Secretion of BMP-2 by tumor-associated macrophages (TAM) promotes microcalcifications in breast cancer

Abstract

Introduction Breast microcalcifications is a characteristic feature in diagnostic imaging and a prognostic factor of breast cancer. However, the underlying mechanisms of breast microcalcifications formation are not fully understood. Previous studies have shown that upregulation of bone morphogenetic protein 2 (BMP-2) is associated with the occurrence of microcalcifications and tumor-associated macrophages (TAMs) in the tumor microenvironment can secrete BMP-2. The aim of this study is to elucidate the role of secretion of BMP-2 by TAMs in promoting microcalcifications of breast cancer through immunohistochemical staining and co-culturing of breast cancer cells with TAMs. Methods A total of 272 patients diagnosed with primary invasive breast cancer from January 2010 to January 2012 in the First Hospital of China Medical University were included in this study. Immunohistochemical staining of CD68 (marker of entire macrophages), CD168 (marker of the M2-like macrophages) and BMP-2 were performed on 4-μm tissue microarray (TMA) sections. Following induction, THP-1 cells were differentiated to M2-like TAMs and were then co-cultured with breast cancer cells (MCF-7). Calcifications and BMP-2 expression were analyzed by Alizarin Red S staining and western blot, respectively. Results Immunohistochemical analysis showed that the expression of CD168 was significantly increased in tissues with microcalcifications and was correlated with the expression of BMP-2 and poor prognosis. The formation of cellular microcalcifications and BMP-2 expression were significantly increased in MCF-7 cells co-cultured with TAMs compared with MCF-7 cells alone. Conclusions These findings support the hypothesis that TAMs secrete BMP-2 to induce microcalcifications in breast cancer cells and influence prognosis via multiple pathways including BMP-2 and its downstream factors.

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

“…Previous studies indicated that compared to in vivo differentiated peritoneal macrophages, BMDMs lie further toward the M1 end of the M1–M2 polarization spectrum [ 44 ]. Interestingly, BMP-2 itself was shown to be produced by M2 macrophages [ 45 , 46 ]. Thus, we searched for M2 marker genes among those upregulated by the last 48 h DHR treatment during macrophage differentiation to determine whether retinoid-treatment might promote M2 polarization.…”

Secretion of BMP-2 by TAMs up-regulates the expression of RUNX2 and TWIST1 to promote the microcalcifications and tumor metastasis in breast cancer

“…For many years, breast calci cations have always been used as an indicator for the diagnosis of early breast cancer, but its underlying mechanism has not yet been fully understood. Previous studies has demonstrated that secretion of BMP-2 by TAMs could promote the deposition of microcalci cations [11,12]. As a conserved branch of the TGFβ superfamily, BMP-2 has been shown to be associated with the upregulating the expression of RUNX2, which plays an important role in osteoblasts and bone formation, and chondrocyte maturation [13,14].…”

“…Alizarin red S staining of breast cancer cells was performed [12]. Alizarin red S staining of mice's tumor was done as follows: after depara nization, alizarin red S (G1038, Servicebio, Wuhan China) was added to the sections for 5 min and the sections were washed.…”

“…Invasive ductal carcinomas (IDC) with microcalci cations are generally associated with poor prognosis [3][4][5][6][7][8][9][10][11], but the molecular mechanism involved in the deposition of microcalci cations is still unclear. Previously it was demonstrated that tumor-associated macrophages (TAMs) can secrete bone morphogenetic protein 2 (BMP-2), which may play a role in inducing microcalci cations in some IDC [11,12]. As a member of the transforming growth factor β (TGFβ) superfamily, BMP-2 has been demonstrated to up-regulate runt-related transcription factor 2 (RUNX2) through the smad1/5/8 signaling pathway by binding to serine-threonine kinase receptors in the plasma membrane to regulate proliferation and differentiation of osteoblasts in normal tissues [13][14][15].…”

Construction of an immune-related gene signature for the prognosis and diagnosis of glioblastoma multiforme

“…They play an important role in the growth and development of the body by coordinating the differentiation, proliferation, and apoptosis of cells in different tissues and organs ( 77 ). Many studies have revealed that BMPs not only regulate bone and cartilage but also exert a variety of biological processes in the development of cancers ( 78 ), including breast cancer ( 79 ), ovarian cancer ( 80 ), and lung cancer bone metastasis ( 81 ). The expression level of BMP2 is related to the degree of tumor malignancy and GBM patient survival; therefore, it is being considered as a prognostic marker for glioma ( 82 , 83 ).…”