Lung cancer pathophysiology: Difference between revisions

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==Overview==
==Overview==
The pathophysiology consists of genetics, smoking, radon gas, asbestos, viruses, infection, and inflammation.
The pathophysiology of lung cancer includes both genetic and environmental factors. Genetic mutations, namely mutations in '''K-ras''' oncogene and '''TP53''' tumor-suppressor gene, are associated with the development of lung cancers. Environmental factors often include smoking (most important carcinogen), radon, asbestos, viral infections, and states of chronic lung inflammation, all of which may predispose to cellular damage and DNA mutations that predispose to the development of lung cancers.


==Pathophysiology==
==Pathophysiology==
===Genetics===
===Genetics===
{{main|Carcinogenesis}}
{{main|Carcinogenesis}}
*Lung cancer is initiated by activation of [[oncogene]]s or inactivation of [[tumor suppressor gene]]s.<ref name="Fong">{{cite journal | last =Fong | first =KM | coauthors = Sekido Y, Gazdar AF, Minna JD | title =Lung cancer. 9: Molecular biology of lung cancer: clinical implications | journal =Thorax | volume =58 | issue =10 | pages =892–900 | publisher = BMJ Publishing Group Ltd. | date =Oct 2003 | pmid =14514947 }}</ref>
*[[Mutation]]s in the ''[[Ras|K-ras]]'' proto-oncogene are responsible for 20% to 30% of non-small cell lung cancer cases.<ref name="Aviel-Ronen">{{cite journal | last =Aviel-Ronen | first =S | coauthors = Blackhall FH, Shepherd FA, Tsao MS | title =K-ras mutations in non-small-cell lung carcinoma: a review | journal =Clinical Lung Cancer | volume =8 | issue =1 | pages =30–38 |publisher =Cancer Information Group | date =Jul 2006 | pmid =16870043 }}</ref>
*[[Chromosome|Chromosomal]] damage may also result in [[loss of heterozygosity]], which subsequently leads to the inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q and 17p are particularly common in small cell lung carcinoma.
*The ''[[TP53]]'' tumor suppressor gene, located in chromosome 17p, is often mutated in lung cancers.<ref name="Devereux">{{cite journal | last =Devereux | first =TR | coauthors = Taylor JA, Barrett JC | title =Molecular mechanisms of lung cancer. Interaction of environmental and genetic factors | journal =Chest | volume =109 | issue =Suppl. 3 | pages =14S-19S | publisher =American College of Chest Physicians | date =Mar 1996 | url =http://www.chestjournal.org/cgi/reprint/109/3/14S| pmid =8598134 | accessdate =2007-08-11 }}</ref>
*Several [[genetic polymorphism]]s are associated with lung cancer. These include polymorphisms in [[gene]]s coding for [[interleukin]]-1,<ref name="Engels">{{cite journal | last =Engels | first =EA | coauthors =Wu X, Gu J et al. | title =Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer | journal =Cancer Research | volume =67 | issue =13 | pages =6520–6527 | publisher =American Association for Cancer Research | date =Jul 2007 | pmid =17596594 }}</ref> [[cytochrome P450]],<ref name="Wenzlaff">{{cite journal | last =Wenzlaff | first =AS | coauthors =Cote ML, Bock CH et al. | title =CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study | journal =Carcinogenesis | volume =26 |issue =12 | pages =2207–2212 | publisher =Oxford University Press | date =Dec 2005 | pmid =16051642 }}</ref> [[apoptosis]] promoters such as [[caspase]]-8,<ref name="Son">{{cite journal | last =Son | first =JW | coauthors =Kang HK, Chae MH et al. | title =Polymorphisms in the caspase-8 gene and the risk of lung cancer | journal =Cancer Genetics and Cytogenetics | volume =169 | issue =2 | pages =121–127 | date =Sep 2006 | pmid =16938569 }}</ref> and DNA repair molecules such as [[XRCC1]].<ref name="Yin">{{cite journal | last =Yin | first =J | coauthors =Vogel U, Ma Y et al. | title =The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population | journal =Lung Cancer | volume =56 | issue =2 | pages =153–160 | date =May 2007 |pmid =17316890 }}</ref> Individuals with these polymorphisms are thought to be more likely to develop lung cancer following exposure to [[carcinogen]]s.


