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Plasma lipopolysaccharide-binding protein and colorectal cancer risk: a nested case–control study in the Multiethnic Cohort

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Abstract

Background

Lipopolysaccharide (LPS), an endotoxin found on the outer cell wall of Gram-negative bacteria, increases inflammatory response signaling and may play a role in the pathogenesis of several adverse outcomes, including inflammatory bowel diseases, cardiovascular disease, and cancer. While LPS is hypothesized to be associated with colorectal carcinogenesis, there are relatively few human studies which have examined this association.

Methods

We examined the association between colorectal cancer (CRC) and plasma lipopolysaccharide-binding protein (LBP), a marker of LPS, in 1,638 participants (819 CRC cases and 819 controls) matched on multiple factors, including age, sex, and race/ethnicity, from the Multiethnic Cohort study. Conditional logistic regression models were used to estimate the multivariable-adjusted odds ratios (OR) and 95% confidence intervals (95% CI).

Results

Compared to individuals whose LBP concentrations were in the lowest quartile, the ORs associated with second, third, and fourth quartiles were 1.23 (95% CI 0.91–1.67), 1.36 (95% CI 1.01–1.83), and 1.01 (95% CI 0.73–1.39), respectively, (p trend = 0.66). No differences were observed by BMI, fiber intake, saturated fat intake, cancer site, or cancer stage.

Conclusions

This study did not find an overall statistically significant association between LBP (as a marker of LPS exposure) and CRC. Further prospective studies with multiple LBP measurements are needed to validate current findings.

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References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30

    Article  PubMed  Google Scholar 

  2. Davis CD, Milner JA (2009) Gastrointestinal microflora, food components and colon cancer prevention. J Nutr Biochem 20:743–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D et al (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772

    Article  CAS  PubMed  Google Scholar 

  4. Erridge C, Attina T, Spickett CM, Webb DJ (2007) A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86:1286–1292

    CAS  PubMed  Google Scholar 

  5. Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM et al (2009) Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32:2281–2287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC et al (2008) Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 87:1219–1223

    CAS  PubMed  Google Scholar 

  7. Stehle JR, Leng X, Kitzman DW, Nicklas BJ, Kritchevsky SB, High KP (2012) Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J Gerontol A 67:1212–1218

    Article  Google Scholar 

  8. Kong SY, Tran HQ, Gewirtz AT, McKeown-Eyssen G, Fedirko V, Romieu I et al (2016) Serum endotoxins and flagellin and risk of colorectal cancer in the European prospective investigation into cancer and nutrition (EPIC) cohort. Cancer Epidemiol Biomarkers Prev 25:291–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D et al (2010) A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 33:1925–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Creely SJ, McTernan PG, Kusminski CM, Fisher ff M, Da Silva NF, Khanolkar M et al (2007) Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292:E740–E747

    Article  CAS  PubMed  Google Scholar 

  11. Pastor Rojo O, López San Román A, Albéniz Arbizu E, de la Hera Martínez A, Ripoll Sevillano E (2007) Albillos Martínez A. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm Bowel Dis 13:269–277

    Article  PubMed  Google Scholar 

  12. Lepper PM, Schumann C, Triantafilou K, Rasche FM, Schuster T, Frank H et al (2007) Association of lipopolysaccharide-binding protein and coronary artery disease in men. J Am Coll Cardiol 50:25–31

    Article  CAS  PubMed  Google Scholar 

  13. Blomkalns AL, Stoll LL, Shaheen W, Romig-Martin SA, Dickson EW, Weintraub NL et al (2011) Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells. J Inflamm 8:4

    Article  CAS  Google Scholar 

  14. Kang M, Edmundson P, Araujo-Perez F, McCoy AN, Galanko J, Keku TO (2013) Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas. BMC Cancer 13:91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S et al (2007) Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133:1869–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang JH, Manning BJ, Wu Q, Di Blankson S, Bouchier-Hayes D, Redmond HP (2003) Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol 170:795–804

    Article  CAS  PubMed  Google Scholar 

  17. Andrews EJ, Wang JH, Winter DC, Laug WE, Redmond HP (2001) Tumor cell adhesion to endothelial cells is increased by endotoxin via an upregulation of beta-1 integrin expression. J Surg Res 97:14–19

    Article  CAS  PubMed  Google Scholar 

  18. Coffey JC, Wang JH, Bouchier-Hayes D, Cotter TG, Redmond HP (2006) The targeting of phosphoinositide-3 kinase attenuates pulmonary metastatic tumor growth following laparotomy. Ann Surg 243:250–256

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang L, Zhu R, Huang Z, Li H, Zhu H (2013) Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci 58:2223–2236

    Article  CAS  PubMed  Google Scholar 

  20. LeVan TD, Slager RE, Romberger DJ, Von Essen SG (2010) Lipopolysaccharide-binding protein (LBP) polymorphisms are associated with serum levels of LBP in agricultural workers. Proc Am Thorac Soc 7:151

    Google Scholar 

  21. Guinan EC, Palmer CD, Mancuso CJ, Brennan L, Stoler-Barak L, Kalish LA et al (2014) Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin. Innate Immun 20:697–711

