We examined the association between circulating IL-6 and IL-8 levels and lung cancer in two independent studies. The first was a case–control study in which the participants resided in the Baltimore, Maryland region. The second was a nested case–control study within the prospective PLCO Cancer Screening Trial, recruited from 10 centers throughout the United States. Our findings demonstrated that increased serum IL-6 and IL-8 levels were associated with lung cancer in the NCI-MD study and lung cancer risk in the PLCO study. High serum IL-8 levels predated subsequent diagnosis of disease; increased IL-8 was present even 5 years before lung cancer diagnosis in the PLCO study. In contrast, IL-6 levels were increased only among those with diagnosed lung cancer (NCI-MD study) or those who soon developed lung cancer (<2 years in PLCO study), whereas no association was seen at longer intervals in the PLCO study. The associations were independent of smoking, age, sex, tumor histology, stage, systemic inflammation, and whether the case patients were screen or clinically diagnosed. In addition, IL-8 and CRP revealed substantial variation in 10-year absolute risk of lung cancer, both in current and former smokers, suggesting that these markers may identify smokers at a lower or higher risk of lung cancer.
Our findings are consistent with evidence that inflammatory mediators contribute to the pathogenesis of many human cancers, including lung cancer (29
). For example, there is an increased risk of lung cancer associated with tuberculosis, adult asthma, and bacterial pneumonia (30
). Under inflammatory stress, IL-6 and IL-8 participate in tumorigenesis by acting directly on lung epithelial cells via signaling through the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) pathway (30
). Additionally, IL-6 and IL-8 are expressed by lung cancer cells and act in an autocrine and/or paracrine fashion to stimulate cancer cell proliferation (33
), migration, and invasion (35
It was surprising that IL-8, but not IL-6, was associated with subsequent development of disease, especially because IL-6 and IL-8 are secreted by premalignant and senescent cells surrounding premalignant lesions (10
), which would likely be present up to several years before lung cancer diagnosis. The IL-6 data are consistent with a report of the prospective Health Aging and Body Composition study of 43 case patients, in which high IL-6 levels were not associated with development of lung cancer (7
). Perhaps IL-8 plays a larger role in tumor initiation and promotion, whereas IL-6 participates primarily in tumor progression. This is supported by our previous report that increased circulating IL-6 levels are associated with lung cancer survival but IL-8 levels are not (24
), and other reports that IL-6 participates in tumor progression in several cancer types (38
). Serial examination of these markers, in addition to CRP, leading up to disease may provide additional crucial information about the relationship of these markers and disease status and progression.
Several factors should be considered in the interpretation of our findings. Strengths of this study include large sample sizes and inclusion of hospital- and population-based control subjects in the NCI-MD study. Although the associations were more robust among the population-based control subjects, there were statistically significant associations using both groups of control subjects. A major strength was replication of results in the PLCO study with a prospective design and broad representative group. An additional strength was the focus on a single race to avoid variability that could be introduced by a diverse population. However, a validation of the results among other ethnicities is needed, as well as an assessment of whether circulating cytokine levels contribute to racial health disparities in lung cancer.
This study has a few limitations. Patients with cancers other than lung cancer were excluded from the analyses, and therefore, we could not determine the specificity of the serum biomarkers for lung cancer among other cancer types. In addition, the absolute risk estimates did not account for competing mortality and thus, these values did not fully represent the observed proportion of individuals developing lung cancer. A minor limitation was the overlap of cytokine levels between case patients and control subjects. However, the relative risk assessment of IL-8 was considerably increased when used in combination with CRP levels, suggesting that development of a combination of biomarkers may yield even stronger predictive values. The cytokine concentrations measured in the NCI-MD and PLCO studies were different, making it difficult to use the same cutoffs for both populations. The reason for this difference is unknown, but may be because of differences in the populations, collection, and handling procedures for serum samples or analytical platforms. Therefore, more research is needed to standardize measurements of these biomarkers. Regardless, the concentrations were higher in case patients than in control subjects in both population groups, suggesting that these markers are targets for follow-up study.
Technologies such as low-dose spiral computed tomography may detect lung tumors at the millimeter range (42
). However, the high rate of false-positive results instigates concern about whether exposure to x-rays, cost, and patient anxiety outweigh the benefits. Although the levels of IL-6, IL-8, and CRP were increased in clinically detected lung cancers, the levels of these biomarkers were increased in the PLCO study before lung cancer diagnosis, suggesting that they may be useful as biomarkers for lung cancer screening. Specifically, IL-6, IL-8, and CRP may be targets for further assay refinement, alone, or in combination with other nonimaging screening targets under development. Furthermore, examination in prospective trials is necessary to determine if serial serum testing of IL-6, IL-8, and CRP can improve the positive predictive value of the current screening modalities, increase overall cost effectiveness, and potentially improve lung cancer survival.