Similar to many other cancers, lung cancer is initiated by activation of [[oncogene]]s or inactivation of [[tumor suppressor gene]]s.<ref name="Fong">{{cite journal | last =Fong | first =KM | coauthors = Sekido Y, Gazdar AF, Minna JD | title =Lung cancer. 9: Molecular biology of lung cancer: clinical implications | journal =Thorax | volume =58 | issue =10 | pages =892–900 | publisher = BMJ Publishing Group Ltd. | date =Oct 2003 | pmid =14514947 }}</ref> Oncogenes are [[gene]]s that are believed to make people more susceptible to cancer. [[Proto-oncogene]]s are believed to turn into oncogenes when exposed to particular carcinogens.<ref name="Salgia">{{cite journal | last =Salgia | first =R | coauthors =Skarin AT | title =Molecular abnormalities in lung cancer |journal =Journal of Clinical Oncology | volume =16 | issue =3 | pages =1207–1217 | date =Mar 1998 | pmid =9508209 }}</ref>[[Mutation]]s in the ''[[Ras|K-ras]]'' proto-oncogene are responsible for 20–30% of non-small cell lung cancers.<ref name="Aviel-Ronen">{{cite journal | last =Aviel-Ronen | first =S | coauthors = Blackhall FH, Shepherd FA, Tsao MS | title =K-ras mutations in non-small-cell lung carcinoma: a review | journal =Clinical Lung Cancer | volume =8 | issue =1 | pages =30–38 |publisher =Cancer Information Group | date =Jul 2006 | pmid =16870043 }}</ref> [[Chromosome|Chromosomal]] damage can lead to [[loss of heterozygosity]]. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q and 17p are particularly common in small cell lung carcinoma. The ''[[TP53]]'' tumor suppressor gene, located on chromosome 17p, is often affected.<ref name="Devereux">{{cite journal | last =Devereux | first =TR | coauthors = Taylor JA, Barrett JC | title =Molecular mechanisms of lung cancer. Interaction of environmental and genetic factors | journal =Chest | volume =109 | issue =Suppl. 3 | pages =14S-19S | publisher =American College of Chest Physicians | date =Mar 1996 | url =http://www.chestjournal.org/cgi/reprint/109/3/14S| pmid =8598134 | accessdate =2007-08-11 }}</ref>
===Environment===
 
Although genetics play a significant role in the pathogenesis of lung cancer, it is thought that exposure to environmental risk factors plays an equally improtant role in the development of lung cancer. The main causes of lung cancer include [[carcinogen]]s (such as those present in tobacco smoke), [[ionizing radiation]], and [[virus (biology)|viral]] infections. Chronic exposure results in cumulative alterations to the [[DNA]] in the tissue lining the [[bronchi]] of the lungs (the bronchial [[epithelium]]). Irreversible DNA changes following exposure to carcinogens are directly associated with the development of lung cancer.
Several [[genetic polymorphism]]s are associated with lung cancer. These include polymorphisms in [[gene]]s coding for [[interleukin]]-1,<ref name="Engels">{{cite journal | last =Engels | first =EA | coauthors =Wu X, Gu J et al. | title =Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer | journal =Cancer Research | volume =67 | issue =13 | pages =6520–6527 | publisher =American Association for Cancer Research | date =Jul 2007 | pmid =17596594 }}</ref> [[cytochrome P450]],<ref name="Wenzlaff">{{cite journal | last =Wenzlaff | first =AS | coauthors =Cote ML, Bock CH et al. | title =CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study | journal =Carcinogenesis | volume =26 |issue =12 | pages =2207–2212 | publisher =Oxford University Press | date =Dec 2005 | pmid =16051642 }}</ref> [[apoptosis]] promoters such as [[caspase]]-8,<ref name="Son">{{cite journal | last =Son | first =JW | coauthors =Kang HK, Chae MH et al. | title =Polymorphisms in the caspase-8 gene and the risk of lung cancer | journal =Cancer Genetics and Cytogenetics | volume =169 | issue =2 | pages =121–127 | date =Sep 2006 | pmid =16938569 }}</ref> and DNA repair molecules such as [[XRCC1]].<ref name="Yin">{{cite journal | last =Yin | first =J | coauthors =Vogel U, Ma Y et al. | title =The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population | journal =Lung Cancer | volume =56 | issue =2 | pages =153–160 | date =May 2007 |pmid =17316890 }}</ref> People with these polymorphisms are more likely to develop lung cancer after exposure to [[carcinogen]]s.
 
The main causes of lung cancer (and cancer in general) include [[carcinogen]]s (such as those in tobacco smoke), [[ionizing radiation]], and [[virus (biology)|viral]] infection. This exposure causes cumulative changes to the [[DNA]] in the tissue lining the [[bronchi]] of the lungs (the bronchial [[epithelium]]). As more tissue becomes damaged, eventually a cancer develops.


===Smoking===
===Smoking===
Cigarette smoke contains over 60 known carcinogens<ref name="Hecht">{{cite journal | last =Hecht | first =S | title =Tobacco carcinogens, their biomarkers and tobacco-induced cancer | journal =Nature Reviews. Cancer | volume =3 | issue =10 | pages =733–744 | publisher =Nature Publishing Group | date =Oct 2003 | url =http://www.nature.com/nrc/journal/v3/n10/abs/nrc1190_fs.html;jsessionid=A78B217DFCAD36DD965F2DBA685CF121 | doi =10.1038/nrc1190 |pmid =14570033 | accessdate =2007-08-10 }}</ref> including [[radioisotopes]] from the [[radon]] decay sequence, [[nitrosamine]], and [[benzopyrene]].  
*Cigarette smoke contains over 60 known carcinogens<ref name="Hecht">{{cite journal | last =Hecht | first =S | title =Tobacco carcinogens, their biomarkers and tobacco-induced cancer | journal =Nature Reviews. Cancer | volume =3 | issue =10 | pages =733–744 | publisher =Nature Publishing Group | date =Oct 2003 | url =http://www.nature.com/nrc/journal/v3/n10/abs/nrc1190_fs.html;jsessionid=A78B217DFCAD36DD965F2DBA685CF121 | doi =10.1038/nrc1190 |pmid =14570033 | accessdate =2007-08-10 }}</ref> including [[radioisotopes]] from the [[radon]] decay sequence, [[nitrosamine]], and [[benzopyrene]].  
 
