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Japanese Journal of Clinical Oncology Pages 740-744

Involvement of Interleukin-6 in the Elevation of Plasma Fibrinogen Levels in Lung Cancer Patients
Introduction
Patients And Methods
   Patients
   Assay of IL-6 and Determinations of Fibrinogen, FDP and CRP
   Statistical Analysis
Results
   Patients' Clinicopathological Characteristics
   Levels of Serum IL-6
   Levels of Fibrinogen, FDP and CRP
Discussion
Acknowledgment
References
Involvement of Interleukin-6 in the Elevation of Plasma Fibrinogen Levels in Lung Cancer Patients

Involvement of Interleukin-6 in the Elevation of Plasma Fibrinogen Levels in Lung Cancer Patients

Toshihiko Yamaguchi1, Yuko Yamamoto2, Soichiro Yokota1, Masaru Nakagawa1, Masami Ito1 and Takeshi Ogura1

1Department of Internal Medicine and 2Clinical Laboratory, Toneyama National Hospital, Osaka, Japan

Background: Involvements of interleukin-6 (IL-6) and fibrinogen in cancer development have been independently studied. However, the association of these molecules in cancer patients remains uncertain. This study was conducted to clarify the association according to the clinicopathological characteristics of lung cancer patients.
Methods: Serum IL-6 levels assayed in 339 patients without pleural effusion were assessed according to clinical stage, histological type of the cancer and levels of fibrin (ogen) degradation products (FDP), and C-reactive protein (CRP).
Results: Elevations of serum IL-6 levels more than 4 pg/ml were found in 37.8% of all patients. According to the clinical stage and histological type, the elevations were significantly more frequent in the advanced stage (44.7%), in squamous cell (49.1%) and large cell carcinomas (63.6%). Similarly, the frequency of the elevated cases (>400 mg/dl) and the mean value of the fibrinogen level were also higher in the advanced stage (54.2%, 455.0 mg/dl) and large cell carcinoma (54.6%, 459.3 mg/dl), respectively. The elevations of fibrinogen, FDP and CRP levels were found to be related to those of the IL-6 level.
Conclusion: In lung cancer, serum IL-6 elevations are particularly frequent in the advanced stages of patients with squamous cell and large cell carcinoma, which are associated with the elevated levels of fibrinogen, suggesting a possibility that IL-6 was involved not only directly, but also indirectly, through regulating plasma fibrinogen with promotion of cancer development in vivo.

Key words: IL-6 - CRP - fibrinogen - FDP - lung cancer patients

INTRODUCTION

Autonomous interleukin-6 (IL-6) production from cancer cells (1-9) and its regulatory effect on cancer cells has been noted in various types of human cancer (10-13). In clinical studies, the elevated serum levels of IL-6 in tumor-bearing patients related to paraneoplastic syndromes (14-17) and patients' prognoses (18,19) have been observed.

On the other hand, previous studies have suggested the involvement of fibrinogen, in paraneoplastic syndrome (20), growth of tumor tissue (21,22) and immunobiological interaction between the tumor and the host (23).

Considering those results together with the stimulative action of IL-6 on fibrinogen production (1), IL-6 may play diverse roles in the development of tumor growth not only through direct action on tumor cells, but also through regulation of the fibrinogen level.

In previous reports, however, little has been reported on the association of these molecules in tumor-bearing patients, and our previous study elucidated a possible association of the elevated levels of IL-6 and fibrinogen in 75 patients with lung cancer (24). The present study was conducted to analyze, in detail, the clinicopathological characteristics of the serum IL-6 elevation and to confirm the definite association of these molecules in a total of 339 patients with lung cancer.

PATIENTS AND METHODS

Patients

The subjects were patients with lung cancer admitted to our institution over the past three years. Their cancer was confirmed cytologically or histologically and classified into histological type and clinical stage according to the UICC TNM classification (1987). Patients with clinical and laboratory data indicating microbial infection and those with pleural effusion were excluded. Finally, 339 patients provided informed consent according to our institutional guidelines; their serum and plasma were prepared before cancer therapy and a part of the serum was stored at -70°C until the cytokine assay.

