Top

Published in:

01-02-2009 | Original Paper

Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis

Authors: Katriina Heikkilä, Ross Harris, Gordon Lowe, Ann Rumley, John Yarnell, John Gallacher, Yoav Ben-Shlomo, Shah Ebrahim, Debbie A. Lawlor

Published in: Cancer Causes & Control | Issue 1/2009

Abstract

Objective

We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk.

Methods

We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses.

Results

CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk.

Conclusions

Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

Available only for authorised users

Lu H, Ouyang W, Huang C (2006) Inflammation, a key event in cancer development. Mol Cancer Res 4(4):221–233. doi:10.1158/1541-7786.MCR-05-0261 PubMedCrossRef

Perwez Hussain S, Harris CC (2007) Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 121(11):2373–2380. doi:10.1002/ijc.23173 PubMedCrossRef

Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14(6):433–439. doi:10.1016/j.semcancer.2004.06.006 PubMedCrossRef

Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72(11):1605–1621. doi:10.1016/j.bcp. 2006.06.029 PubMedCrossRef

Danesh J, Wheeler JG, Hirschfield GM et al (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350(14):1387–1397. doi:10.1056/NEJMoa032804 PubMedCrossRef

Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16):2502–2512. doi:10.1016/j.ejca.2005.08.016 PubMedCrossRef

Ishihara K, Hirano T (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 13(4–5):357–368. doi:10.1016/S1359-6101(02)00027-8 PubMedCrossRef

Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110(9):1911–1928. doi:10.1002/cncr.22999 PubMedCrossRef

Jabs WJ, Busse M, Kruger S, Jocham D, Steinhoff J, Doehn C (2005) Expression of C-reactive protein by renal cell carcinomas and unaffected surrounding renal tissue. Kidney Int 68(5):2103–2110. doi:10.1111/j.1523-1755.2005.00666.x PubMedCrossRef

10.

Nozoe T, Korenaga D, Futatsugi M, Saeki H, Maehara Y, Sugimachi K (2003) Immunohistochemical expression of C-reactive protein in squamous cell carcinoma of the esophagus—significance as a tumor marker. Cancer Lett 192(1):89–95. doi:10.1016/S0304-3835(02)00630-4 PubMedCrossRef

11.

Heikkila K, Ebrahim S, Lawlor DA (2007) A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health 61(9):824–833. doi:10.1136/jech.2006.051292 PubMedCrossRef

12.

Heikkila K, Ebrahim S, Lawlor DA (2008) A systematic review of circulating concentrations of interleukin-6 (IL-6) and cancer. Eur J Cancer 44(7):937–945. doi:10.1016/j.ejca.2008.02.047 PubMedCrossRef

13.

Basso D, Fabris C, Meani A et al (1988) C reactive protein in pancreatic cancer and chronic pancreatitis. Ann Clin Res 20(6):414–416PubMed

14.

O’Hanlon DM, Lynch J, Cormican M, Given HF (2002) The acute phase response in breast carcinoma. Anticancer Res 22(2B):1289–1293PubMed

15.

Lawlor DA, Okasha M, Gunnell D, Davey Smith G, Ebrahim S (2003) Associations of adult measures of childhood growth with breast cancer: findings from the British Women’s Heart and Health Study. Br J Cancer 89(1):81–87. doi:10.1038/sj.bjc.6600972 PubMedCrossRef

16.

MRC Epidemiology Unit C (2007) Caerphilly prospective study. Department of Social Medicine, University of Bristol

17.

Lawlor DA, Ebrahim S, Davey SG (2002) Socioeconomic position in childhood and adulthood and insulin resistance: cross sectional survey using data from British women’s heart and health study. BMJ 325(7368):805–807. doi:10.1136/bmj.325.7368.805 PubMedCrossRef

18.

Caruso C, Lio D, Cavallone L, Franceschi C (2004) Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci 1028:1–13. doi:10.1196/annals.1322.001 PubMedCrossRef

19.

Bruunsgaard H, Pedersen M, Pedersen BK (2001) Aging and proinflammatory cytokines. Curr Opin Hematol 8(3):131–136. doi:10.1097/00062752-200105000-00001 PubMedCrossRef

20.

Himmerich H, Fulda S, Linseisen J et al (2006) TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population. Eur Cytokine Netw 17(3):196–201PubMed

21.

Mendall MA, Patel P, Asante M et al (1997) Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart 78(3):273–277PubMed

22.

