Annals of Oncology Advance Access originally published online on October 24, 2007
Annals of Oncology 2008 19(2):353-358; doi:10.1093/annonc/mdm448
gastrointestinal tumors |
Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma
,*
1 Internal Medicine and Medical Oncology
2 Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Matteo University Hospital Foundation, Pavia
3 Department of Computer Science and Systems, University of Pavia, Pavia
4 Department of Biochemistry, Istituto di Ricovero e Cura a Carattere Scientifico San Matteo University Hospital Foundation, Pavia, Italy
* Correspondence to: Dr C. Porta, Internal Medicine and Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico San Matteo University Hospital Foundation, Piazzale C. Golgi, 19, I-27100 Pavia, Italy. Tel: +39-0382-501355; Fax: +39-0382-526223; E-mail: c.porta{at}smatteo.pv.it
 |
Abstract |
|---|
 Top Abstract introductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Background: A large amount of evidence suggests a possible role of interleukin-6 (IL-6) in the pathogenesis of hepatocellular carcinoma (HCC).
Patients and methods: We studied both IL-6 and A1FP in patients with HCC, non-neoplastic liver disease or in healthy controls.
Results: IL-6 titers were four-fold higher in cancer than in cirrhotic patients and 25-fold higher than in healthy controls. As for alpha1-fetoprotein (A1FP) titers, the highest levels were observed in cancer patients. Receiver operating characteristic (ROC) curves analysis demonstrated that IL-6 is significantly more discriminant than A1FP, with ‘optimal’ cut-off values of 7.9 pg/ml (sensitivity = 0.83, specificity = 0.83, efficiency = 0.83). The ROC curves used to distinguish HCC from cirrhotic patients only, showed higher discriminant power of IL-6 versus A1FP titers, with a new cut-off value of 12 pg/ml (sensitivity = 0.73, specificity = 0.87, efficiency = 0.8). Discriminant analysis on HCC and non-HCC subjects yielded sensitivity, specificity and efficiency rates of 77%, 93% and 88%, respectively. The overall efficiency of the two tests combined was 82%.
Conclusions: IL-6 could be considered a promising tumor marker for HCC. In particular, the diagnostic value of the test is significantly increased when combined with A1FP.
Key words: A1FP, cirrhosis, HCC, IL-6, tumor markers
|
introduction |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in hematopoiesis, as well as in the differentiation and growth of a number of cells of different histologic origin, e.g. endothelial cells, keratinocytes, neuronal cells, osteoclasts, and osteoblasts [1]. Moreover, IL-6 induces the hepatic acute phase response by modulating the transcription of several liver-specific genes during inflammation [2].
IL-6 exerts its complex biological activities through different mechanisms [3]: it can bind to the membrane-bound interleukin-6 receptor (IL-6R) that is found on a comparatively small number of cells, including hepatocytes [4]; alternatively, IL-6 and its soluble receptor (sIL-6R), formed either by alternative splicing [5] or by shedding of the membrane-bound IL-6R [6], may contribute to the activation of cells that do not express the membrane-bound IL-6R, a process called ‘transignaling’ [7].
Altered levels of IL-6 have been associated with morbidity and disease activity in an astonishing variety of chronic diseases [7], including human immunodeficency virus infection, arthritis, psoriasis, inflammatory bowel disease and liver cirrhosis.
IL-6 may also regulate cell growth and act as a paracrine and autocrine growth factor in different malignancies [8], especially multiple myeloma [9, 10].
However, IL-6 blood levels have been shown to be elevated not only in multiple myeloma patients [10] but also in patients affected with several solid malignancies, including renal cell carcinoma [11], head and neck cancer [12], colorectal cancer, especially with liver metastases [13], pancreatic cancer [14], prostate cancer [15], ovarian cancer [16], gastric cancer [17] and cholangiocarcinoma [18].
