700 of tobacco smoke without nicotine and water content. 29 00:01:25.920 --> 00:01:28.425 So tar is a mixture, actually, 30 00:01:28.425 --> 00:01:30.240 of thousands of compounds 31 00:01:30.240 --> 00:01:31.260 resulting from the combustion 32 00:01:31.260 --> 00:01:33.153 of tobacco and tobacco resins. 33 00:01:34.290 --> 00:01:36.870 And it's estimated that lungs of a chronic smoker 34 00:01:36.870 --> 00:01:39.390 of 20 or more cigarettes per day for 40 years 35 00:01:39.390 --> 00:01:41.853 are exposed to 8 to 10 kilograms of tar. 36 00:01:43.740 --> 00:01:45.330 So when it comes to lung cancer, 37 00:01:45.330 --> 00:01:47.760 there are several synergistic risk factors. 38 00:01:47.760 --> 00:01:51.030 So key risk factors are asbestos fibers, 39 00:01:51.030 --> 00:01:55.320 radon, arsenic, cadmium, lead, dioxins, 40 00:01:55.320 --> 00:01:57.423 genetic predisposition, and diet. 41 00:01:58.950 --> 00:02:03.120 And in particular, all these exposures 42 00:02:03.120 --> 00:02:04.380 can be responsible 43 00:02:04.380 --> 00:02:06.360 for chronic inflammation in lung tissues, 44 00:02:06.360 --> 00:02:08.250 and it's the inflammation that's responsible 45 00:02:08.250 --> 00:02:11.223 for the increased risk of lung cancer. 46 00:02:12.120 --> 00:02:15.390 So to begin with, or to touch upon one example, 47 00:02:15.390 --> 00:02:19.170 radon is a key risk factor for lung cancer. 48 00:02:19.170 --> 00:02:21.690 It's a colorless and odorless gas, 49 00:02:21.690 --> 00:02:24.330 and it's capable of damaging DNA, 50 00:02:24.330 --> 00:02:25.620 which can cause mutations 51 00:02:25.620 --> 00:02:26.970 that can lead to carcinogenesis 52 00:02:26.970 --> 00:02:29.089 and the development of lung cancer. 53 00:02:29.089 --> 00:02:31.866 There have been several studies 54 00:02:31.866 --> 00:02:34.500 that have pointed to radon 55 00:02:34.500 --> 00:02:36.270 as a risk factor for lung cancer. 56 00:02:36.270 --> 00:02:40.230 So in early ecological study of lung cancer in Maine, 57 00:02:40.230 --> 00:02:42.930 estimates of radon levels in domestic water supplies 58 00:02:42.930 --> 00:02:44.790 were found to be significantly correlated 59 00:02:44.790 --> 00:02:47.970 with county rates of lung cancer across the states. 60 00:02:47.970 --> 00:02:51.300 A study also found that exposure to radon in uranium miners 61 00:02:51.300 --> 00:02:53.347 was found to be independently, 62 00:02:53.347 --> 00:02:55.746 or was found to independently increase 63 00:02:55.746 --> 00:02:58.710 the miner's risk of lung cancer. 64 00:02:58.710 --> 00:03:01.200 Finally, the Iowa Radon Study 65 00:03:01.200 --> 00:03:04.560 found a significant dose response and lung cancer risk 66 00:03:04.560 --> 00:03:07.380 in women with communicative radon exposures 67 00:03:07.380 --> 00:03:09.297 exceeding five picocuries, 68 00:03:09.297 --> 00:03:13.500 which is the measure of exposure to radon. 69 00:03:13.500 --> 00:03:16.680 So in 1994, the US EPA, 70 00:03:16.680 --> 00:03:18.660 or the Environmental Protection Agency, 71 00:03:18.660 --> 00:03:19.980 issued a warning that radon 72 00:03:19.980 --> 00:03:22.530 could be the second most frequent cause of lung cancer, 73 00:03:22.530 --> 00:03:23.883 after cigarette smoking. 