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

ABSTRACT 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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    • "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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    • "Of particular interest is the difference in CD68, a marker for TAMs. In human breast tumors, infiltrating TAMs correlate with poor prognostic features, higher tumor grade and decreased disease free survival [32], [33]. This may be, in part due to increased angiogenesis that has been shown in mouse models of mammary gland tumors and in human breast tumors where CD68 levels correlate with VEGF expression [34], [35]. "
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    ABSTRACT: Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted.
    PLoS ONE 05/2013; 8(5):e64225. DOI:10.1371/journal.pone.0064225 · 3.23 Impact Factor
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