Lowe GD (2005) Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 3(8):1618–1627. doi:10.1111/j.1538-7836.2005.01416.x PubMedCrossRef

23.

Fernandez-Real JM, Vayreda M, Richart C et al (2001) Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 86(3):1154–1159. doi:10.1210/jc.86.3.1154 PubMedCrossRef

24.

Colbert LH, Visser M, Simonsick EM et al (2004) Physical activity, exercise, and inflammatory markers in older adults: findings from the health, aging and body composition study. J Am Geriatr Soc 52(7):1098–1104. doi:10.1111/j.1532-5415.2004.52307.x PubMedCrossRef

25.

Jousilahti P, Salomaa V, Rasi V, Vahtera E, Palosuo T (2003) Association of markers of systemic inflammation, C reactive protein, serum amyloid A, and fibrinogen, with socioeconomic status. J Epidemiol Community Health 57(9):730–733. doi:10.1136/jech.57.9.730 PubMedCrossRef

26.

Lawlor DA, Davey Smith G, Rumley A, Lowe GD, Ebrahim S (2005) Associations of fibrinogen and C-reactive protein with prevalent and incident coronary heart disease are attenuated by adjustment for confounding factors. British Women’s Heart and Health Study. Thromb Haemost 93(5):955–963PubMed

27.

Rexrode KM, Pradhan A, Manson JE, Buring JE, Ridker PM (2003) Relationship of total and abdominal adiposity with CRP and IL-6 in women. Ann Epidemiol 13(10):674–682. doi:10.1016/S1047-2797(03)00053-X PubMedCrossRef

28.

Ford ES (2003) Asthma, body mass index, and C-reactive protein among US adults. J Asthma 40(7):733–739. doi:10.1081/JAS-120023497 PubMedCrossRef

29.

Harris RE, Beebe-Donk J, Doss H, Burr DD (2005) Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13(4):559–583PubMed

30.

Berg J, Fellier H, Christoph T, Grarup J, Stimmeder D (1999) The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro. Inflamm Res 48(7):369–379. doi:10.1007/s000110050474 PubMedCrossRef

31.

Gonzalez E, de la Cruz CC, de Nicolas NR, Egido J, Herrero-Beaumont G (1994) Long-term effect of nonsteroidal anti-inflammatory drugs on the production of cytokines and other inflammatory mediators by blood cells of patients with osteoarthritis. Agents Actions 41(3–4):171–178. doi:10.1007/BF02001912 PubMedCrossRef

32.

Prasad K (2006) C-reactive protein (CRP)-lowering agents. Cardiovasc Drug Rev 24(1):33–50. doi:10.1111/j.1527-3466.2006.00033.x PubMedCrossRef

33.

Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP (1999) Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 19(4):893–899PubMed

34.

Manns PJ, Williams DP, Snow CM, Wander RC (2003) Physical activity, body fat, and serum C-reactive protein in postmenopausal women with and without hormone replacement. Am J Hum Biol 15(1):91–100. doi:10.1002/ajhb.10117 PubMedCrossRef

35.

Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD (2002) Postmenopausal hormone replacement therapy: scientific review. JAMA 288(7):872–881. doi:10.1001/jama.288.7.872 PubMedCrossRef

36.

Pradhan AD, Manson JE, Rossouw JE et al (2002) Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA 288(8):980–987. doi:10.1001/jama.288.8.980 PubMedCrossRef

37.

Silvestri A, Gebara O, Vitale C et al (2003) Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 107(25):3165–3169. doi:10.1161/01.CIR.0000074208.02226.5E PubMedCrossRef

38.

39.

MRC Unit (South Wales) (1985) The Caerphilly Collaborative Heart Disease Study Project Description and Manual of Operations. MRC Unit, South Wales

40.

Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ (2004) C-reactive protein and the risk of incident colorectal cancer. JAMA 291(5):585–590. doi:10.1001/jama.291.5.585 PubMedCrossRef

41.

Ito Y, Suzuki K, Tamakoshi K et al (2005) Colorectal cancer and serum C-reactive protein levels: a case–control study nested in the JACC Study. J Epidemiol 15(Suppl 2):S185–S189. doi:10.2188/jea.15.S185 PubMedCrossRef

42.

Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S (2006) Plasma C-reactive protein and risk of colorectal cancer in a nested case–control study: Japan Public Health Center-based prospective study. Cancer Epidemiol Biomarkers Prev 15(4):690–695. doi:10.1158/1055-9965.EPI-05-0708 PubMedCrossRef

43.

