Abstract
IntroductionTumor-associated macrophages, which are derived from the infiltration of circulating bone marrow-derived monocytes, consist primarily of a polarized M2 macrophage (M2-Mϕ) population and are associated with poor prognosis in various cancers. In the present study, we attempted to assess whether M2-Mϕs derived from bone marrow stimulate the promotion and progression of mammary tumors.Methods4T1 murine mammary carcinoma cells were injected either alone or coupled with M2-Mϕs into the mammary fat pads of syngeneic female Balb/C mice. M2-Mϕs were prepared by treating monocytes isolated from female Balb/C mouse bone marrow with IL-4. Tumor cell growth was determined using an in vivo imaging system and the expression of cell proliferation-related, angiogenesis-related, and lymphangiogenesis-related proteins in tumor tissues was immunohistochemically analyzed. To evaluate the effects of the crosstalk between 4T1 cells and M2-Mϕs on the secretion and mRNA expression of cytokines and the migration of monocytes, 4T1 cells and M2-Mϕs were co-cultured and cytokine antibody array, real-time RT-PCR, and trans-well migration assays were conducted.ResultsThe co-injection of M2-Mϕs into the mammary fat pads of mice increased solid tumor growth and lung metastasis of 4T1 cells as well as the infiltration of CD45+ leukocytes into tumor tissues. The proportions of Ki-67+ proliferating cells and the expression of hypoxia inducible factor-1α, vascular endothelial cell growth factor A, CD31, vascular endothelial cell growth factor C, and lymphatic vessel endothelial receptor-1 were increased significantly in the tumor tissues of mice co-injected with 4T1 cells and M2-Mϕs. The in vitro results revealed that the proliferation of 4T1 cells, the migration of monocytes, and the secretion of granulocyte colony-stimulating factor, IFNγ, IL-1α, IL-2, IL-16, IFNγ-induced protein-10, keratinocyte-derived chemokine, macrophage colony-stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and RANTES were increased when 4T1 cells were co-cultured with M2-Mϕs, as compared with when the 4T1 cells were cultured alone.ConclusionThe crosstalk between 4T1 cells and M2-Mϕs increased the production of cytokines, which may have induced immune cell infiltration into tumor tissues, tumor cell proliferation, angiogenesis, and lymph angiogenesis, thereby increasing solid tumor growth and lung metastasis.
Highlights
Tumor-associated macrophages, which are derived from the infiltration of circulating bone marrowderived monocytes, consist primarily of a polarized M2 macrophage (M2-Mj) population and are associated with poor prognosis in various cancers
Using a 4T1 orthotopic Balb/C mammary cancer model in which 4T1 mammary carcinoma cells were injected into the mammary fat pads of syngeneic Balb/C mice, Luo and colleagues have shown that a legumain-based DNA vaccine targeting tumor-associated macrophage (TAM) suppressed tumor angiogenesis and metastasis [8]
We demonstrated that the co-injection of M2-Mjs with mammary carcinoma cells into the mammary fat pad of syngeneic Balb/C mice increased solid tumor growth and lung metastasis
Summary
Tumor-associated macrophages, which are derived from the infiltration of circulating bone marrowderived monocytes, consist primarily of a polarized M2 macrophage (M2-Mj) population and are associated with poor prognosis in various cancers. The differentiated phenotype of recruited macrophages reflects signals from the microenvironment in which they dwell These macrophages are broadly divided into two main classes; classically activated macrophages, or alternatively activated macrophages (M2-Mjs). Tumor microenvironments produce a variety of factors, which lead to promotion of the differentiation and polarization of infiltrated monocytes into M2-Mjs [5]. The macrophage within the tumor, which is referred to as tumor-associated macrophage (TAM), exhibits several pro-tumoral functions, including the promotion of angiogenesis, the suppression of adaptive immunity, and the expression of growth factors and matrix proteases (reviewed in [1]). Using a 4T1 orthotopic Balb/C mammary cancer model in which 4T1 mammary carcinoma cells were injected into the mammary fat pads of syngeneic Balb/C mice, Luo and colleagues have shown that a legumain-based DNA vaccine targeting TAM suppressed tumor angiogenesis and metastasis [8]
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