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  • Review Article
  • Published:

Mechanistic links between COPD and lung cancer

Nature Reviews Cancer volume 13, pages 233–245 (2013)Cite this article

Subjects

Key Points

  • Numerous epidemiological studies have consistently demonstrated an increased incidence of lung cancer in patients who have chronic obstructive pulmonary disease (COPD).

  • The emphysema component of COPD, which is characterized by excessive inflammation and matrix destruction, is sufficient to confer an increased risk for lung cancer. Taken together, the epidemiological literature suggests that entities involved in the airways and airspace components of COPD are both operative in increasing lung cancer risk.

  • Both COPD and lung cancer involve a substantial role for genetic susceptibility to disease, as only a minority of chronic cigarette smokers will develop one, or both, of the diseases. Several single nucleotide polymorphisms (SNPs) in candidate gene families (for example, detoxifying enzymes, proteinases, anti-proteinases and cytokines) have been implicated in disease pathogenesis for both COPD and lung cancer, and may confer a proportion of the risk.

  • The oxidant and noxious stress encountered in the lungs of cigarette smokers is overwhelming. These species cause sufficient damage to some epithelial cells such that they undergo apoptosis, resulting in emphysema. They additionally represent genotoxic stress capable of DNA adduct formation, thereby promoting the earliest stages of carcinogenesis.

  • Inflammatory cell infiltrates are common to both COPD and lung cancer. Their quantity and quality must be taken in context. Inflammation encountered in emphysema is typically cytotoxic and destructive to matrix structures. Such cells would not be expect to promote the growth of an existing tumour, but would provide the necessary genotoxic stress for tumour initiation. Once formed, small tumours polarize immune cells to alternatively activated phenotypes, which promote tumour growth and angiogenesis.

  • Matrix-degrading enzymes, especially those capable of degrading elastin (elastases) are essential for the development of emphysema. Many of these enzymes have been shown to promote lung tumour growth by a variety of mechanisms, including enhanced cellular proliferation and increased angiogenesis, which permits endovascular invasion. Therefore, these enzymes are likely to represent a proportion of the link between emphysema and lung cancer.

  • As operative mechanisms linking COPD to lung cancer are discovered, the opportunity for chemoprevention will arise. Ideally, new therapies will be developed that have the ability to retard COPD progression while reducing lung cancer risk.

Abstract

Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independently of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress towards uncovering this link has been hampered by the heterogeneous nature of the two disorders: each is characterized by multiple sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two diseases and consider specific mechanisms that operate in both COPD and lung cancer, some of which might represent either chemopreventive or chemotherapeutic targets.

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Figure 1: Candidate mechanisms linking COPD to lung cancer.
Figure 2: Fields at risk.
Figure 3: Immune cell profiles in COPD and lung cancer.

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    A. McGarry Houghton

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Glossary

Proximal lung cancers

Proximal refers to cancers arising in the large airways (bronchi) that are easily accessible by bronchoscopy. These lesions are most commonly squamous cell carcinoma or small-cell lung cancer by histology.

Distal lung cancers

Distal cancers arising in the peripheral zones of the lung are more difficult to sample using bronchoscopy. These lesions are most commonly adenocarcinoma by histology.

A1AT

There are more than 75 known mutations in SERPINA1. The normal allele has been designated M. The most commonly encountered abnormal alleles are Z and S. A1AT deficiency is most commonly seen in ZZ or SZ subjects. Common carrier states include MZ and MS.

Bronchoalveolar lavage

(BAL). To sample the contents of the distal lung, physicians insert a bronchoscope into the smallest airway in which it can fit. Once 'wedged' into position, saline is infused into the lung, followed by suctioning to return the fluid, which now contains cells and proteins.

Medicare

A national health insurance programme in the United States, and the largest payer of health care services in the United States.

ß-agonist

Inhaled drug that stimulates the ß-adrenergic receptors located on airway epithelial cells. Their stimulation results in the dilation of the airways. Commonly used for the treatment of asthma and chronic obstructive pulmonary disease.

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Houghton, A. Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13, 233–245 (2013). https://doi.org/10.1038/nrc3477

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