Lung cancer pathophysiology

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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. Cafer Zorkun, M.D., Ph.D. [2] Dildar Hussain, MBBS [3] Michael Maddaleni, B.S.

Overview

The pathophysiology of lung cancer includes both genetic and environmental factors. Causality of the majority of lung cancer is linked to tobacco usage. Carcinogenic effects of tobacco smoking may result in DNA mis-replication and mutation. Smoking starts a cascade of events that leads to cancer development, even decades after smoking cessation. Besides smokers, patients with the history of prior respiratory tract or gastrointestinal tract cancer comprise a high-risk population. Other environmental factors include 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

The pathophysiology of lung cancer includes both genetic and environmental factors.

• Lung cancer consists of several histological types.
• Main histological types of lung cancer include:
  • Small cell lung cancer
  • Non small cell lung cancer
    • Adenocarcinoma of the lung
    • Squamous cell carcinoma of the lung
    • Large cell carcinoma of the lung
    • Sarcomatoid carcinoma of the lung
• Smoking starts a cascade of events that leads to cancer.

Lung Cancer Pathogenesis

• Lung cancer pathogenesis can be understood with the help of the following hypothesis:

Familial lung cancer

• • 6q23–25 locus has been identified as a susceptibility gene for familial lung cancer.

Multistep tumorigenesis

• • Tumors of organs such as skin, lung and colon are developed through a process called multistep tumorigenesis.
  • As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa.
  • Multistep tumorigenesis is the development of tumor through a series of progressive pathologic events such as preneoplastic or precursor lesions with corresponding genetic and epigenetic aberrations.
  • Hyperplasia, squamous metaplasia, squamous dysplasia, and carcinoma in situ (CIS) comprise changes in the large airways that precede or accompany invasive squamous cell carcinoma of the lung.
  • Multistep tumorigenesis explains pathogenesis of centrally located squamous cell carcinoma of the lung very well but fails to explain the pathogenesis of large cell lung carcinomas, lung adenocarcinomas, and small cell lung cancer.

Accumulation of Molecular Abnormalities

• • Another theory on the pathogenesis of lung cancer is the accumulation of molecular abnormalities beyond a certain threshold point, rather than the sequence of alterations.
  • There are no known preneoplastic lesions for the most common type of neuroendocrine lung tumors, small cell carcinoma of the lung,
  • Atypical adenomatous hyperplasia (AAH) is the only sequence of morphologic change identified leading to the development of invasive adenocarcinoma of the lung.
• Pathogenesis of lung cancer is thought to be result of both due to stepwise, sequence-specific and multistage molecular pathogenesis and due to accumulation and combination of genetic and epigenetic abnormalities.

Field of Injury and Field Cancerization

• Preneoplastic lung lesions frequently extend throughout the respiratory epithelium, indicating a field effect in which much of the respiratory epithelium has been mutagenized, presumably from exposure to tobacco-related carcinogens.
• Epithelial cells lining the entire respiratory tract that have been exposed to smoking show molecular alterations that may signify the onset of lung cancer, a paradigm known as the "airway field of injury”.
• Premalignant airway fields in the molecular pathogenesis of lung cancer:
  • Smoking induces widespread molecular alterations, such as gene expression changes in exposed epithelia throughout the respiratory tract.
  • The airway field of injury can be seen in smokers with or without lung cancer and is highly relevant for the identification of markers for minimally invasive and early detection of lung cancer.
  • The adjacent airway field of carcinoma represents the field in normal appearing airways adjacent to lung tumors.
  • It has been suggested that in this adjacent field of tumor, there is closer molecular genealogy between lung cancers and airways that are in closest proximity to the tumors compared to airways that are more distant from the tumors.
  • The progression of the molecular airway field of injury to preneoplasia and lung malignancy is still not clear.
  • Molecular changes involved in the development of the airway field of injury and changes mediating progression of this field to lung preneoplasia may help the identification of early markers for lung cancer detection and chemoprevention.

Genetics

• Lung cancer development is initiated by the activation of oncogenes or inactivation of tumor suppressor genes.
• Mutations in the K-ras proto-oncogene are responsible for 20% to 30% of non-small cell lung cancer cases.
• Chromosomal damage may also result in the loss of heterozygosity, which subsequently leads to the inactivation of tumor suppressor genes.
• Damage to the following chromosomes are particularly common in small cell lung carcinoma:
  • Chromosome 3p
  • Chromosome 5q
  • Chromosome 13q
  • Chromosome 17p
• The TP53 tumor suppressor gene, located on chromosome 17p, is often mutated in lung cancers.
• Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for:
  • Interleukin-1
  • Cytochrome P450
  • Caspase-8, an apoptosis promoter
  • XRCC1, a DNA repair molecule
• Individuals with these polymorphisms are thought to be more likely to develop lung cancer following exposure to carcinogens.

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 important 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 smoking is a leading cause of lung cancer.
• Cigarette smoke contains over 60 known carcinogens including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
• Nicotine is thought to reduce the immune response to malignant growths in the 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.
• It is thought that the risk of lung cancer among persons with a history of smoking (even when stopped) is always higher than those who never smoked.

Radon Gas

The association of radon gas exposure to lung cancer is described below:

• 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.
• 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.

Asbestos

• Asbestos exposure is associated with many lung diseases, including lung cancer.
• Tiny asbestos fibers 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 known to be associated with the development of lung cancer in animals and humans include:
  • Human papillomavirus
  • JC virus
  • Simian virus 40 (SV40)
  • BK virus
  • Cytomegalovirus
  • HIV
• 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.

Infection and Inflammation

• There may be a correlation between general inflammation of lung tissue and the development of lung cancer.
• 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.