Stress-Induced beta2-Adrenoceptor-Mediated M2 Macrophage Polarization Promoting Tumor Growth in a Mouse Model of Breast Cancer

m2 macrophage polarization tumor
M2 Macrophage Polarization – Tumor Growth

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.

Usually, the expression of norepinephrine (NE) and epinephrine (E) will increase significantly when the body is in acute or chronic stress state. The research enunciated recently that the adrenergic system played pivotal roles in the initiation and promotion of tumor caused by stress.

Adrenergic receptors (ADRs) are expressed on multiple kinds of cancers such as pancreatic cancer, oral squamous cell cancer, colon cancer, ovarian cancer and breast cancer. Stress hormones NE and E could affect the proliferation and migration of breast cancer cells and enhance VEGF expression . ADRα2 was detected in a variety of human breast cancer cell lines.

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).

Khan S demonstrated that lipid-mobilizing factor (LMF) released by carcinoma cells could promote lipolysis and give rise to cachexia and meanwhile promote tumor angiogenesis and VEGF, MMP-2 and MMP-9 expression through ADRβ-cAMP-PKA signaling pathway, thus create a vital microenvironment which suits for the metastasis and settling of carcinoma cells.

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

Cover Image Credit (right panel): The different stumili, surface markers, secreted cytokines, and biological functions between M1 and M2 macrophages were summarized. CCL, chemokine (C-C motif) ligand; cMaf, c-musculoaponeurotic fibrosarconna; CXCL, chemokine (C-X-C) ligand; FIZZ1, resistin-like α; HIF, hypoxia inducible factor; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-gamma; IL, interleukin; IRF, interferon regulatory factor; JMJD, Jumonji doman-containing protein; KLF, Kruppel-like factor; NF-κB, nuclear factor κB; KLF, Kruppel-like factor; LPS, lipopolysaccharides; MHC, major histocompatibility complex; PPAR, peroxisome proliferator-activated receptors; STAT, signal transducer and activator of transcription; TLR, Toll-like receptor; TNF-α, tumor necrosis factor alpha; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; Ym1, chitinase 3-like 3. From: Macrophage Polarization in Physiological and Pathological Pregnancy; Front. Immunol., 15 April 2019, by Yongli Yao, Xiang-Hong Xu and Liping Jin

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