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. 2015:2015:974615.
doi: 10.1155/2015/974615. Epub 2015 Mar 25.

Activating transcription factor 4 promotes angiogenesis of breast cancer through enhanced macrophage recruitment

Chen Liu  1 , Zongjin Li  2 , Lina Wang  3 , Lingling Tong  4 , Ningning He  2 , Yanan Chen  2 , Yanhua Liu  2 , Zhongjun Wu  1 , Peiqing Sun  5 , Rong Xiang  6 , Guosheng Ren  1 , Weijun Su  2
Affiliations

Activating transcription factor 4 promotes angiogenesis of breast cancer through enhanced macrophage recruitment

Chen Liu et al. Biomed Res Int. 2015.

Abstract

Angiogenesis plays an important role in the progression of tumor. Besides being regulated by tumor cells per se, tumor angiogenesis is also influenced by stromal cells in tumor microenvironment (TME), for example, tumor associated macrophages (TAMs). Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, has been reported to be related to tumor angiogenesis. In this study, we found that exogenous overexpression of ATF4 in mouse breast cancer cells promotes tumor growth via increasing tumor microvascular density. However, ATF4 overexpression failed to increase the expression level of a series of proangiogenic factors including vascular endothelial growth factor A (VEGFA) in tumor cells in this model. Thus, we further investigated the infiltration of proangiogenic macrophages in tumor tissues and found that ATF4-overexpressing tumors could recruit more macrophages via secretion of macrophage colony stimulating factor (M-CSF). Overall, we concluded that exogenous overexpression of ATF4 in breast cancer cells may facilitate the recruitment of macrophages into tumor tissues and promote tumor angiogenesis and tumor growth indirectly.

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Figures

Figure 1
Figure 1
ATF4 promotes the growth of breast cancer in vivo. (a) ATF4-overexpressing breast cancer grew faster than MCS group in vivo. (b) Representative tumor tissues from ATF4 group and MCS group on day 16 and day 31. (c) Fluc imaging of subcutaneous breast cancers from ATF4 group and MCS group on day 0, day 4, day 7, day 10, and day 13. For each group, a representative mouse at each time point was shown. (d) Quantitative analysis of BLI signals in (c) was shown as photons/sec/cm2/sr. MCS is the abbreviation of multiple cloning sites, and MCS group is used as control here.
Figure 2
Figure 2
ATF4 does not influence the proliferation of mouse breast cancer cells in vitro. (a) ATF4 overexpression did not influence the proliferation of 4T1-Luc cells in vitro. (b) ATF4 overexpression did not influence the proliferation of 4TO7 cells in vitro. (c) ATF4 overexpression did not influence Ki67 expression level in 4T1-Luc and 4TO7 cells.
Figure 3
Figure 3
ATF4 increases the microvascular density in breast cancer tissue. (a) Immunofluorescence staining of CD31 showed the increased microvascular density in ATF4-overexpressing 4T1-Luc breast cancers. (b) Immunofluorescence staining of CD31 showed the increased microvascular density in ATF4-overexpressing 4TO7 breast cancers. (c) ATF4 did not significantly influence the expression of proangiogenic factors.
Figure 4
Figure 4
ATF4 facilitates the recruitment of macrophages both in vitro and in vivo. (a) Immunofluorescence staining of F4/80 showed more macrophages infiltrating into ATF4-overexpressing 4T1-Luc breast cancer tissue compared to MCS group. (b) Immunofluorescence staining of F4/80 showed more macrophages infiltrating into ATF4-overexpressing 4TO7 breast cancer tissue compared to MCS group. (c) More Raw264.7 cells were recruited by the conditioned medium of ATF4-overexpressing 4T1-Luc cells. Data were representative of three independent experiments. (d) More Raw264.7 cells were recruited by the conditioned medium of ATF4-overexpressing 4TO7 cells. Data were representative of three independent experiments.
Figure 5
Figure 5
ATF4 increases the expression of M-CSF in breast cancer cells. (a) The mRNA level of M-CSF was increased in ATF4-overexpressing breast cancer cells. (b) The protein level of M-CSF was increased in ATF4-overexpressing breast cancer cells. (c) Immunohistochemical staining showed increased M-CSF level in ATF4-overexpressing breast cancer tissues.
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References

    1. Marignol L., Rivera-Figueroa K., Lynch T., Hollywood D. Hypoxia, notch signalling, and prostate cancer. Nature Reviews Urology. 2013;10(7):405–413. doi: 10.1038/nrurol.2013.110. - DOI - PMC - PubMed
    1. Yang Y., Sun M., Wang L., Jiao B. HIFs, angiogenesis, and cancer. Journal of Cellular Biochemistry. 2013;114(5):967–974. doi: 10.1002/jcb.24438. - DOI - PubMed
    1. Fong G.-H. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis. 2008;11(2):121–140. doi: 10.1007/s10456-008-9107-3. - DOI - PubMed
    1. Bertout J. A., Patel S. A., Simon M. C. The impact of O2 availability on human cancer. Nature Reviews Cancer. 2008;8(12):967–975. doi: 10.1038/nrc2540. - DOI - PMC - PubMed
    1. Semenza G. L. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013;32(35):4057–4063. doi: 10.1038/onc.2012.578. - DOI - PMC - PubMed

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