Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome

Department of Surgery, University of California, San Francisco, CA, USA.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 08/2011; 128(3):703-11. DOI: 10.1007/s10549-010-1154-y
Source: PubMed


Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages-proliferating macrophages (promacs)-with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P = 0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions.

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    • "Insufficient attention was given to the intratumoral heterogeneity of TAM subtypes, in particular in relation to the different intratumoral structures. In human breast cancer following intratumoral compartments can be defined: (1) areas with soft fibrous stroma characterized by pronounced inflammatory infiltrates that are beneficial for invasive cell growth (Ham and Moon, 2013); (2) areas with coarse fibrous stroma containing collagen fibers and characterized by impaired synthesis of extracellular matrix proteins (ECM) (Campbell et al., 2011; Eiro et al., 2012; Ruffell et al., 2012; Tang, 2013); (3) areas of maximum stromaland-parenchymal relationship revealing certain similarities with soft fibrous stroma (Mahmoud et al., 2012); (4) parenchymal elements ; (5) gaps of ductal tumor structures (Pinder, 2010). All five stromal subtypes demonstrate functionally distinct areas of tumor mircoenvironment with not yet identified mechanistic role in metastatic spread. "
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    ABSTRACT: Tumor associated macrophages (TAM) support tumor growth and metastasis in several animal models of breast cancer, and TAM amount is predictive for efficient tumor growth and metastatic spread via blood circulation. However, limited information is available about intratumoral TAM heterogeneity and functional role of TAM subpopulations in tumor progression. The aim of our study was to examine correlation of TAM presence in various morphological segments of human breast cancer with clinical parameters. Thirty six female patients with nonspecific invasive breast cancer T1-4N0-3M0 were included in the study. Morphological examination was performed using Carl Zeiss Axio Lab.A1 and MiraxMidiZeiss. Immunohistochemical and immunofluorescence/confocal microcopy analysis was used to detect CD68 and stabilin-1 in 5 different tumor segments: (1) areas with soft fibrous stroma; (2) areas with coarse fibrous stroma; (3) areas of maximum stromal-and-parenchymal relationship; (4) parenchymal elements; (5) gaps of ductal tumor structures. The highest expression of CD68 was in areas with soft fibrous stroma or areas of maximum stromal-and-parenchymal relationship (79%). The lowest expression of CD68 was in areas with coarse fiber stroma (23%). Inverse correlation of tumor size and expression of CD68 in gaps of tubular tumor structures was found (R=-0.67; p=0.02). In case of the lymph node metastases the average score of CD68 expression in ductal gaps tumor structures was lower (1.4±0.5) compared to negative lymph nodes case (3.1±1.0; F=10.9; p=0.007). Confocal microscopy identified 3 phenotypes of TAM: CD68(+)/stabilin-1(-); CD68(+)/stabilin-1(+) (over 50%); and CD68(-)/stabilin-1(+). However, expression of stabilin-1 did not correlate with lymph node metastasis. We concluded, that increased amount of CD68+TAM in gaps of ductal tumor structures is protective against metastatic spread in regional lymph nodes.
    Immunobiology 09/2015; DOI:10.1016/j.imbio.2015.09.011 · 3.04 Impact Factor
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    • "Tissue macrophages originate from circulating monocytes, and are found in large abundance in the breast tumor microenvironment; a trait associated with poor prognosis in cancer patients [20]. Specifically, a 77% increased risk of mortality was associated with increased double immunostaining of cluster of differentiation (CD)68 + and proliferating cell nuclear antigen (PCNA) + macrophages in human breast adenocarcinomas [20]. These tumor-associated macrophages (TAMs) represent the largest proportion of leukocytes in the breast tumor microenvironment and are attractive targets for immunotherapy. "
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    ABSTRACT: Observational research suggests that exercise may reduce the risk of breast cancer and improve survival. One proposed mechanism for the protective effect of aerobic exercise related to cancer risk and outcomes, but has not been examined definitively, is the immune response to aerobic exercise. Two prevailing paradigms are proposed. The first considers the host immune response as modifiable by aerobic exercise training. This exercise-modulated immune-tumor crosstalk in the mammary microenvironment may alter the balance between tumor initiation and progression versus tumor suppression. The second paradigm considers the beneficial role of exercise-induced, skeletal muscle-derived cytokines, termed “myokines”. These myokines exert endocrine-like effects on multiple organs, including the mammary glands. In this systematic review, we i) define the role of macrophages and T-cells in breast cancer initiation and progression; ii) address the two paradigms that support exercise-induced immunomodulation; iii) systematically assessed the literature for exercise intervention that assessed biomarkers relevant to both paradigms in human intervention trials of aerobic exercise training, in healthy women and women with breast cancer; iv) incorporated pre-clinical animal studies and non-RCTs for background discussion of putative mechanisms, through which aerobic exercise training modulates the immunological crosstalk, or the myokine-tumor interaction in the tumor microenvironment; and v) speculated on the potential biomarkers and mechanisms that define an exercise-induced, anti-tumor “signature”, with a view toward developing relevant biomarkers for future aerobic exercise intervention trials.
    American Journal of Translational Research 06/2014; 6(5):422-438. · 3.40 Impact Factor
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    • "Till now, TAMs have been found to play dual functions, both positively or negatively affect tumor growth through interactions with the microenvironment, and these actions are tissue specific [6,7]. Several clinical studies showed that high density TAMs were present in more advanced stages of cancer with a worse prognosis in breast [8,9], lung [10,11], and bladder cancer [12,13]. Although a high TAM density has been reported in poorly differentiated papillary thyroid carcinoma (PTC) or anaplastic thyroid cancer [14], the distribution and function of TAMs in the most common PTC have not been studied yet. "
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    ABSTRACT: Tumor-associated macrophages (TAMs) play a tumorigenic role related to advanced staging and poor prognosis in many human cancers including thyroid cancers. Yet, a functional role of TAMs in papillary thyroid carcinoma (PTC) has not been established. The aim of this study was to investigate TAM expression in human PTC with lymph node (LN) metastasis. Thirty-six patients who underwent surgery after being diagnosed with PTC with LN metastasis were included. Primary tumor tissues were immunohistochemically stained with an anti-CD68 antibody and clinical characteristics according to TAM density were evaluated. The TAM densities (CD68(+) cells) varied from 5% to 70%, in all tumor areas, while few cells were stained in adjacent normal tissues. TAMs were identified as CD68(+) cells with thin, elongated cytoplasmic extensions that formed a canopy structure over tumor cells. Comparing clinicopathologic characteristics between tumors with low (<25%) and high (25% to 70%) TAM densities, primary tumors were larger in the high density group than in the low density group (2.0±0.1 vs. 1.5±0.1; P=0.009). TAMs were identified in primary PTC tumors with LN metastasis and higher TAM densities were related to larger tumor sizes, suggesting a tumorigenic role of TAMs in human PTCs.
    09/2013; 28(3):192-8. DOI:10.3803/EnM.2013.28.3.192
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