Skip to main content
SpringerLink
Log in

Leptin Expression Correlates with Favorable Clinicopathologic Phenotype and Better Prognosis in Colorectal Adenocarcinoma

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Leptin, the product of the ob gene, is an adipocyte-derived neurohormone that regulates body fat storage and feeding behavior. Some studies have suggested that leptin has growth-factor-like functions in epithelial cells and its abnormal expression may be involved in cancer development and progression. We investigated leptin expression in normal and neoplastic colorectal tissues and its association with clinicopathological features and clinical outcome in colorectal adenocarcinoma patients. Leptin expression was evaluated on the tissue microarray of 44 normal colon mucosal tissues, 44 adenomatous polyps, and 437 colorectal adenocarcinomas by immunohistochemistry. Data were analyzed by chi-square test, one-way analysis of variance (ANOVA), Cox regression hazards model, and log-rank test with Kaplan–Meier curves. Frequency of leptin expression was dramatically increased from normal colonic mucosa (2/44, 4.5%) to adenomas (13/44, 29.5%) and adenocarcinomas (321/437, 73.5%) as neoplastic progression. Interestingly, leptin expression was correlated with favorable tumor features in depth of invasion (p = 0.033), lymph node metastasis (p = 0.019), American Joint Committee on Cancer (AJCC) and Dukes’ stage (p = 0.021 and p = 0.005, respectively), differentiation (p = 0.010), and lymphatic invasion (p = 0.003). In univariate survival analysis, patients with leptin-positive adenocarcinoma revealed better overall and disease-free survivals (p = 0.032 and p = 0.004, respectively, log-rank test). In multivariate survival analysis with Cox proportional hazards model, leptin expression was an independent prognostic marker of disease-free survival (p = 0.009). We conclude that leptin was gradually expressed during the normal–adenoma–adenocarcinoma sequence, suggesting an association in colorectal carcinogenesis. In addition, high leptin expression was an indicator of favorable tumor features and better survival of colorectal cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Tuynman JB, Peppelenbosch MP, Richel DJ. COX-2 inhibition as a tool to treat and prevent colorectal cancer. Crit Rev Oncol Hematol. 2004;52:81–101.

    Article  PubMed  CAS  Google Scholar 

  2. Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol. 2003;16:376–88.

    Article  PubMed  Google Scholar 

  3. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122:327–34.

    PubMed  CAS  Google Scholar 

  4. Pan SY, Johnson KC, Ugnat AM, Wen SW, Mao Y. Association of obesity and cancer risk in Canada. Am J Epidemiol. 2004;159:259–68.

    Article  PubMed  Google Scholar 

  5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 2003;348:1625–38.

    Article  PubMed  Google Scholar 

  6. Stattin P, Lukanova A, Biessy C, et al. Obesity and colon cancer: does leptin provide a link? Int J Cancer. 2004;109:149–52.

    Article  PubMed  CAS  Google Scholar 

  7. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–5.

    Article  PubMed  CAS  Google Scholar 

  8. Ogunwobi OO, Beales ILP. The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involve activation of JNK mitogenic activated protein kinase, JAK2 and PI3 kinase/Akt. Int J Colorectal Dis. 2007;22:401–9.

    Article  PubMed  Google Scholar 

  9. Stattin P, Soderberg S, Hallmans G, et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J Clin Endocrinol Metab. 2001;86:1341–5.

    Article  PubMed  CAS  Google Scholar 

  10. Stephenson GD, Rose DP. Breast cancer and obesity: an update. Nutr Cancer. 2003;45:1–16.

    Article  PubMed  CAS  Google Scholar 

  11. Zhao X, Huang K, Zhu Z, Chen S, Hu R. Correlation between expression of leptin and clinicopathological features and prognosis in patients with gastric cancer. J Gastroenterol Hepatol. 2007;22:1317–21.

    Article  PubMed  CAS  Google Scholar 

  12. Attele AS, Shi ZQ, Yuan CS. Leptin, gut, and food intake. Biochem Pharmacol. 2002;63:1579–83.

    Article  PubMed  CAS  Google Scholar 

  13. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse ob gene and its human homologue. Nature. 1994;372:425–32.

    Article  PubMed  CAS  Google Scholar 

  14. Hong SJ, Kwon KW, Kim SG, et al. Variation in expression of gastric leptin according to differentiation and growth pattern in gastric adenocarcinoma. Cytokine. 2006;33:66–71.

    Article  PubMed  CAS  Google Scholar 

  15. Senaris R, Garcia-Caballero T, Casabiell X, et al. Synthesis of leptin in human placenta. Endocrinology. 1997;138:4501–4.

    Article  PubMed  CAS  Google Scholar 

  16. Smith-Kirwin SM, O’Connor DM, De Johnston J, Lancey ED, Hassink SG, Funanage VL. Leptin expression in human mammary epithelial cells and breast milk. J Clin Endocrinol Metab. 1998;83:1810–3.

    Article  PubMed  CAS  Google Scholar 

  17. Bohlender J, Rauh M, Zenk J, et al. Differential distribution and expression of leptin and the functional leptin receptor in major salivary glands of humans. J Endocrinol. 2003;178:217–23.