    Article  PubMed  Google Scholar 

  22. Chien JW, Boeckh MJ, Hansen JA, Clark JG (2008) Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation. Blood 111:2462–2469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ikebe M, Kitaura Y, Nakamura M, Tanaka H, Yamasaki A, Nagai S et al (2009) Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol 100:725–731

    Article  CAS  PubMed  Google Scholar 

  24. Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch C et al (2002) Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 101:415–422

    Article  CAS  PubMed  Google Scholar 

  25. Kolonel LN, Henderson BE, Hankin JH, Nomura AM, Wilkens LR, Pike MC et al (2000) A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am J Epidemiol 151:346–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL et al (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252–271

    Article  PubMed  Google Scholar 

  27. Park S-Y, Wilkens LR, Henning SM, Le Marchand L, Gao K, Goodman MT et al (2009) Circulating fatty acids and prostate cancer risk in a nested case–control study: the Multiethnic Cohort. Cancer Causes Control 20:211–223

    Article  PubMed  Google Scholar 

  28. NHLBI Obesity Education Initiative Expert Panel on the Identification E and T of O in A (US) (1998) Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. National Heart, Lung, and Blood Institute

  29. U.S. Department of Health and Human Services and U.S. Department of Agriculture (2015) 2015–2020 Dietary guidelines for Americans. Washington DC. http://health.gov/dietaryguidelines/2015/

  30. Chen R, Luo F-K, Wang Y-L, Tang J-L, Liu Y-S (2011) LBP and CD14 polymorphisms correlate with increased colorectal carcinoma risk in Han Chinese. World J Gastroenterol 17:2326–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schröder NWJ, Morath S, Alexander C, Hamann L, Hartung T, Zähringer U et al (2003) Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem 278:15587–15594

    Article  PubMed  Google Scholar 

  32. Schröder NW, Opitz B, Lamping N, Michelsen KS, Zähringer U, Göbel UB et al (2000) Involvement of lipopolysaccharide binding protein, CD14, and Toll-like receptors in the initiation of innate immune responses by Treponema glycolipids. J Immunol 165:2683–2693

    Article  PubMed  Google Scholar 

  33. Dobrovolskaia MA, Neun BW, Clogston JD, Ding H, Ljubimova J, McNeil SE (2010) Ambiguities in applying traditional Limulus amebocyte lysate tests to quantify endotoxin in nanoparticle formulations. Nanomedicine 5:555–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Novitsky TJ (1998) Limitations of the Limulus amebocyte lysate test in demonstrating circulating lipopolysaccharides. Ann N Y Acad Sci 851:416–421

    Article  CAS  PubMed  Google Scholar 

  35. Munford RS (2005) Detoxifying endotoxin: time, place and person. J Endotoxin Res 11:69–84

    CAS  PubMed  Google Scholar 

  36. Laugerette F, Vors C, Géloën A, Chauvin MA, Soulage C, Lambert-Porcheron S, Peretti N, Alligier M, Burcelin R, Laville M, Vidal HMM (2011) Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J Nutr Biochem 22:53–59

    Article  CAS  PubMed  Google Scholar 

  37. Clemente-Postigo M, Queipo-Ortuño MI, Murri M, Boto-Ordoñez M, Perez-Martinez P, Andres-Lacueva C et al (2012) Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients. J Lipid Res 53:973–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blairon L, Wittebole X, Laterre P-F (2003) Lipopolysaccharide-binding protein serum levels in patients with severe sepsis due to gram-positive and fungal infections. J Infect Dis 187:287–291

    Article  PubMed  Google Scholar 

  39. Gonzalez-Quintela A, Alonso M, Campos J, Vizcaino L, Loidi L, Gude F (2013) Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS ONE 8:e54600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Citronberg JS, Wilkens LR, Lim U, Hullar MAJ, White E, Newcomb PA et al (2016) Reliability of plasma lipopolysaccharide-binding protein (LBP) from repeated measures in healthy adults. Cancer Causes Control 27:1–4

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health Grants, P01 CA168530 (National Cancer Institute), K05 CA154337 (National Cancer Institute and Office of Dietary Supplements), and R25CA094880 (National Cancer Institute).

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Authors and Affiliations

  1. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Jessica S. Citronberg, Emily White, Polly A. Newcomb & Johanna W. Lampe

  2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, M4-B402, PO Box 19024, Seattle, WA, USA

    Jessica S. Citronberg, Meredith A. J. Hullar, Emily White, Polly A. Newcomb & Johanna W. Lampe

  3. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

    Lynne R. Wilkens, Loic Le Marchand & Unhee Lim

  4. Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

    Kristine R. Monroe

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  1. Jessica S. Citronberg
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  4. Unhee Lim
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Correspondence to Jessica S. Citronberg.

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Citronberg, J.S., Wilkens, L.R., Le Marchand, L. et al. Plasma lipopolysaccharide-binding protein and colorectal cancer risk: a nested case–control study in the Multiethnic Cohort. Cancer Causes Control 29, 115–123 (2018). https://doi.org/10.1007/s10552-017-0990-z

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