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. 2012 Jul 23;12:306.
doi: 10.1186/1471-2407-12-306.

The Presence of Tumor Associated Macrophages in Tumor Stroma as a Prognostic Marker for Breast Cancer Patients

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Free PMC article

The Presence of Tumor Associated Macrophages in Tumor Stroma as a Prognostic Marker for Breast Cancer Patients

Catharina Medrek et al. BMC Cancer. .
Free PMC article

Abstract

Background: Tumor associated macrophages (TAMs) are alternatively activated macrophages that enhance tumor progression by promoting tumor cell invasion, migration and angiogenesis. TAMs have an anti-inflammatory function resembling M2 macrophages. CD163 is regarded as a highly specific monocyte/macrophage marker for M2 macrophages. In this study we evaluated the specificity of using the M2 macrophage marker CD163 as a TAM marker and compared its prognostic value with the more frequently used pan-macrophage marker CD68. We also analyzed the prognostic value of the localization of CD163(+) and CD68(+) myeloid cells in human breast cancer.

Methods: The extent of infiltrating CD163(+) or CD68(+) myeloid cells in tumor nest versus tumor stroma was evaluated by immunohistochemistry in tissue microarrays with tumors from 144 breast cancer cases. Spearman's Rho and χ(2) tests were used to examine the correlations between CD163(+) or CD68(+) myeloid cells and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the impact of CD163(+) and CD68(+) myeloid cells in tumor stroma and tumor nest, respectively, on recurrence free survival, breast cancer specific and overall survival.

Results: We found that infiltration of CD163(+) and CD68(+) macrophages into tumor stroma, but not into tumor nest, were of clinical relevance. CD163(+) macrophages in tumor stroma positively correlated with higher grade, larger tumor size, Ki67 positivity, estrogen receptor negativity, progesterone receptor negativity, triple-negative/basal-like breast cancer and inversely correlated with luminal A breast cancer. Some CD163(+) areas lacked CD68 expression, suggesting that CD163 could be used as a general anti-inflammatory myeloid marker with prognostic impact. CD68(+) macrophages in tumor stroma positively correlated to tumor size and inversely correlated to luminal A breast cancer. More importantly, CD68 in tumor stroma was an independent prognostic factor for reduced breast cancer specific survival.

Conclusion: These findings highlight the importance of analyzing the localization rather than merely the presence of TAMs as a prognostic marker for breast cancer patients.

Figures

Figure 1
Figure 1
IHC staining of primary breast tumors. CD163+AB and CD68+CD, cells with a macrophage-morphology were present in both TS and TN. CD208+ cells were located in peri-tumoral T cell zones only, E. Gene expression levels of CD163 in luminal and basal-like breast cancer, using the microarray profile set [GenBank:GDS1329] [21] from NCBI Gene Expression Omnibus profiles, F. *** P<0.001.
Figure 2
Figure 2
OS according to the infiltration density of CD163+and CD68+cells in primary breast cancer. OS curves according to the infiltration density of CD163+ and CD68+ cells in TS. Non grouped data A,B. Grouped data C,D,E,F. OS curves according to the infiltration density of CD163+ and CD68+ cells in TS C,D and TN E,F.
Figure 3
Figure 3
RFS according to the infiltration of CD68+cells in TS. RFS curve according to the infiltration density of CD68+ cells in TS, A. Gene expression levels of CD68 in breast cancer patients under endocrine therapy, who were disease-free or who had recurrence, using the microarray profile set [GenBank:GDS806] [22] from NCBI Gene Expression Omnibus profiles B. ** P<0.01.
Figure 4
Figure 4
Infiltration of CD163+cells in different breast cancer subtypes. OS curves according to the infiltration density of CD163+ cells in TS, for patients with luminal A breast cancer A, or triple-negative/basal-like breast cancer B.

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