In malignancies other than multiple myeloma, IL-6 signaling involves the activation of the growth factor tyrosine kinase receptors ErbB2/neu and ErbB3, the Ras/mitogen-activating protein kinase pathway [19], the phosphoinositide 3-kinases/Etk/Bmx pathway [20], as well as the signal transducers and activators of transcription protein (STAT-3) pathway [21].
The presence of IL-6R on hepatocytes [4], the up-regulation of IL-6 expression by the hepatitis B virus X-protein [22] and the increased hepatic expression of IL-6 in liver cirrhosis [22], have made IL-6 an intriguing cytokine to study in hepatocellular carcinoma (HCC), a major health problem worldwide due to both its increasing frequency and its poor prognosis [23].
Indeed, Malaguarnera et al. [24] showed a significant increase in serum IL-6 concentrations in HCC patients compared with controls, as well as an elevated positive correlation between IL-6 and the size of the tumor.
Furthermore, Giannitrapani et al. [25] have already indicated that IL-6 could be more sensitive in identifying HCCs than A1FP, which still remains the most commonly used marker for this cancer, even though its real utility for detecting HCC seems to be limited [26], especially in Europe, where the number of HCCs poorly expressing A1FP seems to be increasing, probably reflecting a more differentiated phenotype.
In the light of these observations, we studied both IL-6 and A1FP serum titers in a cohort of HCC patients, as well as in patients with non-neoplastic liver disease, and in healthy controls. We investigated the discriminant power of the individual tests and whether their combination would increase accuracy in discriminating HCC patients from healthy subjects and from cirrhotics.
|
material and methods |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patients
Three groups were studied; the first group included 30 patients (21 males and nine females, median age: 62.3 years, range: 50–74) affected with histologically proven HCC; these patients were divided into two subgroups according to Cancer of the Liver Italian Program (CLIP) score [27] (Table 1): 26 of them had a CLIP score of 1 to 3, while the remaining four patients had more advanced (CLIP score >3), or frankly metastatic, disease.
|
A second group included 30 age- and sex-matched hepatitis B virus and/or hepatitis C virus-related cirrhotic patients with no histologic evidence of cancer, while a third group included 30 age- and sex-matched healthy volunteer controls, with no evidence of liver disease and/or of neoplasm.
All patients and controls gave their informed consent to enrollment in the present study, which was ethically conducted in accordance with the Helsinki Declaration.
Ten of the above 30 HCC patients received the progestational anabolizing agent medroxy-progesterone acetate (Mitogen-activating protein (MAP), ProveraTM, Pharmacia & Upjohn, Italy) at the dose of 1000 mg b.i.d. for a consecutive month, as a supportive treatment for their disease, before being reevaluated for IL-6 and A1FP circulating titers.
methods
IL-6 serum titers were evaluated in the peripheral blood of all the above patients; blood samples were taken from an antecubital vein of the forearm of each study subject, after overnight fasting; serum was centrifuged and then frozen at –40°C for subsequent analysis.
Serum IL-6 was titered using a commercial enzyme-linked immunosorbent assay kit (Human IL-6 Immunoassay, R&D Systems, Minneapolis, MN) following the manufacturer's instructions and the results were expressed as pg/ml.
Serum A1FP was evaluated using a commercially available kit (ADVIA Centaur® System, Bayer Healthcare, Tarrytown, NJ) and the results were expressed as Ul/ml.
statistical analysis
Statistics were carried out using the packages S-Plus (MathSoft Inc., Bagshot, UK) and MedCalc (MedCalc Software, Mariakerke, Belgium).
Considering the low sample size and nonnormal distribution, median, interquartile range and range were used as descriptive statistics; intergroup differences were evaluated using the nonparametric Mann–Whitney U test for IL-6 and A1FP. The Wilcoxon signed rank test was used to compare paired data pre- and post-MAP treatment.
Logarithmic transformation of A1FP values allowed to improve distribution normality.
Correlation between IL-6 and A1FP was tested by Spearman rho coefficient.
