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Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Breast Cancer | Primary research

Combined high expression of CD47 and CD68 is a novel prognostic factor for breast cancer patients

Authors: Jingping Yuan, Huihua He, Chuang Chen, Juan Wu, Jie Rao, Honglin Yan

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Avoiding the phagocytosis by tumor-associated macrophages (TAMs) is necessary for the growth and metastasis of solid tumors. CD47 binds to the receptor signal-regulatory protein-α (SIRP-α) on the macrophages to avoid normal phagocytosis. In this study, we evaluated the expression and prognostic significance of CD47 and CD68-labeled TAMs in breast cancer solid tumors.

Methods

Two hundred seventeen cases of breast cancer tissues and 40 cases of benign breast lesions were collected for immunohistochemical staining of CD47 and CD68.

Results

Both of the CD47 and CD68 expression were significantly higher in breast cancer tissues (P < 0.001), and associated with multiple clinicopathological parameters in breast cancer (P < 0.05). However, CD47 or CD68 expression alone was not an independent predictor of poor DFS in multivariate survival analysis (P > 0.05). Interestingly, combined high expression of CD47 and CD68 (CD47highCD68high) not only had a significant association with advanced TNM stage, histological grade, LNM, ER status, PR status and recurrence (P < 0.05), but also displayed a poorer 5-DFS (P = 0.011). Strikingly, CD47highCD68high served as a novel independent prognostic factor for poor DFS compared to the expression of CD47 or CD68 alone (P = 0.045). Furthermore, our study also showed for the first time that the prognostic significance of CD47highCD68high not only in breast cancer in general, but also in hormone receptor-negative breast cancer in particular.