74 00:03:25.740 --> 00:03:30.330 And it's important to note or to remember 75 00:03:30.330 --> 00:03:33.570 the discussion of Hill's criteria of causality, 76 00:03:33.570 --> 00:03:35.430 that the determination 77 00:03:35.430 --> 00:03:37.743 that radon is a significant risk factor, 78 00:03:39.390 --> 00:03:41.040 that conclusion was only made 79 00:03:41.040 --> 00:03:43.800 after looking at a number of independent studies 80 00:03:43.800 --> 00:03:46.050 and seeing that their conclusions all pointed 81 00:03:46.890 --> 00:03:49.893 to radon as a risk factor. 82 00:03:51.210 --> 00:03:53.640 Next, to discuss another risk factor, 83 00:03:53.640 --> 00:03:56.130 asbestos causes mesothelioma 84 00:03:56.130 --> 00:04:00.183 and malignancy of the tissue surrounding the lung. 85 00:04:01.860 --> 00:04:04.050 The etiologic link between mesothelioma 86 00:04:04.050 --> 00:04:06.156 and asbestos exposure is well established 87 00:04:06.156 --> 00:04:08.163 through numerous studies. 88 00:04:09.180 --> 00:04:13.849 And the way that asbestos leads to lung inflammation 89 00:04:13.849 --> 00:04:15.828 is that the inhaled fibers migrate 90 00:04:15.828 --> 00:04:17.749 to the periphery of the lung 91 00:04:17.749 --> 00:04:19.350 where they become trapped 92 00:04:19.350 --> 00:04:24.229 and cause repetitive inflammatory events, 93 00:04:24.229 --> 00:04:27.063 which lead to carcinogenesis. 94 00:04:28.020 --> 00:04:30.000 It's also estimated those asbestos workers 95 00:04:30.000 --> 00:04:31.380 with a history of chronic smoking 96 00:04:31.380 --> 00:04:33.390 have eightfold higher lung cancer risk 97 00:04:33.390 --> 00:04:36.750 than smokers who have not been exposed to asbestos. 98 00:04:36.750 --> 00:04:39.810 In addition, asbestos-exposed male smokers 99 00:04:39.810 --> 00:04:42.180 have roughly 50 times the lung cancer risk 100 00:04:42.180 --> 00:04:44.700 of unexposed men who do not smoke. 101 00:04:44.700 --> 00:04:46.380 And we see that from this figure here, 102 00:04:46.380 --> 00:04:48.450 that smoking and asbestos exposure 103 00:04:48.450 --> 00:04:50.400 really acts synergistically 104 00:04:50.400 --> 00:04:52.983 to increase one's risk of lung cancer. 105 00:04:54.117 --> 00:04:58.200 Next, wood smoke is another important risk factor 106 00:04:58.200 --> 00:04:59.250 for lung cancer. 107 00:04:59.250 --> 00:05:01.650 It contains a mixture of harmful chemicals 108 00:05:01.650 --> 00:05:03.780 in the form of gases and particulate matter, 109 00:05:03.780 --> 00:05:07.050 like carbon monoxide, ozone, nitrous oxides, 110 00:05:07.050 --> 00:05:10.170 sulfur dioxide, volatile organic compounds, 111 00:05:10.170 --> 00:05:12.180 dioxin, potential carcinogens, 112 00:05:12.180 --> 00:05:14.220 and inhalable particles. 113 00:05:14.220 --> 00:05:16.355 And certain of these compounds 114 00:05:16.355 --> 00:05:18.690 are not only irritating and toxic, 115 00:05:18.690 --> 00:05:21.243 but also potent carcinogens on their own. 116 00:05:22.260 --> 00:05:24.690 It's been estimated that residential wood combustion 117 00:05:24.690 --> 00:05:26.490 may account for up to 75% 118 00:05:26.490 --> 00:05:29.520 of the exposure to particulate associated organics 119 00:05:29.520 --> 00:05:31.650 and account for a significant fraction 120 00:05:31.650 --> 00:05:32.520 of the cancer risk 121 00:05:32.520 --> 00:05:35.580 in the upper respiratory tract of non-smokers. 122 00:05:35.580 --> 00:05:36.750 Exposure to wood smoke 123 00:05:36.750 --> 00:05:38.310 may increase the risk of lung cancer 124 00:05:38.310 --> 00:05:41.340 via a mechanism similar to that of tobacco. 