patients with malignant pleurisy. Methods: IL-6, fibrinogen and the related molecules in blood and pleural effusion of 38 patients were assayed at 3-day intervals.
Jpn J Clin Oncol 2000;30(2)53–58
Original Articles
Effect of IL-6 Elevation in Malignant Pleural Effusion on Hyperfibrinogenemia in Lung Cancer Patients Toshihiko Yamaguchi1, Hiromi Kimura1, Soichiro Yokota1, Yuko Yamamoto2, Taikichi Hashimoto2, Masaru Nakagawa1, Masami Ito1 and Takeshi Ogura1 1Department
of Internal Medicine and 2Clinical Laboratory, Toneyama National Hospital, Toyonaka, Osaka, Japan
Received August 27, 1999; accepted November 2, 1999
Background: The involvements of interleukin-6 (IL-6) and fibrinogen in cancer development were elucidated independently, irrespective of IL-6 activity to induce fibrinogen. This study was undertaken to clarify the clinicopathological association of these molecules in lung cancer patients with malignant pleurisy. Methods: IL-6, fibrinogen and the related molecules in blood and pleural effusion of 38 patients were assayed at 3-day intervals. Results: IL-6 levels were elevated in sera of 27 cases (71.1%) and in all the effusions with mean values of 20.5 and 9970.5 pg/ml, respectively. Their correlation in 22 cases who were examined on the same day was statistically strong (r = 0.902, p < 0.0001). Occasional elevations of tumor necrosis factor-α were independent of IL-6 elevation. Levels of plasma fibrinogen, fibrin(ogen) degradation products (FDP) and C-reactive protein (CRP) were more frequently elevated in the IL-6-elevated cases than those without IL-6 elevation. In all pleural effusions, fibrinogen levels were significantly decreased to 0.3 mg/dl, fibrinogen levels of >450 mg/dl and FDP levels of 10 µg/ml were regarded as elevated levels. Fibrinogen and FDP in the pleural effusions were also examined.
Clinical stage Histology
Male
27
Female
11
10 µg/ml). †Calculated for patients with elevated levels of CRP. The p value was calculated by ‡the χ2 test, §the Mann–Whitney test or ¶Student’s t-test.
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IL-6 and fibrinogen in malignant pleurisy
Figure 2. Correlations between fibrinogen (A, B), FDP (C, D) or CRP (E, F) levels in venous blood and serum or pleural IL-6 levels, respectively. Open and closed symbols indicate the samples obtained on different days (n = 16) and on the same day (n = 22), respectively. R is calculated for the closed symbols.
from lung cancer cells has been demonstrated in different cell lines (7,15–17) and biopsied specimens (18). Although it was also immunocytologically detected in many cases of adenocarcinoma in this study (Fig. 4), no correlation with elevation of IL-6 level was observed. In addition to cancer cells, various host cells such as mesothelial cells and macrophages, which are predominantly involved in the affected pleural tissue and capable of producing IL-6, are also considered to be concerned. Indeed, clinical observations that IL-6 elevation in benign pleural effusion is as high as that in malignant pleural effusion (6,7,19,20) strongly suggest an important contribution from host inflammatory cells to IL-6 elevation in malignant pleural effusion. Thus, IL-6 elevation in the serum of lung cancer patients with malignant pleural effusion may be due mainly to leakage into the systemic circulation of IL-6 produced by cancer cells as well as host cells in both malignant effusion and affected pleural tissue. The correlation of IL-6 levels between serum and pleural effusion shown in Fig.1 strongly supports this idea.
Figure 3. Correlation between levels of pleural IL-6 and pleural fibrinogen (A) or FDP (B). The solid line was computer fitted for all the symbols (n = 31).
IL-6 produced in the primary lung cancer site may also participate in its elevation in serum, as reported previously (11,12,18). In the present study, however, the incidence of serum IL-6 elevation was 71.1% (27/38 cases), whereas it was 44.3% in 183 lung cancer patients at the corresponding clinical stage (IIIB, IV) without pleural effusion in our previous study (12). This difference in the incidence of serum IL-6 elevations may be due to the major contribution from IL-6 produced in the affected pleural cavity. Although the maximum and mean serum IL-6 levels were low compared with those reported previously (12), the underlying mechanism still remains unknown. Paracrine stimulation of IL-6 production by TNF-α, which has been demonstrated in tumor cells (7,16,17) and host cells (21), may be involved in the IL-6 elevation in the pleural effusion. At present, however, this possibility can be excluded because elevation of TNF-α level was found to be rare and not related to markedly high IL-6 levels. The biological effect of serum IL-6 elevation was evidenced as a difference in the incidence of fibrinogen, FDP and CRP
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Acknowledgments This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan and a Grant from the Osaka Foundation for Promotion of Clinical Immunology.
References
Figure 4. Representative immunohistochemical staining of human IL-6 in a case of a lung cancer patient with malignant pleural effusion. A, clear staining of pleural adenocarcinoma cells (peroxidase/hematoxylin, ×1000); B, negative control (×1000). Bar, 10 µm.
levels in venous blood (Table 3). In addition, it was even more clearly evidenced by significant correlations between levels of serum or pleural IL-6 and CRP (Fig. 2). These, taken together with other findings that no strong correlation was observed between levels of serum IL-6 and plasma fibrinogen and that fibrinogen decreased significantly and FDP increased in proportion to IL-6 levels in the pleural effusion, strongly suggested that plasma fibrinogen, increased in response to the elevated serum IL-6 level, was exudated predominantly into the affected pleural cavity. A similar process has been observed in experimental and human tumors and has been studied mainly with respect to local alterations in coagulation– fibrinolytic factors secreted from tumor tissue (3,22). Recently, fibrin(ogen) deposition on the surfaces of tumor cells and lymphocytes (23,24) and in primary and invasive lesion of the tumor (25) have been regarded as adverse events leading to tumor development. In addition, IL-6 may also function as a growth stimulating factor (5,26,27). Thus, in patients with malignant pleural effusion in whom the serum IL-6 level is substantially increased, IL-6 may promote cancer development not only directly but also indirectly through induction of hyperfibrinogenemia. In this regard, local treatment with intrapleural instillation of agents such as bleomycin, tetracycline, quinacrine or IL-2, which have been shown to increase the levels of plasma fibrinogen and IL-6 (4,9,10), needs to be reconsidered for its therapeutic rationale, although it has generally been used to produce pleurodesis for preventing pleural effusion.
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