    Article  PubMed  CAS  Google Scholar 

  18. Koda M, Sulkowska M, Kanczuga-Koda L, Surmacz E, Sulkowski S. Overexpression of the obesity hormone leptin in human colorectal cancer. J Clin Pathol. 2007;60:902–6.

    Article  PubMed  Google Scholar 

  19. Wang SN, Yeh YT, Yang SF, Chai CY, Lee KT. Potential role of leptin expression in hepatocellular carcinoma. J Clin Pathol. 2006;59:930–4.

    Article  PubMed  Google Scholar 

  20. Hardwick JCH, van Den Brink GR, Offerhaus GJ, van Deventer SJH, Peppelenbosch MP. Leptin is a growth factor for colonic epithelial cells. Gastroenterology. 2001;121:79–90.

    Article  PubMed  CAS  Google Scholar 

  21. Schneider R, Bornstein SR, Chrousos GP, Boxberger S, Ehninger G, Breidert M. Leptin mediates a proliferative response in human gastric mucosa cells with functional receptor. Horm Metab Res. 2001;33:1–6.

    Article  PubMed  CAS  Google Scholar 

  22. Sierra-Honigmann MR, Nath AK, Murakami C, et al. Biological action of leptin as an angiogenic factor. Science. 1998;281:1683–95.

    Article  PubMed  CAS  Google Scholar 

  23. Rouet-Benzineb P, Aparicio T, Guilmeau S, et al. Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT–29 cells via NF-kappaB signaling. J Biol Chem. 2004;279:16495–502.

    Article  PubMed  CAS  Google Scholar 

  24. Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 2004;10:4325–31.

    Article  PubMed  CAS  Google Scholar 

  25. Garofalo C, Koda M, Cascio S, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res. 2006;12:1447–53.

    Article  PubMed  CAS  Google Scholar 

  26. Attoub S, Noe V, Pirola L, et al. Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways. FASEB J. 2000;14:2329–38.

    Article  PubMed  CAS  Google Scholar 

  27. van de Rijn M, Gilks CB. Applications of microarray to histopathology. Histopathology. 2004;44:97–108.

    Article  PubMed  Google Scholar 

  28. Jourdan F, Sebbagh N, Comperat E, et al. Tissue microarray technology: validation in colorectal carcinoma and analysis of p53, hMLH1, and hMSH2 immunohistochemical expression. Virchows Arch. 2003;443:115–21.

    Article  PubMed  CAS  Google Scholar 

  29. Baldi A, Santini D, Russo P, et al. Analysis of APAF-1 expression in human cutaneous melanoma progression. Exp Dermatol. 2004;13:93–7.

    Article  PubMed  CAS  Google Scholar 

  30. Zlobec I, Terracciano L, Jass JR, Lugli A. Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer. Virchows Arch. 2007;451:763–9.

    Article  PubMed  CAS  Google Scholar 

  31. Liu Z, Uesaka T, Watanabe H, et al. High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin. Int J Oncol. 2001;19:1009–14.

    PubMed  CAS  Google Scholar 

  32. Aparicio T, Kotelevets L, Tsocas A, et al. Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) mice. Gut. 2005;54:1136–45.

    Article  PubMed  CAS  Google Scholar 

  33. Tessitore L, Vizio B, Jenkins O, et al. Leptin expression in colorectal and breast cancer patients. Int J Mol Med. 2000;5:421–6.

    PubMed  CAS  Google Scholar 

  34. Bolukbas FF, Kilic H, Bolukbas C, et al. Serum leptin concentration and advanced gastrointestinal cancers: a case controlled study. BMC Cancer. 2004;4:29–32.

    Article  PubMed  Google Scholar 

  35. Stattin P, Soderberg S, Biessy C, et al. Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat. 2004;86:191–6.

    Article  PubMed  CAS  Google Scholar 

  36. Ishikawa M, Kitayama J, Nagawa H. Expression pattern of leptin and leptin receptor (OB-R) in human gastric cancer. World J Gastroenterol. 2006;12:5517–22.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the research fund of Hanyang University (HY-2006-C) to S. S. Paik.

Author information

Authors and Affiliations

  1. Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea

    Seung Sam Paik MD, Se-Min Jang MD & Ki-Seok Jang MD

  2. Department of Surgery, College of Medicine, Hanyang University, Seoul, Korea

    Kang Hong Lee MD

  3. Department of Surgery, College of Medicine, Soon Chun Hyang University, Seoul, Korea

    Dongho Choi MD

  4. Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, 388-1 Poongnap-Dong, Songpa-Ku, 138-736, Seoul, Republic of Korea

    Se Jin Jang MD

Authors
  1. Seung Sam Paik MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Se-Min Jang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ki-Seok Jang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kang Hong Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongho Choi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Se Jin Jang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Se Jin Jang MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paik, S.S., Jang, SM., Jang, KS. et al. Leptin Expression Correlates with Favorable Clinicopathologic Phenotype and Better Prognosis in Colorectal Adenocarcinoma. Ann Surg Oncol 16, 297–303 (2009). https://doi.org/10.1245/s10434-008-0221-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-008-0221-7

Keywords

Search

Navigation