*Nicotine is thought to reduce the immune response to malignant growths in exposed tissue. The length of time an individual smokes, as well as the amount, significantly increases the person's chance of developing lung cancer.
Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. The length of time a person smokes as well as the amount smoked increases the person's chance of developing lung cancer. If a person stops smoking, this chance steadily decreases as damage to the lungs is repaired and contaminant particles are gradually removed. Across the developed world, almost 90% of lung cancer deaths are caused by smoking.<ref name="Peto">{{cite book | last = Peto R | first = R | coauthors = Lopez AD, Boreham J et al. | title = Mortality from smoking in developed countries 1950–2000: Indirect estimates from National Vital Statistics | publisher = Oxford University Press | date = 2006 | url=http://www.ctsu.ox.ac.uk/~tobacco/ | id = ISBN 0-19-262535-7 |accessdate =2007-08-10 }}</ref>  
*Among individuals who stopped smoking, the risk of lung cancer steadily decreases as lung tissue repairs itself and as contaminant particles are eliminated from the lungs. Nonetheless, it is thought that the risk of lung cancer among ever-smokers (even when stopped) is always higher than those who never smoked.<ref name="Peto">{{cite book | last = Peto R | first = R | coauthors = Lopez AD, Boreham J et al. | title = Mortality from smoking in developed countries 1950–2000: Indirect estimates from National Vital Statistics | publisher = Oxford University Press | date = 2006 | url=http://www.ctsu.ox.ac.uk/~tobacco/ | id = ISBN 0-19-262535-7 |accessdate =2007-08-10 }}</ref><ref name="Nordquist">{{cite journal | last =Nordquist | first =LT | authorlink = | coauthors =Simon GR, Cantor A et al. | title =Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung | journal =Chest | volume =126 | issue =2 | pages =347–351| publisher = American College of Chest Physicians | date =Aug 2004 | url =http://www.chestjournal.org/cgi/content/full/126/2/347 |pmid =15302716 | accessdate =2007-08-10 }}</ref>  
 
*Passive smoking, the inhalation of smoke from another's smoking, is also a risk factor of lung cancer among non-smokers.<ref>{{cite web | last =CDC | authorlink =Centers for Disease Control and Prevention |title =1986 Surgeon General's report: the health consequences of involuntary smoking | publisher =CDC | date =Dec 1986 | url =http://www.cdc.gov/mmwr/preview/mmwrhtml/00000837.htm | pmid =3097495 | accessdate =2007-08-10 }}<br />* {{cite book | last =National Research Council | title =Environmental tobacco smoke: measuring exposures and assessing health effects | publisher =National Academy Press | date =1986 | url =http://www.nap.edu/catalog.php?record_id=943#toc | isbn =0-309-07456-8 }}<br />* {{cite paper | author =EPA | authorlink=United States Environmental Protection Agency | title =Respiratory health effects of passive smoking: lung cancer and other disorders | publisher =EPA | date =1992 | url =http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=2835 | accessdate =2007-08-10 }}<br />* {{cite journal | last =California Environmental Protection Agency | title =Health effects of exposure to environmental tobacco smoke | journal =Tobacco Control | volume =6 | issue =4 | pages =346–353 | date =1997 |url =http://www.druglibrary.org/schaffer/tobacco/caets/ets-main.htm | pmid =9583639 | accessdate =2007-08-10 }}<br />* {{cite journal | last =CDC | authorlink=Centers for Disease Control and Prevention | title =State-specific prevalence of current cigarette smoking among adults, and policies and attitudes about secondhand smoke—United States, 2000 | journal =Morbidity and Mortality Weekly Report | volume =50 | issue =49 | pages =1101–1106 | publisher =CDC | date =Dec 2001 | url =http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5049a1.htm | pmid =11794619 | accessdate =2007-08-10 }}<br />* {{cite journal | last =Alberg | first =AJ | coauthors =Samet JM | title =Epidemiology of lung cancer | journal =Chest | volume =123 | issue =S1 | pages =21S-49S | publisher =American College of Chest Physicians | date =Jan 2003 | url =http://www.chestjournal.org/cgi/content/full/123/1_suppl/21S | pmid =12527563 | accessdate =2007-08-10 }}</ref><ref name="Boffetta">{{cite journal | last =Boffetta | first =P | coauthors = Agudo A, Ahrens W et al. | title =Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe | journal =Journal of the National Cancer Institute |volume =90 | issue =19 | pages =1440–1450 | publisher =Oxford University Press | date =Oct 1998 | url =http://jnci.oxfordjournals.org/cgi/reprint/90/19/1440 | pmid =9776409 | accessdate =2007-08-10 }}</ref><ref name="Committee">{{cite web | title =Report of the Scientific Committee on Tobacco and Health | publisher =Department of Health |date =Mar 1998 | url =http://www.archive.official-documents.co.uk/document/doh/tobacco/contents.htm | accessdate =2007-07-09 }}<br />* {{cite journal | last =Hackshaw | first =AK | title =Lung cancer and passive smoking | journal =Statistical Methods in Medical Research | volume =7 | issue =2 | pages =119–136 | date =Jun 1998 | pmid =9654638 }}</ref><ref name="NHMRC">{{cite paper | author =National Health and Medical Research Council | title =The health effects and regulation of passive smoking |publisher =Australian Government Publishing Service | date =Apr 1994 | url =http://www.obpr.gov.au/publications/submission/healthef/index.html | accessdate =2007-08-10 }}</ref>
In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers,<ref name="Nordquist">{{cite journal | last =Nordquist | first =LT | authorlink = | coauthors =Simon GR, Cantor A et al. | title =Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung | journal =Chest | volume =126 | issue =2 | pages =347–351| publisher = American College of Chest Physicians | date =Aug 2004 | url =http://www.chestjournal.org/cgi/content/full/126/2/347 |pmid =15302716 | accessdate =2007-08-10 }}</ref> and that patients who smoke at the time of diagnosis have shorter survival than those who have quit.<ref name="Tammemagi">{{cite journal | last =Tammemagi | first =CM | authorlink = | coauthors =Neslund-Dudas C, Simoff M, Kvale P | title =Smoking and lung cancer survival: the role of comorbidity and treatment | journal =Chest | volume =125 |issue =1 | pages =27–37 | publisher =American College of Chest Physicians | date =Jan 2004 | url =http://www.chestjournal.org/cgi/content/full/125/1/27 | pmid =14718417 | accessdate =2007-08-10 }}</ref>
 
