Annals of Surgical Oncology

, Volume 21, Issue 4, pp 1304–1313 | Cite as

Combination of Osteopontin with Peritumoral Infiltrating Macrophages is Associated with Poor Prognosis of Early-Stage Hepatocellular Carcinoma after Curative Resection

  • Wenwei Zhu
  • Lei Guo
  • Bo Zhang
  • Lili Lou
  • Zhenghai Lin
  • Xiaodong Zhu
  • Ning Ren
  • Qiongzhu Dong
  • Qinghai Ye
  • Lunxiu Qin
Hepatobiliary Tumors

Abstract

Background

Crosstalk between a tumor and the microenvironment plays a key role in tumor progression and metastasis. This study was performed to elucidate the prognostic significance of combining tumor-secreted osteopontin (OPN) with microenvironment-associated peritumoral macrophages (PTMs) in hepatocellular carcinoma (HCC), especially for those with early-stage disease.

Methods

Tissue microarray-based immunohistochemistry was used to investigate OPN and PTMs expression in two independent cohorts consisting of 374 patients with HCC who underwent radical resection. The prognostic value for the two factors alone or in combination was investigated in these patients.

Results

OPN combined with PTMs was an independent prognostic factor for both overall survival (OS; p < 0.0001) and time to recurrence (TTR; p = 0.003) from the learning cohort (n = 96). Their combined value for prognosis was validated in early-stage HCCs using another independent cohort (n = 278; OS, p < 0.001; TTR, p = 0.001). This combination remained significant in HCCs with low α-fetoprotein levels in both cohorts, and was predictive for early recurrence/death risk (<2 years) compared with a single marker. Only OPN+HCCs had a significant correlation of PTMs levels with OS (p = 0.01) or TTR (p = 0.011).

Conclusions

Tumor OPN combined with PTMs is a promising predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. The interplay of OPN and PTMs represents a new insight into tumor progression and therapeutic targets for HCC.

Keywords

Overall Survival Barcelona Clinic Liver Cancer Barcelona Clinic Liver Cancer Staging Barcelona Clinic Liver Cancer Staging System Independent Validation Cohort 

Notes

Acknowlegdment

This work was supported in part by grants from the National Key Project for Infectious Disease of China (2012ZX10002012-003), the State Key Basic Research Program of China (2009CB521701), the “973” State Key Basic Research Program of China (2014CB542101) and the National Natural Science Foundation of China (81071993, 30672037, 30300400, and 30700991).

Conflict of interest

The authors made no disclosures.

Supplementary material

10434_2013_3445_MOESM1_ESM.docx (243 kb)
Supplementary material 1 (DOCX 243 kb)

References

  1. 1.
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Tang ZY, Ye SL, Liu YK, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:187–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakakura EK, Choti MA. Management of hepatocellular carcinoma. Oncology (Williston Park). 2000;14:1085–1098, discussion 1098–102.Google Scholar
  4. 4.
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.PubMedCrossRefGoogle Scholar
  5. 5.
    McAllister SS, Weinberg RA. Tumor-host interactions: a far-reaching relationship. J Clin Oncol. 2010;28:4022–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104:2224–34.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen JJ, Lin YC, Yao PL, et al. Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol. 2005;23:953–64.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhu XD, Zhang JB, Zhuang PY, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16.PubMedCrossRefGoogle Scholar
  10. 10.
    Kuang DM, Wu Y, Chen N, et al. Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood. 2007;110:587–595.PubMedCrossRefGoogle Scholar
  11. 11.
    Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Sun BS, Dong QZ, Ye QH, et al. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology. 2008;48:1834–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Xue YH, Zhang XF, Dong QZ, et al. Thrombin is a therapeutic target for metastatic osteopontin-positive hepatocellular carcinoma. Hepatology. 2010;52:2012–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Feng B, Rollo EE, Denhardt DT. Osteopontin (OPN) may facilitate metastasis by protecting cells from macrophage NO-mediated cytotoxicity: evidence from cell lines down-regulated for OPN expression by a targeted ribozyme. Clin Exp Metastasis. 1995;13:453–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Crawford HC, Matrisian LM, Liaw L. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res. 1998;58:5206–15.PubMedGoogle Scholar
  17. 17.
    Wittekind C. Pitfalls in the classification of liver tumors [in German]. Pathologe. 2006;27:289–93.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang XR, Xu Y, Shi GM, et al. Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection. Clin Cancer Res. 2008;14:3850–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Qian YB, Zhang JB, Wu WZ, et al. P48 is a predictive marker for outcome of postoperative interferon-alpha treatment in patients with hepatitis B virus infection-related hepatocellular carcinoma. Cancer. 2006;107:1562–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Sun HC, Zhang W, Qin LX, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47:684–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.PubMedCrossRefGoogle Scholar
  23. 23.
    Yang GH, Fan J, Xu Y, et al. Osteopontin combined with CD44, a novel prognostic biomarker for patients with hepatocellular carcinoma undergoing curative resection. Oncologist. 2008;13:1155–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med. 2008;359:2045–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol. 2009;51:890–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Iizuka N, Oka M, Yamada-Okabe H, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87.PubMedCrossRefGoogle Scholar
  28. 28.
    Wai PY, Kuo PC. Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev. 2008;27:103–18.PubMedCrossRefGoogle Scholar
  29. 29.
    Rittling SR. Osteopontin in macrophage function. Expert Rev Mol Med. 2011;13:e15.PubMedCrossRefGoogle Scholar
  30. 30.
    Rollo EE, Laskin DL, Denhardt DT. Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages. J Leukoc Biol. 1996;60:397–404.PubMedGoogle Scholar
  31. 31.
    Qin LX, Tang ZY. Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature. J Cancer Res Clin Oncol. 2004;130:497–513.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Wenwei Zhu
    • 1
    • 2
  • Lei Guo
    • 1
    • 2
  • Bo Zhang
    • 1
    • 2
  • Lili Lou
    • 1
  • Zhenghai Lin
    • 1
    • 2
  • Xiaodong Zhu
    • 1
    • 2
  • Ning Ren
    • 1
    • 2
  • Qiongzhu Dong
    • 1
    • 2
  • Qinghai Ye
    • 1
    • 2
  • Lunxiu Qin
    • 1
    • 2
  1. 1.Liver Cancer Institute and Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of EducationFudan UniversityShanghaiChina

Personalised recommendations