ROC curves [28] were produced for the two parameters, to investigate their capability to distinguish between HCC and non-HCC and between HCC and cirrhosis.
Discriminant analysis [29] was used to combine A1FP and IL-6 in a single diagnostic test, and also to distinguish HCC patients from cirrhotics and from healthy controls. The result of this type of analysis is a set of functions of A1FP and IL-6 that can assign an individual to one of the two or three classes. Finally, we also evaluated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficiency of both the single parameters and the discriminant functions.
|
results |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Descriptive statistics (median, 25th–75th percentiles, range) summarizing the parameters examined are reported in Table 2. IL-6 titers in cancer patients were four-fold higher than in cirrhotics and 25-fold higher than in healthy controls. In both cases, the observed differences were statistically significant (P < 0.0001).
|
As for A1FP titers, higher levels were observed in cancer patients than in healthy controls (P < 0.0001), while the difference between HCC and cirrhosis was less evident (P = 0.06).
A positive correlation was found between the two parameters (Spearman rho = 0.32, P < 0.005).
IL-6 titers were significantly (P = 0.003) higher in patients with more advanced disease (CLIP score >3, or with extrahepatic metastases versus CLIP score 1–3), while no significant difference could be observed in A1FP titers (Table 3), even though the limited number of patients with a CLIP score of >3 clearly renders these observations less relevant.
|
The 10 patients who were treated with high-dose MAP for a month had highly reduced IL-6 titers (P = 0.006). Indeed, median pretreatment IL-6 titers decreased from 26.6 pg/ml (25th–75th percentile: 18.80–35.06) to 15.03 pg/ml (25th–75th percentile: 7.38–21.11).
ROC curves analysis carried out on A1FP titers and IL-6 to distinguish between HCC and non-HCC (controls plus cirrhotics) is illustrated in Figure 1. Results show that IL-6 is significantly more discriminant than A1FP (P = 0.03). The ‘optimal’ (closest to the upper left corner) cut-off values were 14 UI/ml for A1FP titers (sensitivity = 0.63, specificity = 0.88, efficiency = 0.8) and 7.9 pg/ml for IL-6 (sensitivity = 0.83, specificity = 0.83, efficiency = 0.83).
|
Figure 2 reports the ROC curves analysis on the same parameters carried out to distinguish HCC from cirrhotic patients only. Again, a higher discriminant power of IL-6 versus A1FP titers is apparent, though with a lower statistical significance (P = 0.05). The same cut-off value of 14 UI/ml was found for A1FP titers (sensitivity = 0.63, specificity = 0.77, efficiency = 0.7), while for IL-6 the new cut-off was 12 pg/ml (sensitivity = 0.73, specificity = 0.87, efficiency = 0.8).
|
Performing discriminant analysis on the two groups of subjects (HCC and non-HCC), we obtained the following two discriminant functions:
 |
 |
A specific subject is classified in the group corresponding to the function with the computed highest value. Sensitivity, specificity and efficiency of these functions were 77%, 93% and 88%, respectively.
To discriminate between HCC and cirrhotic patients (thus excluding healthy controls from the analysis), the two functions were:
 |
 |
Sensitivity, specificity and efficiency of these functions were 77%, 93% and 85%, respectively.
Discriminant analysis results of the three groups are shown in Figure 3. In this case, the discriminant functions were the following ones:
 |
 |
|
The classification matrix reported in Figure 3 shows that the overall efficiency of the two tests combined (rate of correctly classified cases in the three classes) is 82% (74/90).
Sensitivity, specificity, PPV, NPV and efficiency of the two tests combined in discriminating each class versus the other two classes are reported in Table 4. Note the increased efficiency of the two tests combined in these paired discriminations.
|
|
discussion |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Worldwide, the commonest causes of HCC are chronic infections with hepatitis C and B, chronic liver inflammation caused by these viruses leading first to liver cirrhosis and, ultimately, to overt cancer [23].