Conclusions

Combined detection of CD47 and CD68 may provide guidance for the prognosis of breast cancer, especially hormone receptor-negative breast cancer.
Literature
2.
go back to reference Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol. 2014;15:e279–89.CrossRef Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol. 2014;15:e279–89.CrossRef
3.
go back to reference Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–8.CrossRef Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–8.CrossRef
4.
go back to reference Katheder NS, Khezri R, O’Farrell F, et al. Microenvironmental autophagy promotes tumour growth. Nature. 2017;541:417–20.CrossRef Katheder NS, Khezri R, O’Farrell F, et al. Microenvironmental autophagy promotes tumour growth. Nature. 2017;541:417–20.CrossRef
5.
go back to reference Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105:1–8.CrossRef Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105:1–8.CrossRef
6.
go back to reference Zhao X, Qu J, Sun Y, et al. Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017;8:30576–86.PubMedPubMedCentral Zhao X, Qu J, Sun Y, et al. Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017;8:30576–86.PubMedPubMedCentral
7.
go back to reference Choi J, Gyamfi J, Jang H, Koo JS. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018;33:133–45.PubMed Choi J, Gyamfi J, Jang H, Koo JS. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018;33:133–45.PubMed
8.
go back to reference Tiainen S, Tumelius R, Rilla K, et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology. 2015;66:873–83.CrossRef Tiainen S, Tumelius R, Rilla K, et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology. 2015;66:873–83.CrossRef
9.
go back to reference Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352:160–8.CrossRef Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352:160–8.CrossRef
10.
go back to reference Hollmen M, Roudnicky F, Karaman S, Detmar M. Characterization of macrophage–cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Sci Rep. 2015;5:9188.CrossRef Hollmen M, Roudnicky F, Karaman S, Detmar M. Characterization of macrophage–cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Sci Rep. 2015;5:9188.CrossRef
11.
go back to reference Feng MY, Chen JY, Weissman-Tsukamoto R, et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci USA. 2015;112:2145–50.CrossRef Feng MY, Chen JY, Weissman-Tsukamoto R, et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci USA. 2015;112:2145–50.CrossRef
12.
go back to reference Vonderheide RH. CD47 blockade as another immune checkpoint therapy for cancer. Nat Med. 2015;21:1122–3.CrossRef Vonderheide RH. CD47 blockade as another immune checkpoint therapy for cancer. Nat Med. 2015;21:1122–3.CrossRef
13.
go back to reference Zhang L, Huang H. Targeting the cancer biomarker CD47: a review on the diverse mechanisms of the CD47 pathway in cancer treatment. Anticancer Agents Med Chem. 2016;16:658–67.CrossRef Zhang L, Huang H. Targeting the cancer biomarker CD47: a review on the diverse mechanisms of the CD47 pathway in cancer treatment. Anticancer Agents Med Chem. 2016;16:658–67.CrossRef
14.
go back to reference Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142:699–713.CrossRef Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142:699–713.CrossRef
15.
go back to reference Chao MP, Alizadeh AA, Tang C, et al. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Can Res. 2011;71:1374–84.CrossRef Chao MP, Alizadeh AA, Tang C, et al. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Can Res. 2011;71:1374–84.CrossRef
16.
go back to reference Chan KS, Espinosa I, Chao M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA. 2009;106:14016–21.CrossRef Chan KS, Espinosa I, Chao M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA. 2009;106:14016–21.CrossRef
17.
go back to reference Baccelli I, Stenzinger A, Vogel V, et al. Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients. Oncotarget. 2014;5:8147–60.CrossRef Baccelli I, Stenzinger A, Vogel V, et al. Co-expression of MET and CD47 is a novel prognosticator for survival of luminal-type breast cancer patients. Oncotarget. 2014;5:8147–60.CrossRef
18.
go back to reference Kim D, Wang J, Willingham SB, et al. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia. 2012;26:2538–45.CrossRef Kim D, Wang J, Willingham SB, et al. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia. 2012;26:2538–45.CrossRef
19.
go back to reference Xiao Z, Chung H, Banan B, et al. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett. 2015;360:302–9.CrossRef Xiao Z, Chung H, Banan B, et al. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett. 2015;360:302–9.CrossRef
20.
go back to reference Casey SC, Tong L, Li YL, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352:227–31.CrossRef Casey SC, Tong L, Li YL, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352:227–31.CrossRef
21.
go back to reference McCracken MN, Cha AC, Weissman IL. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “Don’t Eat Me” signals. Clin Cancer Res. 2015;21:3597–601.CrossRef McCracken MN, Cha AC, Weissman IL. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “Don’t Eat Me” signals. Clin Cancer Res. 2015;21:3597–601.CrossRef
22.
go back to reference Nagahara M, Mimori K, Kataoka A, et al. Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res. 2010;16:4625–35.CrossRef Nagahara M, Mimori K, Kataoka A, et al. Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res. 2010;16:4625–35.CrossRef
23.