Suzuki K, Ito Y, Wakai K et al (2006) Serum heat shock protein 70 levels and lung cancer risk: a case–control study nested in a large cohort study. Cancer Epidemiol Biomarkers Prev 15(9):1733–1737. doi:10.1158/1055-9965.EPI-06-0005 PubMedCrossRef

44.

Baillargeon J, Platz EA, Rose DP et al (2006) Obesity, adipokines, and prostate cancer in a prospective population-based study. Cancer Epidemiol Biomarkers Prev 15(7):1331–1335. doi:10.1158/1055-9965.EPI-06-0082 PubMedCrossRef

45.

Chene G, Thompson SG (1996) Methods for summarizing the risk associations of quantitative variables in epidemiologic studies in a consistent form. Am J Epidemiol 144(6):610–621PubMed

46.

Greenland S, Longnecker MP (1992) Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol 135(11):1301–1309PubMed

47.

Gunter MJ, Stolzenberg-Solomon R, Cross AJ et al (2006) A prospective study of serum C-reactive protein and colorectal cancer risk in men. Cancer Res 66(4):2483–2487. doi:10.1158/0008-5472.CAN-05-3631 PubMedCrossRef

48.

Helzlsouer KJ, Erlinger TP, Platz EA (2006) C-reactive protein levels and subsequent cancer outcomes: results from a prospective cohort study. Eur J Cancer 42(6):704–707. doi:10.1016/j.ejca.2006.01.008 PubMedCrossRef

49.

Il’yasova D, Colbert LH, Harris TB et al (2005) Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev 14(10):2413–2418. doi:10.1158/1055-9965.EPI-05-0316 PubMedCrossRef

50.

Llorca J, Lopez-Diaz MJ, Gonzalez-Juanatey C, Ollier WE, Martin J, Gonzalez-Gay MA (2007) Persistent chronic inflammation contributes to the development of cancer in patients with rheumatoid arthritis from a defined population of northwestern Spain. Semin Arthritis Rheum 37(1):31–38. doi:10.1016/j.semarthrit.2007.01.002 PubMedCrossRef

51.

McSorley MA, Alberg AJ, Allen DS et al (2007) C-reactive protein concentrations and subsequent ovarian cancer risk. Obstet Gynecol 109(4):933–941PubMed

52.

Platz EA, De Marzo AM, Erlinger TP et al (2004) No association between pre-diagnostic plasma C-reactive protein concentration and subsequent prostate cancer. Prostate 59(4):393–400. doi:10.1002/pros.10368 PubMedCrossRef

53.

Rifai N, Buring JE, Lee IM, Manson JE, Ridker PM (2002) Is C-reactive protein specific for vascular disease in women? Ann Intern Med 136(7):529–533PubMed

54.

Siemes C, Visser LE, Coebergh JW et al (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 24(33):5216–5222. doi:10.1200/JCO.2006.07.1381 PubMedCrossRef

55.

Trichopoulos D, Psaltopoulou T, Orfanos P, Trichopoulou A, Boffetta P (2006) Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol Biomarkers Prev 15(2):381–384. doi:10.1158/1055-9965.EPI-05-0626 PubMedCrossRef

56.

Zhang SM, Buring JE, Lee IM, Cook NR, Ridker PM (2005) C-reactive protein levels are not associated with increased risk for colorectal cancer in women. Ann Intern Med 142(6):425–432PubMed

57.

Zhang SM, Lin J, Cook NR et al (2007) C-reactive protein and risk of breast cancer. J Natl Cancer Inst 99(11):890–894. doi:10.1093/jnci/djk202 PubMedCrossRef

58.

Breen EC, MM van der, Cumberland W, Kishimoto T, Detels R, Martinez-Maza O (1999) The development of AIDS-associated Burkitt’s/small noncleaved cell lymphoma is preceded by elevated serum levels of interleukin 6. Clin Immunol 92(3):293–299. doi:10.1006/clim.1999.4760 PubMedCrossRef

59.

Gan WQ, Man SFP, Senthilselvan A, Sin DD (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59(7):574–580. doi:10.1136/thx.2003.019588 PubMedCrossRef

60.

Daniels CE, Jett JR (2005) Does interstitial lung disease predispose to lung cancer? Curr Opin Pulm Med 11(5):431–437. doi:10.1097/01.mcp. 0000170521.71497.ba PubMedCrossRef

61.