[[Tobacco smoking#Passive smoking|Passive smoking]]&mdash;the inhalation of smoke from another's smoking&mdash;is a cause of lung cancer in non-smokers. Studies from the U.S.,<ref>{{cite web | last =CDC | authorlink =Centers for Disease Control and Prevention |title =1986 Surgeon General's report: the health consequences of involuntary smoking | publisher =CDC | date =Dec 1986 | url =http://www.cdc.gov/mmwr/preview/mmwrhtml/00000837.htm | pmid =3097495 | accessdate =2007-08-10 }}<br />* {{cite book | last =National Research Council | title =Environmental tobacco smoke: measuring exposures and assessing health effects | publisher =National Academy Press | date =1986 | url =http://www.nap.edu/catalog.php?record_id=943#toc | isbn =0-309-07456-8 }}<br />* {{cite paper | author =EPA | authorlink=United States Environmental Protection Agency | title =Respiratory health effects of passive smoking: lung cancer and other disorders | publisher =EPA | date =1992 | url =http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=2835 | accessdate =2007-08-10 }}<br />* {{cite journal | last =California Environmental Protection Agency | title =Health effects of exposure to environmental tobacco smoke | journal =Tobacco Control | volume =6 | issue =4 | pages =346–353 | date =1997 |url =http://www.druglibrary.org/schaffer/tobacco/caets/ets-main.htm | pmid =9583639 | accessdate =2007-08-10 }}<br />* {{cite journal | last =CDC | authorlink=Centers for Disease Control and Prevention | title =State-specific prevalence of current cigarette smoking among adults, and policies and attitudes about secondhand smoke—United States, 2000 | journal =Morbidity and Mortality Weekly Report | volume =50 | issue =49 | pages =1101–1106 | publisher =CDC | date =Dec 2001 | url =http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5049a1.htm | pmid =11794619 | accessdate =2007-08-10 }}<br />* {{cite journal | last =Alberg | first =AJ | coauthors =Samet JM | title =Epidemiology of lung cancer | journal =Chest | volume =123 | issue =S1 | pages =21S-49S | publisher =American College of Chest Physicians | date =Jan 2003 | url =http://www.chestjournal.org/cgi/content/full/123/1_suppl/21S | pmid =12527563 | accessdate =2007-08-10 }}</ref> Europe,<ref name="Boffetta">{{cite journal | last =Boffetta | first =P | coauthors = Agudo A, Ahrens W et al. | title =Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe | journal =Journal of the National Cancer Institute |volume =90 | issue =19 | pages =1440–1450 | publisher =Oxford University Press | date =Oct 1998 | url =http://jnci.oxfordjournals.org/cgi/reprint/90/19/1440 | pmid =9776409 | accessdate =2007-08-10 }}</ref> the UK,<ref name="Committee">{{cite web | title =Report of the Scientific Committee on Tobacco and Health | publisher =Department of Health |date =Mar 1998 | url =http://www.archive.official-documents.co.uk/document/doh/tobacco/contents.htm | accessdate =2007-07-09 }}<br />* {{cite journal | last =Hackshaw | first =AK | title =Lung cancer and passive smoking | journal =Statistical Methods in Medical Research | volume =7 | issue =2 | pages =119–136 | date =Jun 1998 | pmid =9654638 }}</ref> and Australia<ref name="NHMRC">{{cite paper | author =National Health and Medical Research Council | title =The health effects and regulation of passive smoking |publisher =Australian Government Publishing Service | date =Apr 1994 | url =http://www.obpr.gov.au/publications/submission/healthef/index.html | accessdate =2007-08-10 }}</ref> have consistently shown a significant increase in [[relative risk]] among those exposed to passive smoke. Recent investigation of sidestream smoke suggests it is more dangerous than direct smoke inhalation.<ref name="Schick">{{cite journal | last=Schick | first=S |coauthors=Glantz S|title=Philip Morris toxicological experiments with fresh sidestream smoke: more toxic than mainstream smoke |journal=Tobacco Control |volume=14 |issue=6 |pages=396–404 |date =Dec 2005 | pmid =16319363 }}</ref>


