High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer
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.
KeywordsInnate 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.
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.
- 1.Gouon-Evans V, Rothenbeg ME, Pollard JW (2000) Postnatal mammary gland development requires macrophages and eosinophils. Development 127:2269–2282Google Scholar
- 12.Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, van den Bossche J, Mack M, Pipeleers D, in't Veld P, de Baetselier P, van Ginderachter JA (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70:5728–5739CrossRefGoogle Scholar
- 19.Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629Google Scholar
- 20.Joensuu K, Leidenius M, Kero M, Andersson LC, Horwitz KB, Heikkilä P (2013) ER, PR, HER2, Ki67 and CK5 in early and late relapsing breast cancer - reduced CK5 expression in metastases. Breast Cancer: Bacic Clin Res 7:23–34Google Scholar
- 30.Nywening TM, Wang-Gillam A, Sanford DA et al (2016) Phase 1b study targeting tumour associated macrophages with CCR2 inhibition plus FOLFIRINOX in locally advanced and borderline resectable pancreatic cancer. Lancet Oncol 17(5):651–662. https://doi.org/10.1016/S1470-2045(16)00078-4 CrossRefGoogle Scholar