Tumor Biology

, Volume 37, Issue 7, pp 8657–8664 | Cite as

The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer

  • Hai Hu
  • Jun-Jie Hang
  • Ting Han
  • Meng Zhuo
  • Feng Jiao
  • Li-Wei Wang
Original Article


Macrophages play a critical role in the initiation and progression of various solid tumors. However, their prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. This study investigated the distribution patterns of macrophages in PDAC and possible association with the overall survival (OS). We found significant differences in macrophage density (identified by CD68 and CD163 immunopositivity; p < 0.001 for both) between primary cancer and paired adjacent normal tissues. Most macrophages in cancerous pancreatic tissues were located in the stroma rather than the islets (p = 0.032 and p < 0.001). We also demonstrated that a high total macrophage density (characterized by CD68 immunopositivity) correlated with an absence of jaundice before surgery (p = 0.03) and that a high density of M2 macrophages (characterized by CD163 immunopositivity) in the stroma strongly correlated with the tumors located in the tail and body of the pancreas (p = 0.04). In addition, OS was shorter in patients with high-density M2 macrophage infiltration than in those with low-density M2 macrophage infiltration (p = 0.012). Moreover, multivariate analysis revealed that dense M2 macrophage infiltration into the stroma was an independent prognostic factor for PDAC patients (p = 0.02).


Immunohistochemistry Macrophage Pancreatic ductal adenocarcinoma Prognosis 



This study was supported by the National Natural Science Foundation of China (Grant Nos. 81171887, 91229117, 81502017, 81502018, and 81572315), by Research Grant from Shanghai Hospital Development Center (SHDC12014128), by Songjiang Liandong Program (0702N14002), and in part by the National Key Clinical Discipline Oncology.

Compliance with ethical standards

Written informed consent and approval from the Ethics Committees of Shanghai General Hospital were obtained for the use of these clinical materials for research purposes.

Conflicts of interest



  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of cancer in China, 2011. Chin J Cancer Res. 2015;27:2–12.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Liu Y, Du L. Role of pancreatic stellate cells and periostin in pancreatic cancer progression. Tumor Biol. 2015;36:3171–7.CrossRefGoogle Scholar
  7. 7.
    Tang D, Gao J, Wang S, Yuan Z, Ye N, Chong Y, et al. Apoptosis and anergy of t cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer. Tumor Biol. 2015;36:5617–26.CrossRefGoogle Scholar
  8. 8.
    Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–72.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    van Furth R. Origin and turnover of monocytes and macrophages; cell kinetics of the inflammatory reaction. Springer; 1989. p. 125–50.Google Scholar
  11. 11.
    Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, et al. Impact of tumor‐associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci. 2012;103:2012–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res. 2011;167:e211–9.CrossRefPubMedGoogle Scholar
  14. 14.
    An T, Sood U, Pietruk T, Cummings G, Hashimoto K, Crissman J. In situ quantitation of inflammatory mononuclear cells in ductal infiltrating breast carcinoma. Relation to prognostic parameters. Am J Pathol. 1987;128:52.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Hiraoka K, Zenmyo M, Watari K, Iguchi H, Fotovati A, Kimura YN, et al. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages. Cancer Sci. 2008;99:1595–602.CrossRefPubMedGoogle Scholar
  16. 16.
    Lin EY, Li J-F, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238–46.CrossRefPubMedGoogle Scholar
  17. 17.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol. 2013;4:210.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen SJ, Zhang QB, Zeng LJ, Lian GD, Li JJ, Qian CC, et al. Distribution and clinical significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma: a retrospective analysis in china. Curr Oncol. 2015;22:e11–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jiao F, Hu H, Han T, Yuan C, Wang L, Jin Z, et al. Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. Int J Mol Sci. 2015;16:6677–93.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Medrek C, Pontén F, Jirström K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 2012;4:376.PubMedPubMedCentralGoogle Scholar
  23. 23.
    De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277–86.CrossRefPubMedGoogle Scholar
  24. 24.
    Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the m2-like macrophage population. Cancer Res. 2014;74:24–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 2012;33:119–26.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108:914–23.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shabo I, Svanvik J. Expression of macrophage antigens by tumor cells; cell fusion in health and disease. Springer; 2011. p. 141–50.Google Scholar
  28. 28.
    Maniecki MB, Møller HJ, Moestrup SK, Møller BK. CD163 positive subsets of blood dendritic cells: the scavenging macrophage receptors CD163 and CD91 are coexpressed on human dendritic cells and monocytes. Immunobiology. 2006;211:407–17.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Medical Oncology and Pancreatic Cancer Center, Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Shanghai Key laboratory of Pancreatic DiseaseShanghaiChina

Personalised recommendations