===Radon gas===
===Radon gas===
[[Radon]] is a colorless and odorless [[gas]] generated by the breakdown of radioactive [[radium]], which in turn is the decay product of [[uranium]], found in the earth's crust. The radiation decay products [[ion]]ize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer after smoking.<ref name="Catelinois">{{cite journal | last =Catelinois | first =O | coauthors = Rogel A, Laurier D et al. | title =Lung Cancer Attributable to Indoor Radon Exposure in France: Impact of the Risk Models and Uncertainty Analysis | journal =Environmental Health Perspectives | volume =114 |issue =9 | pages =1361–1366 | publisher =National Institute of Environmental Health Science | date =May 2006 | url =http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16966089 | doi =10.1289/ehp.9070 | pmid =16966089 |accessdate =2007-08-10 }}</ref>
*[[Radon]] is a colorless and odorless [[gas]] generated by the breakdown of radioactive [[radium]] (decay product of [[uranium]]) found in the earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous.
 
*Radon exposure is the second major cause of lung cancer following smoking.<ref name="Catelinois">{{cite journal | last =Catelinois | first =O | coauthors = Rogel A, Laurier D et al. | title =Lung Cancer Attributable to Indoor Radon Exposure in France: Impact of the Risk Models and Uncertainty Analysis | journal =Environmental Health Perspectives | volume =114 |issue =9 | pages =1361–1366 | publisher =National Institute of Environmental Health Science | date =May 2006 | url =http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16966089 | doi =10.1289/ehp.9070 | pmid =16966089 |accessdate =2007-08-10 }}</ref>
'''Mechanism of damage'''<ref name="radon">University of Minnesota. http://enhs.umn.edu/hazards/hazardssite/radon/radonmolaction.html#Anchor-Molecular-23240/</ref>
*The mechanism of lung damage following radon exposure is not thought to be due to the radon gas itself, but due to the short-lived alpha decay products that cause cellular damage and DNA mutations.<ref name="radon">University of Minnesota.http://enhs.umn.edu/hazards/hazardssite/radon/radonmolaction.html#Anchor-Molecular-23240/</ref>
*Not from Radon gas itself
**Short lived [[alpha decay]] products cause cellular damage
**Lung cancer develops mainly from decay products irradiating lung tissue
***Lung DNA is likely damaged when an [[alpha particle]] passes through it
*Alpha particles are comparatively heavy
**Since they are heavy, alpha radiation travels very short distances
**The lungs are generally the only organ the radiation can reach, therefore lung cancer is likely the only hazard of Radon
***When a particle passes through the nucleus of a cell, the DNA will likely be damaged
***DNA Damage usually in the form of a [[point mutation]] or [[transformation]]


=== Asbestos ===
===Asbestos===
[[Asbestos]] can cause a variety of lung diseases, including lung cancer. Tiny asbestos fibers are released into the air and those fibers are breathed into the lungs. The fibers become lodged in the lungs and are stuck there for an indefinite amount of time. They can eventually lead to scarring and inflammation. Also, there is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.<ref name="O'Reilly">{{cite journal | last=O'Reilly | first=KM | coauthors =Mclaughlin AM, Beckett WS, Sime PJ | title =Asbestos-related lung disease | journal=American Family Physician | volume=75 | issue=5 | pages=683–688| date=Mar 2007 | url=http://www.aafp.org/afp/20070301/683.html | pmid=17375514 | accessdate=2007-08-18 }}</ref> Many asbestos related lung cancer patients also suffer from [[Asbestosis]]. Asbestos can also cause cancer of the [[pleura]], called [[mesothelioma]] (which is different from lung cancer).
*[[Asbestos]] exposure is associated with many lung diseases, including lung cancer.
*Tiny asbestos fibers are released into the air are breathed into the lungs. The fibers become lodged in the lungs and are stuck for an indefinite amount of time. They can eventually lead to scarring and inflammation.  