125 00:05:41.340 --> 00:05:43.140 And the role of air pollution 126 00:05:43.140 --> 00:05:44.400 in the genesis of lung cancer 127 00:05:44.400 --> 00:05:46.320 was examined in a prospective cohort study 128 00:05:46.320 --> 00:05:48.900 of more than one million American men and women 129 00:05:48.900 --> 00:05:50.220 conducted by investigators 130 00:05:50.220 --> 00:05:52.053 at the American Cancer Society. 131 00:05:53.820 --> 00:05:56.730 These study results showed that for each 1% increase 132 00:05:56.730 --> 00:05:58.920 in the the concentration of particles in the air 133 00:05:58.920 --> 00:06:00.750 led to a 14% increase 134 00:06:00.750 --> 00:06:03.298 in the risk of developing a lung cancer. 135 00:06:03.298 --> 00:06:04.950 It's important to note, too, 136 00:06:04.950 --> 00:06:08.160 that people can be exposed to wood smoke 137 00:06:08.160 --> 00:06:10.923 and various sources of air pollution in different ways. 138 00:06:11.760 --> 00:06:13.380 So in certain parts of the world, 139 00:06:13.380 --> 00:06:17.790 wood and burning wood can be used to heat one's home, 140 00:06:17.790 --> 00:06:20.490 and it's also a key way 141 00:06:20.490 --> 00:06:22.050 that people in some countries 142 00:06:22.050 --> 00:06:24.120 and communities will cook food. 143 00:06:24.120 --> 00:06:29.040 So there's lots of exposure related to people who cook, 144 00:06:29.040 --> 00:06:31.590 especially when there's wood-burning stoves 145 00:06:31.590 --> 00:06:33.933 inside a house without proper ventilation. 146 00:06:35.100 --> 00:06:37.920 So next, to briefly touch 147 00:06:37.920 --> 00:06:41.280 upon chronic obstructive pulmonary disease, or COPD, 148 00:06:41.280 --> 00:06:43.050 which causes three million deaths annually 149 00:06:43.050 --> 00:06:44.463 in the world population, 150 00:06:46.440 --> 00:06:48.090 it's a chronic inflammatory condition 151 00:06:48.090 --> 00:06:50.643 and it increases the risk of lung cancer. 152 00:06:53.070 --> 00:06:55.831 Other key risk factors for lung cancer 153 00:06:55.831 --> 00:06:59.792 are dioxins and arsenic. 154 00:06:59.792 --> 00:07:03.060 So dioxins are metabolized by a couple of liver enzymes 155 00:07:03.060 --> 00:07:05.370 into compounds with carcinogenic potential 156 00:07:05.370 --> 00:07:07.969 in lung cells and other tissues. 157 00:07:07.969 --> 00:07:10.560 One study that looked at the population 158 00:07:10.560 --> 00:07:12.888 of a town in Italy, Sevenso, 159 00:07:12.888 --> 00:07:15.510 there was exposed to dioxin 160 00:07:15.510 --> 00:07:18.900 after an industrial accident that occurred in 1976. 161 00:07:18.900 --> 00:07:20.670 Then, after this accident, 162 00:07:20.670 --> 00:07:22.260 lung cancer mortality among men 163 00:07:22.260 --> 00:07:25.773 in high exposure zones was significantly increased. 164 00:07:27.047 --> 00:07:28.530 The results of this study 165 00:07:28.530 --> 00:07:30.720 support the continued evaluation of dioxin 166 00:07:30.720 --> 00:07:32.190 as a lung carcinogen 167 00:07:32.190 --> 00:07:34.590 and underscore the need to also study interactions 168 00:07:34.590 --> 00:07:37.740 with tobacco and other risk factors. 169 00:07:37.740 --> 00:07:39.300 Longterm exposure to low levels 170 00:07:39.300 --> 00:07:40.320 of arsenic in drinking water 171 00:07:40.320 --> 00:07:41.850 have been linked to human health risks 172 00:07:41.850 --> 00:07:43.920 associated with cancer at multiple sites, 173 00:07:43.920 --> 00:07:46.920 including the lung, bladder, and skin. 174 00:07:46.920 --> 00:07:49.620 Studies have shown that the malignant transformation 175 00:07:49.620 --> 00:07:52.540 of mammalian cells by inorganic arsenic occurs 176 00:07:54.240 --> 00:07:56.520 and that arsenic exposure is both mutagenic 177 00:07:56.520 --> 00:07:58.443 and carcinogenic in humans. 