An increasing body of evidence indicates a key role of the pleiotropic cytokine IL-6 in the process of liver damage and carcinogenesis.
Indeed, liver cirrhosis is usually associated with increased hepatic expression of several cytokines, including IL-6 [30], and during chronic hepatitis B virus infection the hepatitis B virus X-protein up-regulates IL-6 by a mechanism involving nuclear factor 
B [22].
IL-6 was also shown to induce the expression of the mitogenic, motogenic, morphogenic and pro-neoangiogenic scatter factor hepatocyte growth factor which, besides being commonly expressed at high levels in HCCs [31], also signals using the same STAT-3 pathway as IL-6 [32]; indeed, transfection of IL-6 into nonmetastatic HCC cells makes them highly metastatic [33].
IL-6 may also decrease HCC cell apoptosis, thus conferring a survival advantage to the tumor; indeed, in a mouse model, IL-6 proved able to reduce Fas-induced apoptosis [34].
Furthermore, it has been postulated that IL-6 may directly stimulate hepatic DNA synthesis, since IL-6–/– transgenic mice showed a lack in DNA synthesis following hepatectomy [35], and double transgenic mice expressing both IL-6 and sIL-6R under a liver-specific promoter develop hepatocellular hyperplasia and adenomas [36], which are considered as precancerous lesions in humans.
Finally, IL-6 has also been proposed as a cause of natural killer cell dysfunctions, thus potentially representing a mechanism of tumor escape from immune surveillance [37].
For all the above reasons, IL-6 is an intriguing cytokine to study in HCC patients.
We found significantly higher circulating IL-6 titers in HCC patients than in both cirrhotics and controls; IL-6 values were highest in patients with more advanced disease. At present, serum A1FP is the most commonly used marker for this neoplasm, but its real clinical usefulness is unclear; indeed, a recent systematic review and critical analysis [26] of the use of this marker in HCC detection yielded sensitivity and specificity rates ranging 41%–65% and 80–94%, respectively—definitely a poorer performance of A1FP relative to IL-6. Furthermore, the role of A1FP in HCC screening and diagnosis has lost most of the appeal that it had in the presophisticated (i.e. multislice, contrast-enhanced computed tomography, magnetic resonance imaging, etc.) imaging era [38].
Our results, which are in substantial agreement with some literature data [24, 25], indicate a potential role for IL-6 as a tumor marker for HCC.
As far as the comparison with A1FP, which is indeed the reference serum markers for HCC, ROC curves showed a higher classification power of IL-6 with respect to A1FP; moreover, discriminant analysis based on A1FP and IL-6 had high diagnostic accuracy in discriminating among healthy controls, HCC patients and cirrhotics, yielding an overall efficiency rate of 82%.
However, since the difference between the discriminant power of IL-6 and A1FP in HCC patients versus cirrhotic ones is of borderline significance, doubts still exist on a possible clinical usefulness of IL-6 in screening cirrhotic patient for HCC on a large scale.
We also demonstrated that IL-6 production can be efficiently down-regulated in vivo by giving our HCC patients the progestational anabolizing agent MAP, which confirms previous findings in other tumors in both the preclinical [39] and clinical [40] settings. This observation indicates that potential, though not fully understood, clinical benefits might be provided by progestins in cancer patients with high IL-6 serum titers.
Though progestins are now used mainly to treat the so-called anorexia-cachexia syndrome in cancer patients [41], that is, at least partly, IL-6-dependent [42, 43], the above observation that IL-6 is also implicated in tumor growth, progression, metastasis and immune evasion also indicates the future possibility of treating cancer through modulation of the IL-6 pathway.