=== Viruses ===
=== Viruses ===
[[Virus]]es are known to cause lung cancer in animals<ref name="Leroux">{{cite journal | last =Leroux | first =C | coauthors =Girard N, Cottin V et al. | title =Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep |journal =Veterinary Research |volume =38 | issue =2 | pages =211–228 | date =Mar-Apr 2007 | pmid =17257570 }}</ref><ref name="Palmarini">{{cite journal | last =Palmarini | first =M | coauthors =Fan H | title =Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer| journal =Journal of the National Cancer Institute | volume =93 | issue =21 | pages =1603–1614 | publisher =Oxford University Press| date =November 2001 | url =http://jnci.oxfordjournals.org/cgi/content/full/93/21/1603 | pmid =11698564 | accessdate =2007-08-11}}</ref> and recent evidence suggests similar potential in humans. Implicated viruses include [[human papillomavirus]],<ref name="Cheng">{{cite journal | last =Cheng | first =YW | coauthors = Chiou HL, Sheu GT et al. | title =The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women | journal =Cancer Research | volume =61 | issue =7| pages =2799–2803 | publisher = American Association for Cancer Research | date =Apr 2001 | url =http://cancerres.aacrjournals.org/cgi/content/full/61/7/2799 | pmid =11306446 | accessdate =2007-08-11 }}</ref> [[JC virus]],<ref name="Zheng">{{cite journal | last =Zheng | first =H | coauthors =Aziz HA, Nakanishi Y et al. | title =Oncogenic role of JC virus in lung cancer | journal =Journal of Pathology | volume =212 | issue =3 | pages =306–315 | date =May 2007 | pmid =17534844 }}</ref>[[SV40|simian virus 40]] (SV40), [[BK virus]] and [[cytomegalovirus]].<ref name="Giuliani">{{cite journal | last =Giuliani | first =L | coauthors =Jaxmar T, Casadio C et al. | title =Detection of oncogenic viruses (SV40, BKV, JCV, HCMV, HPV) and p53 codon 72 polymorphism in lung carcinoma | journal =Lung Cancer | volume=57 | issue=3 | pages=273–281 | date =Sep 2007 | pmid =17400331}}</ref> These viruses may affect the [[cell cycle]] and inhibit [[apoptosis]], allowing uncontrolled cell division. [[HIV]] has also been considered as a disease that may increase the chance for development of lung cancer. Although the mechanism is unknown, there are some hypotheses for why this may be true.  HIV may amplify the effects of smoking as well as the fact that HIV is associated with prolonged lung infections/inflammation.<ref name="Engels 2">Eric A Engels.11/30/11. Inflammation in the development of lung cancer:epidemiological evidence.Expert Review of Anticancer Therapy.Apr.2008.p605</ref>
*[[Virus]]es are known to be associated with the development of lung cancer in animals and humans.<ref name="Leroux">{{cite journal | last =Leroux | first =C | coauthors =Girard N, Cottin V et al. | title =Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep |journal =Veterinary Research |volume =38 | issue =2 | pages =211–228 | date =Mar-Apr 2007 | pmid =17257570 }}</ref><ref name="Palmarini">{{cite journal | last =Palmarini | first =M | coauthors =Fan H | title =Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer| journal =Journal of the National Cancer Institute | volume =93 | issue =21 | pages =1603–1614 | publisher =Oxford University Press| date =November 2001 | url =http://jnci.oxfordjournals.org/cgi/content/full/93/21/1603 | pmid =11698564 | accessdate =2007-08-11}}</ref>
*Viruses include [[human papillomavirus]],<ref name="Cheng">{{cite journal | last =Cheng | first =YW | coauthors = Chiou HL, Sheu GT et al. | title =The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women | journal =Cancer Research | volume =61 | issue =7| pages =2799–2803 | publisher = American Association for Cancer Research | date =Apr 2001 | url =http://cancerres.aacrjournals.org/cgi/content/full/61/7/2799 | pmid =11306446 | accessdate =2007-08-11 }}</ref> [[JC virus]],<ref name="Zheng">{{cite journal | last =Zheng | first =H | coauthors =Aziz HA, Nakanishi Y et al. | title =Oncogenic role of JC virus in lung cancer | journal =Journal of Pathology | volume =212 | issue =3 | pages =306–315 | date =May 2007 | pmid =17534844 }}</ref>[[SV40|simian virus 40]] (SV40), [[BK virus]], and [[cytomegalovirus]].<ref name="Giuliani">{{cite journal | last =Giuliani | first =L | coauthors =Jaxmar T, Casadio C et al. | title =Detection of oncogenic viruses (SV40, BKV, JCV, HCMV, HPV) and p53 codon 72 polymorphism in lung carcinoma | journal =Lung Cancer | volume=57 | issue=3 | pages=273–281 | date =Sep 2007 | pmid =17400331}}</ref>
*These viruses may affect the [[cell cycle]] and inhibit [[apoptosis]], allowing uncontrolled cell division.
*[[HIV]] has also been thought to increase the risk of developing lung cancer. Although the mechanism is unknown, HIV is thought to be associated with a state of chronic lung inflammation that may potentiate cellular damage and DNA mutations.<ref name="Engels 2">Eric A Engels.11/30/11. Inflammation in the development of lung cancer:epidemiological evidence.Expert Review of Anticancer Therapy.Apr.2008.p605</ref>


===Infection and Inflammation===
===Infection and Inflammation===
New studies have shown that there may be a correlation between general inflammation of lung tissue and the development of lung cancers. One of the models that supports this idea has to do with the release of [[neutrophils]], which are released in response to bacterial infection and the initial stages of inflammation. The hypothesis is that neutrophils may activate reactive oxygen or nitrogen species which can bind to DNA, subsequently leading to genomic alterations. Based on this idea, it can be inferred that inflammation may be a cancer initiator or [[promoter]]. Also, tissue repair from inflammation is associated with cellular proliferation. During cellular proliferation there may be errors in chromosomal replication that can cause further DNA mutation. The final part of the hypothesis refers to [[angiogenesis]], which is very important in regards to the growth of tumors. These three different causes put together make for a good environment for the development of lung cancers.<ref name="Engels 2">Eric A Engels.11/30/11. Inflammation in the development of lung cancer:epidemiological evidence.Expert Review of Anticancer Therapy.Apr.2008.p605</ref>
*There may be a correlation between general inflammation of lung tissue and the development of lung cancers.
 