178 00:08:00.360 --> 00:08:03.670 A study in Chile over the course of 50 years 179 00:08:04.560 --> 00:08:06.360 looking at a population exposed 180 00:08:06.360 --> 00:08:08.869 to arsenic contaminated drinking water, 181 00:08:08.869 --> 00:08:11.098 it was shown that toxic arsenic exposure 182 00:08:11.098 --> 00:08:13.740 greatly increased lung cancer risk 183 00:08:13.740 --> 00:08:17.253 when exposure occurred in utero or early in life. 184 00:08:18.420 --> 00:08:20.850 Another key risk factor 185 00:08:20.850 --> 00:08:22.736 is environmental tobacco smoke, 186 00:08:22.736 --> 00:08:24.393 or secondhand smoke. 187 00:08:25.650 --> 00:08:27.840 We see that environmental tobacco smoke 188 00:08:27.840 --> 00:08:30.060 inhaled by non-smokers has higher levels 189 00:08:30.060 --> 00:08:32.700 of nitrosamines and smaller particle sizes, 190 00:08:32.700 --> 00:08:36.270 leading to easier deposition within the bronchial tree. 191 00:08:36.270 --> 00:08:38.940 Approximately one-third of lung cancer in non-smokers 192 00:08:38.940 --> 00:08:40.320 results from passive exposure 193 00:08:40.320 --> 00:08:42.300 to secondhand cigarette smoke, 194 00:08:42.300 --> 00:08:45.300 and environmental tobacco smoke or secondhand smoke 195 00:08:45.300 --> 00:08:47.010 increases the risk of heart attacks 196 00:08:47.010 --> 00:08:49.230 and myocardial infraction in adults, 197 00:08:49.230 --> 00:08:52.290 and is also linked to various conditions in children, 198 00:08:52.290 --> 00:08:54.360 including sudden infant death syndrome, 199 00:08:54.360 --> 00:08:57.033 ear infections, and asthmatic effects. 200 00:08:59.820 --> 00:09:03.090 To turn slightly from the risk factors 201 00:09:03.090 --> 00:09:04.860 we've been discussing, 202 00:09:04.860 --> 00:09:07.803 we'll next discuss the Japanese smoking paradox. 203 00:09:08.640 --> 00:09:11.910 So the Japanese smoking paradox stems 204 00:09:11.910 --> 00:09:14.190 from discrepancies in lung cancer rates 205 00:09:14.190 --> 00:09:16.515 in Japan versus the US. 206 00:09:16.515 --> 00:09:18.270 Despite the fact that the prevalence 207 00:09:18.270 --> 00:09:20.730 of chronic cigarette smoking among Japanese men 208 00:09:20.730 --> 00:09:23.250 is approximately twice that of American men, 209 00:09:23.250 --> 00:09:26.430 their lung cancer rates are substantially lower. 210 00:09:26.430 --> 00:09:28.470 An early international case-control study 211 00:09:28.470 --> 00:09:32.010 of smoking and lung cancer in Japan and the United States 212 00:09:32.010 --> 00:09:33.510 found that the relative risk 213 00:09:33.510 --> 00:09:35.820 of lung cancer development among chronic smokers 214 00:09:35.820 --> 00:09:38.250 is tenfold higher in US men 215 00:09:38.250 --> 00:09:39.573 compared to Japanese men. 216 00:09:40.470 --> 00:09:43.830 Japanese smokers are exposed to lower concentrations 217 00:09:43.830 --> 00:09:45.925 of carcinogens in their cigarettes 218 00:09:45.925 --> 00:09:48.510 because tobacco blends used 219 00:09:48.510 --> 00:09:51.540 in formulating cigarettes differ in the US and Japan, 220 00:09:51.540 --> 00:09:52.950 and most Japanese cigarettes 221 00:09:52.950 --> 00:09:54.330 are made with charcoal filters 222 00:09:54.330 --> 00:09:56.130 that more effectively filter out 223 00:09:56.130 --> 00:09:58.410 nitrates and nitrous amines. 