Virchows Archiv

, Volume 474, Issue 1, pp 3–12 | Cite as

High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer

  • Marja Heiskala
  • Marjut Leidenius
  • Kristiina JoensuuEmail author
  • Päivi Heikkilä
Original Article


Macrophages are important for the function of the innate immune system, and in solid tumors, they represent a significant proportion of the tumor mass. Tumor-associated macrophages (TAM) have a M2 phenotype and show a multitude of pro-tumoral functions, promoting tumor cell survival, proliferation, and dissemination. CCL2, synthesized by tumor and stromal cells, initiates a chemokine cascade inducing these processes. We studied by immunohistochemistry (IHC) the frequency of TAMs and CCL2 expressing cells in three groups of primary tumor (PT)-recurrence (R) pairs, where relapse was recorded within 2 years (group 1), between 5 and 10 years (group 2), and after 10 years (group 3). In our study all established breast cancers were heavily infiltrated by CD68 positive cells. Both in PTs and in R lesions the infiltration was more abundant in the peritumoral than in the intratumoral stroma. The mean frequency of M2 marker and CD14 positive cells in the intratumoral stroma and CCL2 expressing tumor cells was higher in the Rs as compared to the corresponding PTs. In PTs, a high frequency of CD14 positive cells and a high expression of CCL2 by tumor cells was associated with an early recurrence. The findings support the current understanding of immune cell orchestrated development, progression and metastatic spread of breast cancer. Our study showed that a high frequency of CCL2 positive tumor cells and CD14 positive TAMs are significant risk factors for rapid tumor recurrence. Potential targets for intervention are discussed.


Innate immunity Breast cancer CCL2 CD14 positive macrophages Prognostic markers in breast cancer 



We thank Eija Heiliö for her excellent technical assistance, and Antti Nevanlinna, Msc, for facilitating the statistical analysis.

Author Contributions

Marja Heiskala: doing the literature search and planning the study, evaluating the samples, writing the article, and preparing the graphics

Marjut Leidenius: planning the study, writing the article

Kristiina Joensuu: planning the study, responsible for the collection and handling of the samples, evaluating the immunohistochemical stainings, making the statistical work, and writing the article

Päivi Heikkilä: planning the study and writing the article, analyzing the stainings.


This work was supported by the Helsinki University Central Hospital Research Foundation, the Finnish Cancer Foundation, the Sigrid Juselius Foundation, and the Finnish Breast Cancer Group.

Compliance with ethical standards

The Ethics Committee of the Helsinki University Central Hospital approved the study protocol.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Marja Heiskala
    • 1
  • Marjut Leidenius
    • 2
  • Kristiina Joensuu
    • 1
    Email author
  • Päivi Heikkilä
    • 1
  1. 1.Department of Pathology and HUSLABHelsinki University Hospital and University of HelsinkiHelsinkiFinland
  2. 2.Breast Surgery UnitComprehensive Cancer Center Helsinki University HospitalHelsinkiFinland

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