COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link

Abstract

Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking-related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour-promoting serum amyloid A (SAA) and IL-17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap. AbbreviationsCOPD, chronic obstructive pulmonary disease; FGFR1, fibroblast growth factor-1; FPR2, formyl peptide receptor 2; LOH, loss of heterozygosity; LXA4, lipoxinA4; NSCLC, non-small cell lung cancer; NFE2L2, nuclear factor, erythroid 2-like 2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homologue; SAA, serum amyloid A; SCC, squamous cell cancer; RvD1, resolvinD1

Multiscale Modeling of Inflammation and Inflammatory Diseases

“…It is now well recognized that although precise mechanisms are not yet fully understood, inflammation and cancer are closely correlated [6][7][8][9]. The link between inflammation and cancer development is particularly strong in patients with lung cancer, as the lungs are constantly exposed to environmental insults that may cause chronic inflammatory injuries and infection [10,11]. Currently, lung cancer is the leading cause of cancer-related deaths worldwide with 5-year survival rates averaging around only 15-18% [11,12].…”

“…The link between inflammation and cancer development is particularly strong in patients with lung cancer, as the lungs are constantly exposed to environmental insults that may cause chronic inflammatory injuries and infection [10,11]. Currently, lung cancer is the leading cause of cancer-related deaths worldwide with 5-year survival rates averaging around only 15-18% [11,12]. Despite ongoing efforts to reduce smoking prevalence, cigarette smoking still remains the main cause of 90% of lung cancers [13,14] with ~15% of lifetime smokers developing the disease [14].…”

“…Cigarette smoke (CS) contains more than 4,500 components including toxins, oxidants, and carcinogens [15]. Long-term CS exposure to the lung induces chronic inflammation, generating an inflammatory microenvironment for lung tumor initiation and progression [11]. CS is also the major risk factor for chronic obstructive pulmonary disease (COPD), which is the third leading cause of death globally without effective therapies [16].…”

“…~50-70% of patients with lung cancer suffer from COPD [14]. A most common link between COPD and LC is chronic inflammation [11,13]. As COPD is a chronic inflammatory disorder, aberrant inflammation in COPD is critical to increase risk of lung cancer [11].…”

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…Identification of additional inflammatory molecules that may be involved in the development of LC among patients with COPD and/or tumor progression is of relevance as they offer potential for the design of novel therapeutic strategies in the treatment of LC (100,102).…”