*[[Neutrophils]] are released in response to bacterial infection and are considered to be the initial responders during inflammation.
Because of smoking, infections, and chronic lung diseases, the lungs are very susceptible to prolonged inflammation. Some examples are [[tuberculosis]], [[asthma]], and [[pneumonia]].
*The hypothesis is that neutrophils may activate reactive oxygen or nitrogen species, which can bind to DNA and lead to genomic alterations. Accordingly, inflammation may be thought of as an initiator or [[promoter]] of lung cancer development. Also, tissue repair from inflammation is associated with cellular proliferation. During cellular proliferation there may be errors in chromosomal replication that can cause further DNA mutation.  
*[[Angiogenesis]], a significant process during tumor growth, may be promoted by chronic states of inflammation, which often require increased blood flow to sites of inflammation.<ref name="Engels 2">Eric A Engels.11/30/11. Inflammation in the development of lung cancer:epidemiological evidence.Expert Review of Anticancer Therapy.Apr.2008.p605</ref>


===Gross Pathology===
===Gross Pathology===
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Kim-Son H. Nguyen, M.D., M.P.A., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, Cafer Zorkun, M.D., Ph.D. [2]; Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Overview

The pathophysiology of lung cancer includes both genetic and environmental factors. Genetic mutations, namely mutations in K-ras oncogene and TP53 tumor-suppressor gene, are associated with the development of lung cancers. Environmental factors often include smoking (most important carcinogen), radon, asbestos, viral infections, and states of chronic lung inflammation, all of which may predispose to cellular damage and DNA mutations that predispose to the development of lung cancers.

Pathophysiology

Genetics

Main article: Carcinogenesis

Environment

Although genetics play a significant role in the pathogenesis of lung cancer, it is thought that exposure to environmental risk factors plays an equally improtant role in the development of lung cancer. The main causes of lung cancer include carcinogens (such as those present in tobacco smoke), ionizing radiation, and viral infections. Chronic exposure results in cumulative alterations to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). Irreversible DNA changes following exposure to carcinogens are directly associated with the development of lung cancer.

Smoking

  • Cigarette smoke contains over 60 known carcinogens[8] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
  • Nicotine is thought to reduce the immune response to malignant growths in exposed tissue. The length of time an individual smokes, as well as the amount, significantly increases the person's chance of developing lung cancer.
  • Among individuals who stopped smoking, the risk of lung cancer steadily decreases as lung tissue repairs itself and as contaminant particles are eliminated from the lungs. Nonetheless, it is thought that the risk of lung cancer among ever-smokers (even when stopped) is always higher than those who never smoked.[9][10]
  • Passive smoking, the inhalation of smoke from another's smoking, is also a risk factor of lung cancer among non-smokers.[11][12][13][14]

Radon gas

  • Radon is a colorless and odorless gas generated by the breakdown of radioactive radium (decay product of uranium) found in the earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous.
  • Radon exposure is the second major cause of lung cancer following smoking.[15]
  • The mechanism of lung damage following radon exposure is not thought to be due to the radon gas itself, but due to the short-lived alpha decay products that cause cellular damage and DNA mutations.[16]

Asbestos

  • Asbestos exposure is associated with many lung diseases, including lung cancer.
  • Tiny asbestos fibers are released into the air are breathed into the lungs. The fibers become lodged in the lungs and are stuck for an indefinite amount of time. They can eventually lead to scarring and inflammation.

Viruses

Infection and Inflammation

  • There may be a correlation between general inflammation of lung tissue and the development of lung cancers.
  • Neutrophils are released in response to bacterial infection and are considered to be the initial responders during inflammation.
  • The hypothesis is that neutrophils may activate reactive oxygen or nitrogen species, which can bind to DNA and lead to genomic alterations. Accordingly, inflammation may be thought of as an initiator or promoter of lung cancer development. Also, tissue repair from inflammation is associated with cellular proliferation. During cellular proliferation there may be errors in chromosomal replication that can cause further DNA mutation.
  • Angiogenesis, a significant process during tumor growth, may be promoted by chronic states of inflammation, which often require increased blood flow to sites of inflammation.[22]

Gross Pathology

Cross section of a human lung. The white area in the upper lobe is cancer; the black areas indicate the patient was a smoker


Microscopic Pathology

Small cell lung carcinoma (microscopic view of a core needle biopsy)