Table 1. Clinicopathological characteristics of the patients studied
Histological type Total cases Sex (M/F) Age average (range) Clinical stage
Limited Advanced
I II Total IIIA IIIB IV Total
Adenocarcinoma 165 101/64 63.5 (38-87) 31 6 37 37 28 63 128
Squamous cell carcinoma 106 97/9 66.8 (38-90) 15 5 20 38 18 30 86
Large cell carcinoma 22 15/7 64.1 (45-87) 3 0 3 5 6 8 19
Small cell carcinoma 46 39/7 64.9 (42-82) 5 1 6 10 12 18 40
Total 339 252/87 64.7 (38-90) 54 12 66 90 64 119 273

Assay of IL-6 and Determinations of Fibrinogen, FDP and CRP

The serum IL-6 level was measured using a commercially available ELISA kit (Fuji Levio, Co., Ltd, Tokyo, Japan) with a lower sensitivity limit of 4 pg/ml and a level more than 4 pg/ml was referred to as an elevated case, based on previous results obtained from 183 normal subjects (data not shown). Fibrinogen, fibrin (ogen) degradation products (FDP) and C-reactive protein (CRP) were measured by methods used in routine clinical examination, and concentrations of more than 400 mg/dl for fibrinogen, 10 µg/ml for FDP and 0.3 mg/dl for CRP were referred to as elevated levels.

Statistical Analysis

All values are expressed as the mean ± standard deviation (SD). The statistical significance between the different groups was analyzed by Student's t-test and [chi]2 test. Correlation between parameters was assayed by linear regression analysis. A two-tailed p < 0.05 was considered to represent a significant difference.

RESULTS

Patients' Clinicopathological Characteristics

The clinicopathological characteristics of 339 patients with primary lung cancer are summarized in Table 1. Overall, aged, male patients with advanced non-small cell cancer were predominant.

Levels of Serum IL-6

Elevations of serum IL-6 were found in 37.8% (128 out of 339) of patients with a mean value of 29.2 pg/ml. Between the limited and advanced stages, significant differences were found in the frequency of the IL-6 elevation (9.1% versus 44.7%, p < 0.0001), but not in the mean values of the elevated or detectable IL-6 levels (upper Table 2). Among histological types, frequencies of the elevated IL-6 levels in squamous and large cell carcinomas were significantly higher than those in adenocarcinoma (p < 0.002) and small cell carcinoma (p < 0.02), but the differences in the mean value of the elevated IL-6 levels were not significant (lower Table 2). In addition, 11 patients with an elevated IL-6 level more than 50 pg/ml, squamous cell and large cell carcinomas occupied six and three cases, respectively, except for one case of small cell carcinoma and adenocarcinoma.

Levels of Fibrinogen, FDP and CRP

Levels of plasma fibrinogen, FDP and CRP assayed were assessed according to clinicopathological characteristic and serum levels of IL-6. As shown in Table 3, the elevated levels of fibrinogen were found in 48.4% (164 out of 339) of patients. The frequency of the elevated fibrinogen level and the mean value of fibrinogen levels were significantly higher in patients in the advanced stage, especially with squamous cell and large cell carcinomas as compared with other histological types, and those with an elevated IL-6 level (Table 4). Levels of FDP assayed in 319 patients were assessed similarly. The elevated levels of FDP were found only in 12.9% of patients examined and these were more frequent in patients with an elevated level of IL-6 and especially in those with an elevated level of fibrinogen, as indicated in Table 5.