224 00:09:58.410 --> 00:10:01.517 We also see that one reason behind this paradox 225 00:10:01.517 --> 00:10:03.420 might be because Japanese men 226 00:10:03.420 --> 00:10:05.670 begin smoking at a later age than American men, 227 00:10:05.670 --> 00:10:07.863 by two to three years on average, 228 00:10:08.820 --> 00:10:10.590 and that Japanese men are exposed 229 00:10:10.590 --> 00:10:15.480 to other risk factors at lower rates than American men. 230 00:10:15.480 --> 00:10:16.313 So for example, 231 00:10:16.313 --> 00:10:19.260 Japanese men consume less alcohol than American men, 232 00:10:19.260 --> 00:10:23.253 they consume less fat in their diets than Americans, 233 00:10:24.390 --> 00:10:29.100 and they have a high level of fish consumption. 234 00:10:29.100 --> 00:10:31.290 In fact, Japan has one of the highest annual levels 235 00:10:31.290 --> 00:10:33.240 of fish consumption in the world, 236 00:10:33.240 --> 00:10:36.000 consuming about 70 kilograms of fish per capita, 237 00:10:36.000 --> 00:10:38.733 which is more than fourfold higher than the US level. 238 00:10:41.190 --> 00:10:44.250 A case control study conducted in 2001 239 00:10:44.250 --> 00:10:46.410 found that consumption of cooked or raw fish 240 00:10:46.410 --> 00:10:47.760 reduced the risk of lung cancer 241 00:10:47.760 --> 00:10:51.300 in both men and women by about 50% in Japan. 242 00:10:51.300 --> 00:10:52.650 Since eating fresh fish 243 00:10:52.650 --> 00:10:53.880 provides an excellent source 244 00:10:53.880 --> 00:10:55.950 of complex polyunsaturated fatty acids 245 00:10:55.950 --> 00:10:58.980 and then have potent anti-inflammatory effects, 246 00:10:58.980 --> 00:11:00.930 it's possible that regular fish consumption 247 00:11:00.930 --> 00:11:02.400 by Japanese smokers inhibits 248 00:11:02.400 --> 00:11:05.373 or delays lung carcinogenesis by tobacco smoke. 249 00:11:06.962 --> 00:11:09.030 Next, we see that certain viruses 250 00:11:09.030 --> 00:11:11.100 have been implicated in lung carcinogenesis 251 00:11:11.100 --> 00:11:13.833 by virtue of their presence in lung cancer specimens. 252 00:11:14.940 --> 00:11:17.250 So we know that chronic lung infections 253 00:11:17.250 --> 00:11:20.700 due to certain viruses can cause lung cancer in animals. 254 00:11:20.700 --> 00:11:25.700 For example, JSRV, which is a kind of sheep retrovirus, 255 00:11:25.920 --> 00:11:28.473 causes pulmonary adenocarcinoma in sheep. 256 00:11:32.610 --> 00:11:34.267 Among viruses that have been found 257 00:11:34.267 --> 00:11:37.710 in human lung cancer specimens, 258 00:11:37.710 --> 00:11:40.620 we see that there have been human papillomavirus strains, 259 00:11:40.620 --> 00:11:44.310 JC-virus, simian virus-40, BK virus, 260 00:11:44.310 --> 00:11:46.863 and cytomegalovirus. 261 00:11:51.210 --> 00:11:54.150 While these viruses have been found in samples, 262 00:11:54.150 --> 00:11:55.380 the role of viral infection 263 00:11:55.380 --> 00:11:56.520 in human lung cancer development 264 00:11:56.520 --> 00:11:59.010 has not been definitively proven. 265 00:11:59.010 --> 00:12:01.020 It's highly likely that acute viral infection 266 00:12:01.020 --> 00:12:03.240 present at the time of lung cancer diagnosis 267 00:12:03.240 --> 00:12:05.520 is an effect of the lower susceptibility 268 00:12:05.520 --> 00:12:07.590 of such patients rather than the cause 269 00:12:07.590 --> 00:12:11.343 of a protracted course of carcinogenesis over many years. 270 00:12:12.670 --> 00:12:15.800 Genetic studies have also identified genetic polymorphisms 271 00:12:15.800 --> 00:12:18.870 and mutant forms of genes that regulate key mechanisms 272 00:12:18.870 --> 00:12:20.523 of lung carcinogenesis. 