In conclusion, our data indicate that IL-6 could be considered a promising tumor marker for HCC. In particular, the diagnostic value of the test is significantly increased when it is associated with the dosage of A1FP. Combining the two markers provides a new perspective in the diagnosis of HCC. Further trials are nevertheless warranted to investigate its diagnostic and especially prognostic roles—e.g. to confirm its clinical usefulness during the follow-up of resected, or otherwise treated, HCC patients, even though other authors did not find any prognostic value for this cytokine (together with other serum biological markers) in large cohort of HCC patients [44]. Finally, the exact biological role of this cytokine in liver tumor genesis, growth and progression also warrants more in-depth investigation.
|
Acknowledgements |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
We gratefully thank R. Gish from California Pacific Medical Center who critically reviewed our manuscript.
|
Footnotes |
|---|
These authors equally contributed to this work. 
Received for publication May 21, 2007. Revision received August 9, 2007. Accepted for publication August 13, 2007.
|
References |
|---|
|
TopAbstractintroductionmaterial and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol (1993) 54:1–78.[Web of Science][Medline]
2. Gauldie J, Richards C, Harnish D, et al. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A (1987) 84:7251–7255.
3. Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J (2003) 374:1–20.[CrossRef][Web of Science][Medline]
4. Peters M, Muller AM, Rose-John S. Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis. Blood (1998) 92:3495–3504.
5. Horiuchi S, Koyanagi Y, Zhou Y, et al. Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur J Immunol (1994) 24:1945–1948.[Web of Science][Medline]
6. Mullberg J, Oberthur W, Lottspeich F, et al. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol (1994) 152:4958–4968.[Abstract]
7. Kallen KJ. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta (2002) 1592:323–343.[Medline]
8. Martinez-Maza O, Berek JS. Interleukin 6 and cancer treatment. In Vivo (1991) 5:583–588.[Medline]
9. Ishikawa H, Tsuyama N, Abroun S, et al. Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation. Leuk Lymphoma (2003) 44:1477–1481.[CrossRef][Web of Science][Medline]
10. Lauta VM. A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer (2003) 97:2440–2452.[CrossRef][Web of Science][Medline]
11. Yoshida N, Ikemoto S, Narita K, et al. Interleukin-6, tumour necrosis factor alpha and interleukin-1beta in patients with renal cell carcinoma. Br J Cancer (2002) 86:1396–1400.[CrossRef][Web of Science][Medline]
12. Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res (1999) 5:1369–1379.
13. Chung YC, Chang YF. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol (2003) 83:222–226.[CrossRef][Web of Science][Medline]
14. Okada S, Okusaka T, Ishii H, et al. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol (1998) 28:12–15.
15. Nakashima J, Tachibana M, Horiguchi Y, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res (2000) 6:2702–2706.
16. Tempfer C, Zeisler H, Sliutz G, et al. Serum evaluation of interleukin 6 in ovarian cancer patients. Gynecol Oncol (1997) 66:27–30.[CrossRef][Web of Science][Medline]
17. De Vita F, Romano C, Orditura M, et al. Interleukin-6 serum level correlates with survival in advanced gastrointestinal cancer patients but is not an independent prognostic indicator. J Interferon Cytokine Res (2001) 21:45–52.[CrossRef][Web of Science][Medline]
18. Goydos JS, Brumfield AM, Frezza E, et al. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg (1998) 227:398–404.[CrossRef][Web of Science][Medline]
19. Qiu Y, Ravi L, Kung HJ. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature (1998) 393:83–85.[CrossRef][Medline]
20. Qiu Y, Robinson D, Pretlow TG, Kung HJ. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci U S A (1998) 95:3644–3649.
