Stress-Induced β2-Adrenoceptor-Mediated M2 Macrophage Polarization Promoting Tumor Growth in a Mouse Model of Breast Cancer

Stress-Induced β2-Adrenoceptor-Mediated M2 Macrophage Polarization Promoting Tumor Growth in a Mouse Model of Breast Cancer

A new study published in the BMB Reports indicates that stress hormones such as epinephrine (adrenaline) may promote the transformation of M1-type macrophages to M2-type macrophages and, thus, accelerate tumor growth in a mouse model of breast cancer.

Several studies have linked psychological stress and breast cancer risk, associating with the involvement of stress mediators such as epinephrine (adrenaline) and norepinephrine (noradrenaline), and their effects on α- and β-adrenergic receptors. Both α- and β- adrenoceptors appear to influence breast cancer progression through increasing breast cancer cell proliferation or affecting angiogenesis and the inflammatory response in the tumor microenvironment (EI Obeid & Conzen SD, 2013; KS Madden et al., 2011).

On the other hand, macrophages are also associated with cancer, being classified in two types: M1 and M2. M1-type macrophages inhibit cancer development, while M2-type stimulate cancer growth and proliferation. In human breast carcinomas, tumor-associated macrophages (TAM) are also reported and their density correlates with poor prognosis (D Laoui et al., 2011). Also, it appears that in breast cancer, tumor cells are able to attract M2 macrophages that further promote invasion and suppress adaptive immunity, promoting tumor growth (RA Mukhtar et al., 2011).

In an attempt to assess the role of psychological stress and M2 macrophages in the development of breast cancer, Jun-Fang Qin and colleagues, from the School of Medicine, Nankai University, China, inoculated breast cancer cell lines 4T1 in mice followed by 3 weeks of social isolation stress, and analyzed the cellular development of the tumor and macrophage differentiation.

The authors found that stressed animals had increased levels of epinephrine, enhanced growth of the breast tumors and greater differentiation of intratumoral M2-type macrophages. In vitro experiments showed that epinephrine induced the transformation from M1-type to M2-type macrophage phenotype. The non-selective β-adrenoceptor antagonist and blocker propranolol reduced the number of M2 macrophages, indicating the involvement of β-adrenoceptors in this process.

The authors also detected β2-adrenoceptors and the human M2 macrophages marker CD163 in tissues obtained from breast cancer patients, and importantly, in this case, β2-adrenoceptors and the CD163 marker were co-expressed on carcinoma cells.

Of note, previous research indicates that psychological stress enhances cancer growth and metastasis, whereas the sympathetic nervous system is involved in leukemia progression and breast cancer metastasis. Thus, these studies and the current report by Jun-Fang Qin et al. highlight the potential therapeutic use of β-adrenoceptor blockers (beta blockers) in cancer treatment.

The study of Jun-Fang Qin et al. may also suggest the usefulness of treatments aimed to control psychological stress and/or stress hormone levels rather than exclusively focusing in the cancer cell.

Source: BMB Reports. 2015. Accepted Article
Read More: BMB Reports

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Source: Cover Image: Macrophage polarization and its function. Tissue macrophages are derived from circulating monocyte and acquire either a classical M1 or alternative M2 phenotype depending on microenvironmental stimuli. M1 phenotype is driven by IFN-γ and LPS, and produce high levels of the pro-inflammatory cytokines such as IL-6, IL-12, IL-23, and TNF-α. M2 phenotype can be subdivided into M2a, M2b, M2c, and M2d according to different stimuli. M2 macrophages generally produced a high level of IL-10 and demonstrated with high levels of scavenger receptor, mannose receptor, IL-1 receptor antagonist, and IL-1 decoy receptor. M1 phenotype drives pro-inflammatory, cytotoxic and antitumor responses. In contrast, M2 phenotype promotes angiogenesis, immunosuppression, and tumor progression. LPS indicates lipopolysaccharide; IC, immune complex; GC, glucocorticoid; SR, scavenger receptor; MR, mannose receptor; IL-1ra, IL-1 receptor antagonist; TLR, Toll-like receptor; MHC, major histocompatibility complex. From: T Chanmee et al., Cancers (Basel). 2014 Sep; 6(3): 1670–1690; Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment, Credit: http://www.mdpi.com/2072-6694/6/3/1670 ; Public domain.

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