273 00:12:22.230 --> 00:12:26.049 So we see that, among genes 274 00:12:26.049 --> 00:12:30.750 that are potentially implicated in lung carcinogenesis, 275 00:12:30.750 --> 00:12:32.430 there are lungs that regulate the cell cycle 276 00:12:32.430 --> 00:12:36.690 and cell division, genes that control DNA repair enzymes, 277 00:12:36.690 --> 00:12:40.470 genes that play a role in the inflammatory cascade, 278 00:12:40.470 --> 00:12:42.540 and genes that modulate phase 1 279 00:12:42.540 --> 00:12:44.463 and phase 2 liver enzymes. 280 00:12:48.600 --> 00:12:53.600 Finally, we will turn to discuss cyclooxygenase-2, 281 00:12:53.700 --> 00:12:57.490 or COX-2, which we begin discussing in this lecture 282 00:12:57.490 --> 00:13:00.060 though it will continue to play a role 283 00:13:00.060 --> 00:13:04.050 throughout this course, as it's a really key factor 284 00:13:04.050 --> 00:13:05.610 in the inflammatory cascade 285 00:13:05.610 --> 00:13:07.683 in multiple tissues of the body. 286 00:13:08.820 --> 00:13:12.420 So it was first suggested that chronic inflammation 287 00:13:12.420 --> 00:13:13.830 leads to cancer development 288 00:13:13.830 --> 00:13:17.133 by a German pathologist in 1863. 289 00:13:18.330 --> 00:13:21.920 Then, more than 100 years later, by 1989, 290 00:13:21.920 --> 00:13:24.510 an inducible enzyme called cyclooxygenase-2, 291 00:13:24.510 --> 00:13:28.410 or COX-2, was discovered 292 00:13:28.410 --> 00:13:31.710 by various scientists. 293 00:13:31.710 --> 00:13:35.163 In 1991, the human version of the gene was cloned, 294 00:13:35.163 --> 00:13:37.620 and it's been found that this gene, COX-2, 295 00:13:37.620 --> 00:13:40.410 is normally silent in non-inflamed tissues. 296 00:13:40.410 --> 00:13:42.837 But when stimulated by inflammatory factors 297 00:13:42.837 --> 00:13:45.390 like those in tobacco smoke, 298 00:13:45.390 --> 00:13:47.261 COX-2 transcription is triggered 299 00:13:47.261 --> 00:13:51.810 leading to the enzymatic conversion of a specific acid 300 00:13:51.810 --> 00:13:55.020 into molecules called prostaglandins 301 00:13:55.020 --> 00:13:56.470 that are highly inflammatory. 302 00:13:58.320 --> 00:14:00.000 So it was really the discovery 303 00:14:00.000 --> 00:14:03.360 of this COX-2 gene that led to the interest 304 00:14:03.360 --> 00:14:06.450 in the causal link between inflammation and cancer. 305 00:14:06.450 --> 00:14:08.250 So after this gene was discovered, 306 00:14:08.250 --> 00:14:10.560 a huge volume of cohesive scientific evidence 307 00:14:10.560 --> 00:14:13.230 from molecular animal and human investigations 308 00:14:13.230 --> 00:14:14.400 support the hypothesis 309 00:14:14.400 --> 00:14:16.020 that sustained induction of COX-2 310 00:14:16.020 --> 00:14:19.500 and upregulation of the prostaglandin cascade 311 00:14:19.500 --> 00:14:21.630 by chronic exposure to inflammatory agents 312 00:14:21.630 --> 00:14:23.070 promotes the development of cancer, 313 00:14:23.070 --> 00:14:25.590 including cancer of the lungs. 314 00:14:25.590 --> 00:14:28.170 Finally, there is evidence that chronic exposure 315 00:14:28.170 --> 00:14:31.410 to many highly inflammatory constituents of cigarette smoke 316 00:14:31.410 --> 00:14:34.080 promotes lung carcinogenesis, and reciprocally, 317 00:14:34.080 --> 00:14:36.960 the blockade of the process has strong potential 318 00:14:36.960 --> 00:14:38.823 for cancer prevention and therapy.