21. May P, Schniertshauer U, Gerhartz C, et al. Signal transducer and activator of transcription STAT-3 plays a major role in gp130-mediated acute phase protein gene activation. Acta Biochim Pol (2003) 50:595–601.[Web of Science][Medline]
22. Lee Y, Park US, Choi I, et al. Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clin Cancer Res (1998) 4:1711–1717.[Abstract]
23. Kaplan DE, Reddy KR. Rising incidence of hepatocellular carcinoma: the role of hepatitis B and C; the impact on transplantation and outcomes. Clin Liver Dis (2003) 7:683–714.[CrossRef][Medline]
24. Malaguarnera M, Di Fazio I, Laurino A, et al. Role of interleukin 6 in hepatocellular carcinoma. Bull Cancer (1996) 83:379–384.[Web of Science][Medline]
25. Giannitrapani L, Cervello M, Soresi M, et al. Circulating IL-6 and sIL-6R in patients with hepatocellular carcinoma. Ann N Y Acad Sci (2002) 963:46–52.[CrossRef][Web of Science][Medline]
26. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med (2003) 139:46–50.
27. The Cancer of Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology (1998) 28:751–755.[CrossRef][Web of Science][Medline]
28. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clinical Chem (1993) 39:561–577.
29. Venables WN, Ripley BD. Modern Applied Statistics with S-PLUS (1999) 3rd edition. Berlin: Springer.
30. Napoli J, Bishop GA, McCaughan GW. Increased intrahepatic messenger RNA expression of interleukins 2, 6, and 8 in human cirrhosis. Gastroenterology (1994) 107:789–798.[Web of Science][Medline]
31. Zhu M, Paddock GV. Expression of the hepatocyte growth factor-like protein gene in human hepatocellular carcinoma and interleukin-6-induced increased expression in hepatoma cells. Biochim Biophys Acta (1999) 1449:63–72.[Medline]
32. Schaper F, Siewert E, Gomez-Lechon MJ, et al. Hepatocyte growth factor/scatter factor (HGF/SF) signals via the STAT3/APRF transcription factor in human hepatoma cells and hepatocytes. FEBS Lett (1997) 405:99–103.[CrossRef][Web of Science][Medline]
33. Reichner JS, Mulligan JA, Spisni R, et al. Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells. Ann Surg Oncol (1998) 5:279–286.[Abstract]
34. Kovalovich K, Li W, DeAngelis R, et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem (2001) 276:26605–26613.
35. Wallenius V, Wallenius K, Hisaoka M, et al. Retarded liver growth in interleukin-6-deficient and tumor necrosis factor receptor-1-deficient mice. Endocrinology (2001) 142:2953–2960.
36. Maione D, Di Carlo E, Li W, et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J (1998) 17:5588–5597.[CrossRef][Web of Science][Medline]
37. Tanner J, Tosato G. Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest (1991) 88:239–247.[Web of Science][Medline]
38. Sherman M. Alphafetoprotein: an obituary. J Hepatol (2001) 34:603–605.[CrossRef][Web of Science][Medline]
39. Kurebayashi J, Otsuki T, Tanaka K, et al. Medroxyprogesterone acetate decreases secretion of Interleukin-6 and parathyroid hormone-related protein in a new anaplastic thyroid cancer cell line, KTC-2. Thyroid (2003) 13:249–258.[CrossRef][Web of Science][Medline]
40. Yamashita J, Hideshima T, Shirakusa T, Ogawa M. Medroxyprogesterone acetate treatment reduces serum interleukin-6 levels in patients with metastatic breast carcinoma. Cancer (1996) 78:2346–2352.[CrossRef][Web of Science][Medline]
41. Mantovani G, Macciò A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs (2001) 61:499–514.[CrossRef][Web of Science][Medline]
42. Barton BE, Murphy TF. Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. Cytokine (2001) 16:251–257.[CrossRef][Web of Science][Medline]
43. Argiles JM, Busquets S, Lopez-Soriano FJ. Cytokines in the pathogenesis of cancer cachexia. Curr Opin Clin Nutr Metab Care (2003) 6:401–406.[CrossRef][Web of Science][Medline]
44. Parasole R, Izzo F, Perrone F, et al. Prognostic value of serum biological markers in patients with hepatocellular carcinoma. Clin Cancer Res (2001) 7:3504–3509.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Mantovani Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma Ann. Onc., July 1, 2008; 19(7): 1355 - 1355. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||