Inflammation has been shown to have a role in cancer initiation and promotion (2
), and may thus be an important contributor to carcinogenesis across many anatomic sites. The carcinogenic influence of inflammation may also extend to cancer progression. Thus, this study was done to investigate the potential role of circulating cytokine concentrations in lung cancer survival. In this study, we observed that IL-6 was associated with worse lung cancer prognosis in both African Americans and Caucasians. IL-10 and IL-12 were associated with lung cancer survival in African Americans, whereas TNF-α was associated with survival in Caucasians.
The role of inflammation and immunity in tumor biology is complex. When the immune response is functioning normally, inflammation is self-limiting. The production of proinflammatory or Th-1 cytokines is followed by anti-inflammatory or Th-2 cytokines (2
). In the case of chronic inflammatory diseases, the balance between Th-1 and Th-2 cytokines is disrupted, and increased inflammation results in greater production of oxygen and/or nitrogen radicals. These radicals may damage both epithelial and stromal cells (4
). Meanwhile, recruitment of inflammatory cells may function to inhibit tumor growth (2
). Furthermore, Th-2–dominant cytokine profiles have been correlated with enhanced tumor promotion and progression (27
), and tumor cells that produce immunosuppressive (Th-2) cytokines may escape host tumor response (29
Consistent with previously reported correlations of Th-2 cytokines with tumor promotion, our study observed an inverse association between lung cancer survival and IL-6 in Caucasians over the entire follow-up period and between lung cancer survival and IL-6 and IL-10 in African Americans within the first 18 months post-diagnosis. Both IL-6 and IL-10 are considered Th-2 cytokines (30
), although IL-6 was reported to produce both Th-1 and Th-2 responses (27
). In addition, our laboratory previously noted that elevated IL-6 and IL-10 mRNA in normal lung tissue were associated with lymph node metastasis (23
Our observation that serum concentrations of IL-6 were associated with lung cancer prognosis in both African Americans and Caucasians was consistent with previous reports (7
). One study noted that the association of IL-6 with lung cancer survival was an independent prognostic factor but only within the first 3 years of follow-up (12
). Our median follow-up was only 31 months (20 for African Americans, 34 for Caucasians); therefore, the association of IL-6 with survival should be evaluated again after a longer follow-up period to determine if and when the association between IL-6 and lung cancer survival diminishes. Furthermore, additional studies are needed to investigate our finding that the association between IL-6 concentrations and survival diminishes more rapidly among African Americans than Caucasians. We also observed that IL-6 concentrations were higher in later-stage lung tumors (data not shown), in agreement with other studies (6
Several studies suggest possible biological mechanisms for increased IL-6 in serum from cancer patients. The tumor cells themselves might have been a source of IL-6; a recent study examined the expression of cytokines from 31 lung cancer cell lines and reported that 55% of the lines expressed IL-6 (5
). In addition, results from several studies indicated that IL-6 may function in angiogenesis (5
). Furthermore, cyclooxygenase-2 expression in lung tumors was shown to induce IL-6 (32
) and was associated with worse lung cancer prognosis (34
In this study, elevated serum IL-10 was associated with worse survival early in follow-up and better survival later in follow-up among African Americans. The latter finding should be interpreted with caution because of the limited sample size; only 42 (25 low and 17 high IL-10) African Americans survived beyond 18 months to be included in this calculation. In previous studies, elevated serum IL-10 levels were predictive of poor survival (14
) even after adjusting for additional covariates, including serum IL-8 and IL-2 levels (14
). However, another report did not observe this association (35
). IL-10 levels have been shown to correlate with both tumor size and stage (11
); therefore, racial differences in tumor characteristics might partially explain why no association was observed with IL-10 among Caucasians. The African American cases in this study tended to have more advanced disease compared with Caucasians. Further, based upon a comparison of the controls from the parent study, which were not included in the present report, Caucasians had higher serum IL-10 levels than African Americans (data not shown). IL-10 is proposed to have several functionalities, which could result in differing effects on lung tumors. Secretion of IL-10 by cancer and immune cells may result in the suppression of cell-mediated immunity, allowing tumors to proliferate and escape immune surveillance, but this immunosuppression may also inhibit angiogenesis, thereby inhibiting tumor growth (36
Associations of Th-1 cytokines with lung cancer survival were also observed. Elevated IL-12 in African Americans and TNF-α in Caucasians were associated with worse survival. Another report observed an association of higher IL-12 levels with improved survival in an Italian population (17
) in contrast to our observations. IL-12 was shown to stimulate antitumor responses in tumor models (37
), be associated with antiangiogenic activity (38
), and induce tumor-associated macrophage proinflammatory profiles as antitumor responses (39
). The reason for the association of higher levels of IL-12 with worse survival only in African Americans in our study is unclear.