Table 2. Serum IL-6 levels according to clinical characteristics
Clinical background Elevated/examined
(%)		 Elevated IL-6 level
Mean ± SD Range
Clinical stage
Limited 6/66 (9.1)* 13.5 ± 7.0 4.2-25.8
Advanced 122/273 (44.7)* 30.0 ± 59.0 4.2-547
   IIIA 41/90 (45.6) 32.1 ± 84.3 5.5-547
   IIIB 30/64 (46.9) 24.6 ± 20.2 4.7-101
   IV 51/119 (42.9) 31.3 ± 49.7 4.2-347
Histological type
Adenocarcinoma 49/165 (29.7)[dagger][Dagger] 19.0 ± 10.8 4.3-56.8
Squamous cell carcinoma 52/106 (49.1)[dagger][Dagger] 30.6 ± 50.4 4.6-347
Large cell carcinoma 14/22 (63.6)[Dagger] 63.3 ± 140.7 5.8-547
Small cell carcinoma 13/46 (28.3)[dagger][Dagger] 25.1 ± 26.1 4.2-101
Total 128/339 (37.8) 29.2 ± 57.7 4.2-547
*p < 0.0001, [dagger]p < 0.002 and [Dagger]p < 0.02 by [chi]2 test.

Table 3. Fibrinogen levels according to clinicopathological characteristics
Clinical background Frequency of fibrinogen elevation elevated/examined (%) Mean ± SD (mg/dl)
Clinical stage
Limited 16/66 (24.2)* 321.9 ± 96.3
Advanced 148/273 (54.2)* 425.7 ± 140.2§
   IIIA 42/90 (46.7) 394.6 ± 130.2
   IIIB 38/64 (59.4) 440.9 ± 138.6
   IV 68/119 (57.1) 441.1 ± 145.4
Histological type
Adenocarconoma 66/165 (40.0)[dagger][Dagger] 374.1 ± 131.4
Squamous cell carcinoma 68/106 (64.2)[dagger][Dagger] 455.0 ± 132.4
Large cell carcinoma 12/22 (54.6)[Dagger] 459.3 ± 166.6¦¦
Small cell carcinoma 18/46 (39.1)[dagger][Dagger] 378.3 ± 128.6
Total 164/339 (48.4) 405.5 ± 138.9
*p < 0.0001, [dagger]p < 0.01 and [Dagger]p < 0.05 by [chi]2 test.
§p < 0.0001 versus limited stage, p < 0.001 and ¦¦p = 0.05 versus adenocarcinoma or small cell carcinoma by Student's t-test.

Table 4. Elevation of fibrinogen levels according to serum IL-6 levels
Serum IL-6 Number of cases Fibrinogen-elevated cases (%) Mean ± SD (mg/dl)
Elevated cases 128 101 (78.9)* 498.0 ± 132.0[dagger]
Non-elevated cases 211 63 (29.9)* 349.4 ± 110.1
*p < 0.0001 by [chi]2 test, [dagger]p < 0.0001 versus non-elevated cases by Student's t-test.

Table 5. Elevation of FDP level according to levels of IL-6 and fibrinogen
Serum IL-6 Number of cases examined FDP-elevated cases
Total With elevated level of fibrinogen
Elevated 122 23 (18.9%)* 18 (78.3%)
Non-elevated 197 18 (9.1%)* 2 (11.1%)
Total 319 41 (12.9%)
*p = 0.0155 by [chi]2 test.

Table 6. Elevation of CRP level according to IL-6 levels
Serum IL-6 Number of cases examined CRP elevated cases (%)
Elevated cases 128 115 (89.8)*
Non-elevated cases 211 80 (37.9)*
Total 339 195 (57.5)
*p < 0.0001 by [chi]2 test.

The elevated CRP levels were found in 57.5% (195 out of 339) of patients, and these were significantly more frequent and higher in patients with an elevated IL-6 level (Table 6). Correlations between the elevated levels of IL-6, fibrinogen and CRP were analyzed statistically. As compared to fibrinogen [Fig. 1 (A)], a stronger correlation was observed between the levels of IL-6 and CRP [Fig. 1 (B)].


Figure 1. Correlation between the levels of IL-6 and fibrinogen (A) or CRP (B) in IL-6-elevated cases. The correlation coefficient is calculated by logarithmic values of IL-6 and linear values of fibrinogen or CRP.

DISCUSSION

The multifunctional cytokine IL-6 has been widely assayed in sera of patients with solid cancer (1). In lung cancer, the present study revealed the elevated level of serum IL-6 to be in 37.8% of 339 patients, which closely matched the previously reported frequencies of 39% and 21.4% in 75 and 183 patients, respectively (19,24).

