Lung cancer pathophysiology


 * Associate Editor(s)-In-Chief: Kim-Son H. Nguyen, M.D., M.P.A., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, ; Assistant Editor(s)-In-Chief: Michael Maddaleni, B.S.

Overview
Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Oncogenes are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Mutations in the K-ras proto-oncogene are responsible for 20–30% of non-small cell lung cancers. 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.

Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1, cytochrome P450, apoptosis promoters such as caspase-8, and DNA repair molecules such as XRCC1. People with these polymorphisms are more likely to develop lung cancer after exposure to carcinogens.

The main causes of lung cancer (and cancer in general) include carcinogens (such as those in tobacco smoke), ionizing radiation, and 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
Cigarette smoke contains over 60 known carcinogens including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.

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.

In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers, and that patients who smoke at the time of diagnosis have shorter survival than those who have quit.

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.,
 * Europe, the UK, and Australia 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.
 * Europe, the UK, and Australia 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.
 * Europe, the UK, and Australia 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.
 * Europe, the UK, and Australia 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.
 * Europe, the UK, and Australia 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.

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 ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer after smoking.

Mechanism of damage
 * 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 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. 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).

Viruses
Viruses are known to cause lung cancer in animals and recent evidence suggests similar potential in humans. Implicated viruses include human papillomavirus, JC virus, simian virus 40 (SV40), BK virus and cytomegalovirus. 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.

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.

Because of smoking, infections, and chronic lung diseases, the lungs are very susceptible to prolonged inflammation. Some examples are tuberculosis, asthma, and pneumonia.