Consistent with our previous TNF-α mRNA expression results (23
), TNF-α serum concentration was associated with worsened lung cancer prognosis. However, other prospective epidemiologic studies have not found serum concentration to be associated with lung cancer survival (7
). The reason for the inconsistency is unclear, but may be due to differences in case population (i.e., distribution of stage or histology). Multiple in vitro
and animal studies have shown TNF-α to have antiproliferative qualities (40
Our group recently observed that elevated expression levels of IL-8 noncancerous lung tissue were associated with lymph node metastasis, whereas IL-8 in tumor tissue was related to lung cancer prognosis in a population of patients with stage I adenocarcinoma (23
). Serum IL-8 was not found to be a predictor of prognosis in this current study for either race. These results may be attributable to differences in local tissues versus circulating in serum. Consistent with the results of this report, Orditura et al. (14
) found that elevated serum IL-8 levels were not associated with poorer lung cancer prognosis after adjusting for other covariates, including IL-10 and IL-2.
Inconsistent results by race (e.g., IL-10, IL-12, and TNF-α) may have been due to differences in genetics, tumor characteristics, or other exposures. Racial variation was observed among controls for many of the cytokines, including IL-10 and TNF-α (data not shown). Cytokine concentrations can be modulated by polymorphisms (45
) and many of the allele frequencies for these polymorphisms vary by race (45
). Additionally, differences could have been due to variation in tumor characteristics (e.g., stage or histology). In this study Caucasians had less advanced tumors (χ2 P
= 0.01) and were more likely to have adenocarcinomas (χ2 P
= 0.02) than African Americans. Variation in concentration and prognostic ability might also have been influenced by racial differences in other exposures, including infection or cigarette smoking. Given the higher incidence and mortality of lung cancer among African Americans (21
), these observations may provide useful avenues for future study.
A limitation of this study is the variability of the cytokine assays and skewed distribution of cytokine concentrations. As noted, variation was higher in the low concentration ranges of cytokine assays. This variability unlikely altered the results shown. Spearman correlations between duplicate samples were consistent with good reproducibility for IL-6, IL-10, TNF-α, and IL-12. Further, all analyses were done using categorization by median cytokine levels. Assuming possible misclassification is nondifferential, results are likely biased towards the null.
Other limitations need to be addressed. Cytokines were measured only once in this study and may be influenced by illnesses (other than lung cancer) or anti-inflammatory medications. Thus, it is not possible to determine how cytokines change over time and if there is an optimal window of time to evaluate cytokines to maximize their prognostic ability. Our findings remained consistent after adjustment for other comorbidities and medication use as well as other possible confounders; however, prospective studies with multiple serial measures are needed. In addition, due to the limited availability of information on tumor histology (surgical sections were unavailable from cases who did not go to surgery and specification of only non–small cell lung cancer on pathology reports), we were unable to examine specific histologic subtypes or tumor size rigorously. Finally, treatment information was not complete for this population and is likely a modifier of cytokine concentrations and survival outcomes. In 1999, however, Martin et al. (12
) investigated whether or not the inclusion of patients with surgically removed early-stage cancers influenced their findings. Although the median survival times were attenuated, after accounting for treatment, patients with elevated IL-6 still had a significantly worse prognosis. Therefore, it is reasonable to believe that better assessment of treatment would not alter the findings of the current study.
A major strength of the present study is that it was large enough to make meaningful comparisons in both African Americans and Caucasians. None of the previous studies were conducted in African Americans. Thus, we not only provided the initial investigation of these cytokines and lung cancer prognosis specifically among African Americans, but also provided a comparison between the two races.
The results of the present study suggest that high serum concentrations of IL-6, IL-10, and IL-12 in African Americans and IL-6 and TNF-α in Caucasians are associated with lung cancer prognosis. The associations of IL-10, IL-12, and TNF-α were only observed in one population; therefore, these results should be considered preliminary. The similar results in both African Americans and Caucasians for IL-6 suggest that this cytokine is possibly equally important in both groups. Moreover, the observation of IL-6 association with survival in both populations strengthens the evidence for a role of IL-6 in lung cancer prognosis. Our study represents a promising line of inquiry, but future prospective studies are needed to clarify whether circulating cytokine concentrations contribute to lung carcinogenesis and/or can be used to assist in the treatment of lung cancer.