Format

Send to

Choose Destination
Breast Cancer Res Treat. 2018 Nov;172(1):69-82. doi: 10.1007/s10549-018-4884-x. Epub 2018 Jul 28.

Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy.

Author information

1
Department of Surgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
2
Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
3
Internal Medicine, Section on Cardiovascular Medicine, Pathology Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
4
Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
5
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
6
Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
7
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA.
8
Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
9
Department of Surgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA. dsotopan@wakehealth.edu.
10
Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. dsotopan@wakehealth.edu.
11
Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. dsotopan@wakehealth.edu.
12
Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. dsotopan@wakehealth.edu.

Abstract

BACKGROUND:

A perennial challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues. The protection of cell viability observed with CD47 is mediated autonomously by activation of protective autophagy. However, whether CD47 protects cancer cells from cytotoxic chemotherapy is unknown.

METHODS:

We tested the effect of CD47 blockade on cancer cell survival using a 2-dimensional high-throughput cell proliferation assay in 4T1 breast cancer cell lines. To evaluate blockade of CD47 in combination with chemotherapy in vivo, we employed the 4T1 breast cancer model and examined tumor and cardiac tissue viability as well as autophagic flux.

RESULTS:

Our high-throughput screen revealed that blockade of CD47 does not interfere with the cytotoxic activity of anthracyclines against 4T1 breast cancer cells. Targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an anti-tumor innate immune response. Moreover, systemic suppression of CD47 protected cardiac tissue viability and function in mice treated with doxorubicin.

CONCLUSIONS:

Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, the absence of CD47 in did not elicit a protective effect in cancer cells, but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells.

KEYWORDS:

Autophagy; Breast cancer; CD47; Cardio-oncology; Cytoprotection

PMID:
30056566
PMCID:
PMC6195817
[Available on 2019-11-01]
DOI:
10.1007/s10549-018-4884-x
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center