go back to reference Willingham SB, Volkmer JP, Gentles AJ, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA. 2012;109:6662–7.CrossRef Willingham SB, Volkmer JP, Gentles AJ, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA. 2012;109:6662–7.CrossRef
24.
go back to reference Yoshida K, Tsujimoto H, Matsumura K, et al. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med. 2015;4:1322–33.CrossRef Yoshida K, Tsujimoto H, Matsumura K, et al. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med. 2015;4:1322–33.CrossRef
25.
go back to reference Baccelli I, Schneeweiss A, Riethdorf S, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–44.CrossRef Baccelli I, Schneeweiss A, Riethdorf S, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–44.CrossRef
26.
go back to reference Bener G, Felix AJ, Sanchez de Diego C, et al. Silencing of CD47 and SIRPalpha by polypurine reverse Hoogsteen hairpins to promote MCF-7 breast cancer cells death by PMA-differentiated THP-1 cells. BMC Immunol. 2016;17:32.CrossRef Bener G, Felix AJ, Sanchez de Diego C, et al. Silencing of CD47 and SIRPalpha by polypurine reverse Hoogsteen hairpins to promote MCF-7 breast cancer cells death by PMA-differentiated THP-1 cells. BMC Immunol. 2016;17:32.CrossRef
27.
go back to reference Kaur S, Elkahloun AG, Singh SP, et al. A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget. 2016;7:10133–52.CrossRef Kaur S, Elkahloun AG, Singh SP, et al. A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget. 2016;7:10133–52.CrossRef
28.
go back to reference Manna PP, Frazier WA. CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res. 2004;64:1026–36.CrossRef Manna PP, Frazier WA. CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res. 2004;64:1026–36.CrossRef
29.
go back to reference Zhang H, Lu H, Xiang L, et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci USA. 2015;112:E6215–23.CrossRef Zhang H, Lu H, Xiang L, et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci USA. 2015;112:E6215–23.CrossRef
30.
go back to reference Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254–65.CrossRef Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254–65.CrossRef
31.
go back to reference Volodko N, Reiner A, Rudas M, Jakesz R. Tumour-associated macrophages in breast cancer and their prognostic correlations. Breast. 1998;7:99–105.CrossRef Volodko N, Reiner A, Rudas M, Jakesz R. Tumour-associated macrophages in breast cancer and their prognostic correlations. Breast. 1998;7:99–105.CrossRef
32.
go back to reference Koelzer VH, Canonica K, Dawson H, et al. Phenotyping of tumor-associated macrophages in colorectal cancer: impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology. 2016;5:e1106677.CrossRef Koelzer VH, Canonica K, Dawson H, et al. Phenotyping of tumor-associated macrophages in colorectal cancer: impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology. 2016;5:e1106677.CrossRef
33.
go back to reference Jaiswal S, Chao MP, Majeti R, Weissman IL. Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 2010;31:212–9.CrossRef Jaiswal S, Chao MP, Majeti R, Weissman IL. Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 2010;31:212–9.CrossRef
34.
go back to reference Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006;1:119–50.CrossRef Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006;1:119–50.CrossRef
35.
go back to reference Zaha DC, Lazar E, Lazureanu C. Clinicopathologic features and five years survival analysis in molecular subtypes of breast cancer. Rom J Morphol Embryol. 2010;51:85–9.PubMed Zaha DC, Lazar E, Lazureanu C. Clinicopathologic features and five years survival analysis in molecular subtypes of breast cancer. Rom J Morphol Embryol. 2010;51:85–9.PubMed
36.
go back to reference Denkert C. The immunogenicity of breast cancer–molecular subtypes matter. Ann Oncol. 2014;25:1453–5.CrossRef Denkert C. The immunogenicity of breast cancer–molecular subtypes matter. Ann Oncol. 2014;25:1453–5.CrossRef
37.
go back to reference Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.CrossRef Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.CrossRef
38.
go back to reference Junker A, Krumbholz M, Eisele S, et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 2009;132:3342–52.CrossRef Junker A, Krumbholz M, Eisele S, et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 2009;132:3342–52.CrossRef
39.
go back to reference Tang W, Qin J, Tang J, et al. Aberrant reduction of MiR-141 increased CD47/CUL3 in Hirschsprung’s disease. Cell Physiol Biochem. 2013;32:1655–67.CrossRef Tang W, Qin J, Tang J, et al. Aberrant reduction of MiR-141 increased CD47/CUL3 in Hirschsprung’s disease. Cell Physiol Biochem. 2013;32:1655–67.CrossRef
40.
go back to reference Suzuki S, Yokobori T, Tanaka N, et al. CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma. Oncol Rep. 2012;28:465–72.CrossRef Suzuki S, Yokobori T, Tanaka N, et al. CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma. Oncol Rep. 2012;28:465–72.CrossRef
41.
go back to reference Noman MZ, Van Moer K, Marani V, et al. CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT. Oncoimmunology. 2018;7:e1345415.CrossRef Noman MZ, Van Moer K, Marani V, et al. CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT. Oncoimmunology. 2018;7:e1345415.CrossRef
Metadata
Title
Combined high expression of CD47 and CD68 is a novel prognostic factor for breast cancer patients
Authors
Jingping Yuan
Huihua He
Chuang Chen
Juan Wu
Jie Rao
Honglin Yan
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0957-0

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