References

  1. ↑ Fong, KM (Oct 2003). "Lung cancer. 9: Molecular biology of lung cancer: clinical implications". Thorax. BMJ Publishing Group Ltd. 58 (10): 892–900. PMID 14514947. Unknown parameter |coauthors= ignored (help)
  2. ↑ Aviel-Ronen, S (Jul 2006). "K-ras mutations in non-small-cell lung carcinoma: a review". Clinical Lung Cancer. Cancer Information Group. 8 (1): 30–38. PMID 16870043. Unknown parameter |coauthors= ignored (help)
  3. ↑ Devereux, TR (Mar 1996). "Molecular mechanisms of lung cancer. Interaction of environmental and genetic factors". Chest. American College of Chest Physicians. 109 (Suppl. 3): 14S–19S. PMID 8598134. Retrieved 2007-08-11. Unknown parameter |coauthors= ignored (help)
  4. ↑ Engels, EA (Jul 2007). "Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer". Cancer Research. American Association for Cancer Research. 67 (13): 6520–6527. PMID 17596594. Unknown parameter |coauthors= ignored (help)
  5. ↑ Wenzlaff, AS (Dec 2005). "CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study". Carcinogenesis. Oxford University Press. 26 (12): 2207–2212. PMID 16051642. Unknown parameter |coauthors= ignored (help)
  6. ↑ Son, JW (Sep 2006). "Polymorphisms in the caspase-8 gene and the risk of lung cancer". Cancer Genetics and Cytogenetics. 169 (2): 121–127. PMID 16938569. Unknown parameter |coauthors= ignored (help)
  7. ↑ Yin, J (May 2007). "The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population". Lung Cancer. 56 (2): 153–160. PMID 17316890. Unknown parameter |coauthors= ignored (help)
  8. ↑ Hecht, S (Oct 2003). "Tobacco carcinogens, their biomarkers and tobacco-induced cancer". Nature Reviews. Cancer. Nature Publishing Group. 3 (10): 733–744. doi:10.1038/nrc1190. PMID 14570033. Retrieved 2007-08-10.
  9. ↑ Peto R, R (2006). Mortality from smoking in developed countries 1950–2000: Indirect estimates from National Vital Statistics. Oxford University Press. ISBN 0-19-262535-7. Retrieved 2007-08-10. Unknown parameter |coauthors= ignored (help)
  10. ↑ Nordquist, LT (Aug 2004). "Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung". Chest. American College of Chest Physicians. 126 (2): 347–351. PMID 15302716. Retrieved 2007-08-10. Unknown parameter |coauthors= ignored (help)
  11. ↑ CDC (Dec 1986). "1986 Surgeon General's report: the health consequences of involuntary smoking". CDC. PMID 3097495. Retrieved 2007-08-10.
    * National Research Council (1986). Environmental tobacco smoke: measuring exposures and assessing health effects. National Academy Press. ISBN 0-309-07456-8.
    * Template:Cite paper
    * California Environmental Protection Agency (1997). "Health effects of exposure to environmental tobacco smoke". Tobacco Control. 6 (4): 346–353. PMID 9583639. Retrieved 2007-08-10.
    * CDC (Dec 2001). "State-specific prevalence of current cigarette smoking among adults, and policies and attitudes about secondhand smoke—United States, 2000". Morbidity and Mortality Weekly Report. CDC. 50 (49): 1101–1106. PMID 11794619. Retrieved 2007-08-10.
    * Alberg, AJ (Jan 2003). "Epidemiology of lung cancer". Chest. American College of Chest Physicians. 123 (S1): 21S–49S. PMID 12527563. Retrieved 2007-08-10. Unknown parameter |coauthors= ignored (help)
  12. ↑ Boffetta, P (Oct 1998). "Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe". Journal of the National Cancer Institute. Oxford University Press. 90 (19): 1440–1450. PMID 9776409. Retrieved 2007-08-10. Unknown parameter |coauthors= ignored (help)
  13. ↑ "Report of the Scientific Committee on Tobacco and Health". Department of Health. Mar 1998. Retrieved 2007-07-09.
    * Hackshaw, AK (Jun 1998). "Lung cancer and passive smoking". Statistical Methods in Medical Research. 7 (2): 119–136. PMID 9654638.
  14. ↑ Template:Cite paper
  15. ↑ Catelinois, O (May 2006). "Lung Cancer Attributable to Indoor Radon Exposure in France: Impact of the Risk Models and Uncertainty Analysis". Environmental Health Perspectives. National Institute of Environmental Health Science. 114 (9): 1361–1366. doi:10.1289/ehp.9070. PMID 16966089. Retrieved 2007-08-10. Unknown parameter |coauthors= ignored (help)
  16. ↑ University of Minnesota.http://enhs.umn.edu/hazards/hazardssite/radon/radonmolaction.html#Anchor-Molecular-23240/
  17. ↑ Leroux, C (Mar–Apr 2007). "Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep". Veterinary Research. 38 (2): 211–228. PMID 17257570. Unknown parameter |coauthors= ignored (help)
  18. ↑ Palmarini, M (November 2001). "Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer". Journal of the National Cancer Institute. Oxford University Press. 93 (21): 1603–1614. PMID 11698564. Retrieved 2007-08-11. Unknown parameter |coauthors= ignored (help)
  19. ↑ Cheng, YW (Apr 2001). "The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women". Cancer Research. American Association for Cancer Research. 61 (7): 2799–2803. PMID 11306446. Retrieved 2007-08-11. Unknown parameter |coauthors= ignored (help)
  20. ↑ Zheng, H (May 2007). "Oncogenic role of JC virus in lung cancer". Journal of Pathology. 212 (3): 306–315. PMID 17534844. Unknown parameter |coauthors= ignored (help)
  21. ↑ Giuliani, L (Sep 2007). "Detection of oncogenic viruses (SV40, BKV, JCV, HCMV, HPV) and p53 codon 72 polymorphism in lung carcinoma". Lung Cancer. 57 (3): 273–281. PMID 17400331. Unknown parameter |coauthors= ignored (help)
  22. ↑ 22.0 22.1 Eric A Engels.11/30/11. Inflammation in the development of lung cancer:epidemiological evidence.Expert Review of Anticancer Therapy.Apr.2008.p605

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