In these previous studies, the clinicopathological features of serum IL-6 elevation were assessed by statistically comparing the control mean value of the serum IL-6 levels assayed in normal subjects or stage I patients, but the results, especially regarding the effect of the existence of metastatic lesions, remained inconclusive. Therefore, the present study assessed the frequencies of IL-6 elevation according to clinical stage and histological type of cancer, and concluded that serum IL-6 levels were elevated mainly at the advanced stage of squamous cell or large cell carcinomas irrespective of the existence of metastatic disease. An additional finding that 89.1% of cases with marked elevated levels of IL-6 of more than 50 pg/ml were occupied by these histological types also indicated differential involvement of histological type in the elevation of serum IL-6 levels.

In other clinical studies, patients with IL-6 production have been reported most often in large cell carcinomas, accounting for only about 6% of whole lung cancers (16,25,26), while mRNA expression and immunoreactive staining of IL-6 have been detected in various types of non-small cell lung cancer (7,12,27). These present and previous results support the idea that elevation of serum IL-6 levels observed in patients with lung cancer, especially with squamous or large cell carcinoma, is attributed in part to autonomous IL-6 production in cancer cells.

In the advanced stage, pleural effusion seems to be more influential than metastatic disease. It is possible that IL-6 is induced locally from various pleural cells such as macrophages or mesothelial cells (1,17,28-30) and subsequently elevated in the serum through leakage into the systemic circulation. In the previous studies, however, it was not described whether patients with pleural effusion were examined or not. Thus, in the present study, we examined only patients without pleural effusion in far larger numbers than those in previous studies and therefore removed the possibility that the IL-6 elevations in the advanced stage were due to IL-6 leakage from pleural effusion. The contribution of tumor burden to serum IL-6 elevation, which was verified in metastatic malignant melanoma (31), remains undetermined.

In addition, other inflammatory cytokines such as IL-1 and tumor necrosis factor-[alpha] (TNF-[alpha]) may play a latent role in the stimulation of IL-6 production (4,5,7). In this study, preliminarily, immunoreactive IL-1[alpha], IL-1[beta] and TNF-[alpha] were also assayed in the sera of 75 patients enrolled initially by using a commercially available assay kit. However, elevations of these cytokines were quite rare and irrespective of the IL-6 elevation (data not shown).

In respect to the biological action of IL-6 in cancer patients, its direct effects on cancer cells have been observed (1,10-13). In a tumor-bearing state, however, the indirect function through the host inflammatory response cannot be disregarded. Among the acute-phase proteins induced by IL-6, fibrinogen has been reported to be elevated in the plasma of patients with advanced cancer (20) and involved in the growth of tumor tissue (22), as well as the inhibition of the cell-mediated immune response to cancer cells (23). In this study, fibrinogen levels, like IL-6 levels, were found to be elevated particularly in patients with advanced squamous cell or large cell carcinoma (Table 3), according to the elevated IL-6 level (Table 4), suggesting an intimate in vivo stimulation of fibrinogen production by IL-6. Although the reason why no strong correlation was found between levels of IL-6 and fibrinogen remains undetermined, it may be concerned in part with the preferential elevations of FDP level found in patients with elevated levels of both IL-6 and fibrinogen (Table 5). This corresponds precisely to previous observations that plasma fibrinogen metabolism at the advanced stage of patients with solid cancer is diversely accelerated in both phases of production and degradable conversion to insoluble fibrin (20-22).

The present results encourage further study to elucidate the latent effect of IL-6, through regulation of fibrinogen, on the development of tumors.

Acknowledgment

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.

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Received June 24, 1998; accepted September 25, 1998
For reprints and all correspondence: Takeshi Ogura, Department of Internal Medicine, Toneyama National Hospital, 5-1-1, Toneyama, Toyonaka, Osaka 560-8552, Japan. E-mail: yamaguct{at}toneyama.hosp.go.jp
Abbreviations: IL-6, interleukin-6; FDP, fibrin or fibrinogen degradation products; CRP, C-reactive protein

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