Sin DD, Man SFP, McWilliams A, Lam S (2006) Progression of airway dysplasia and C-reactive protein in smokers at high risk of lung cancer. Am J Respir Crit Care Med 173(5):535–539. doi:10.1164/rccm.200508-1305OC PubMedCrossRef

62.

Tsilidis KK, Branchini C, Guallar E, Helzlsouer KJ, Erlinger TP, Platz EA (2008) C-reactive protein and colorectal cancer risk: a systematic review of prospective studies. Int J Cancer 123(5):1133–1140. doi:10.1002/ijc.23606 PubMedCrossRef

63.

Fain JN (2006) Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Interleukins 74:443–477. doi:10.1016/S0083-6729(06)74018-3 CrossRef

64.

Mohamed-Ali V, Goodrick S, Rawesh A et al (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-{alpha}, in vivo. J Clin Endocrinol Metab 82(12):4196–4200. doi:10.1210/jc.82.12.4196 PubMedCrossRef

65.

Bluher S, Kratzsch J, Kiess W (2005) Insulin-like growth factor I, growth hormone and insulin in white adipose tissue. Best Pract Res Clin Endocrinol Metab 19(4):577–587. doi:10.1016/j.beem.2005.07.011 PubMedCrossRef

66.

Riedemann J, Macaulay VM (2006) IGF1R signalling and its inhibition. Endocr Relat Cancer 13(Supplement_1):S33–S43PubMedCrossRef

67.

Paule B, Terry S, Kheuang L, Soyeux P, Vacherot F, de la Taille A (2007) The NF-kappaB/IL-6 pathway in metastatic androgen-independent prostate cancer: new therapeutic approaches? World J Urol 25(5):477–489. doi:10.1007/s00345-007-0175-6 PubMedCrossRef

68.

Weinberg RA (2007) Crowd control: tumour immunology and immunotherapy. In: The biology of cancer, 1st edn. Garland Science, Taylor and Francis Group, LLC

69.

Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6(11):836–848. doi:10.1038/nri1961 PubMedCrossRef

70.

Ness RB, Cottreau C (1999) Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 91(17):1459–1467. doi:10.1093/jnci/91.17.1459 PubMedCrossRef

71.

Kulbe H, Thompson R, Wilson JL et al (2007) The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 67(2):585–592. doi:10.1158/0008-5472.CAN-06-2941 PubMedCrossRef

72.

Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32(1):1–22. doi:10.1093/ije/dyg070 PubMedCrossRef

73.

Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey SG (2007) Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med 27(8):1133–1163. doi:10.1002/sim.3034 CrossRef

74.

Theodoropoulos G, Papaconstantinou I, Felekouras E et al (2006) Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. World J Gastroenterol 12(31):5037–5043PubMed

75.

Balasubramanian SP, Azmy IA, Higham SE et al (2006) Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review. BMC Cancer 6:188. doi:10.1186/1471-2407-6-188 PubMedCrossRef

76.

Kamangar F, Abnet CC, Hutchinson AA et al (2006) Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). Cancer Causes Control 17(1):117–125. doi:10.1007/s10552-005-0439-7 PubMedCrossRef

77.

Gunter MJ, Canzian F, Landi S, Chanock SJ, Sinha R, Rothman N (2006) Inflammation-related gene polymorphisms and colorectal adenoma. Cancer Epidemiol Biomarkers Prev 15(6):1126–1131. doi:10.1158/1055-9965.EPI-06-0042 PubMedCrossRef

78.

Lan Q, Zheng T, Rothman N et al (2006) Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood 107(10):4101–4108. doi:10.1182/blood-2005-10-4160 PubMedCrossRef

Title: Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis
Authors: Katriina Heikkilä
Ross Harris
Gordon Lowe
Ann Rumley
John Yarnell
John Gallacher
Yoav Ben-Shlomo
Shah Ebrahim
Debbie A. Lawlor
Publication date: 01-02-2009
Publisher: Springer Netherlands
Published in: Cancer Causes & Control / Issue 1/2009
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI: https://doi.org/10.1007/s10552-008-9212-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2009

Coffee consumption, genetic susceptibility and bladder cancer risk

A cluster of vulvar cancer and vulvar intraepithelial neoplasia in young Australian Indigenous women

Genetic polymorphisms in the estrogen receptor beta (ESR2) gene and the risk of epithelial ovarian carcinoma

Issues related to implementing a smoking cessation clinical trial for cancer patients

Oral contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai

Risk factors for thyroid cancer: an epidemiological review focused on nutritional factors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer