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28.07.2018 | Preclinical study

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

verfasst von: Yismeilin R. Feliz-Mosquea, Ashley A. Christensen, Adam S. Wilson, Brian Westwood, Jasmina Varagic, Giselle C. Meléndez, Anthony L. Schwartz, Qing-Rong Chen, Lesley Mathews Griner, Rajarshi Guha, Craig J. Thomas, Marc Ferrer, Maria J. Merino, Katherine L. Cook, David D. Roberts, David R. Soto-Pantoja

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2018

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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.

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Titel: Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy
verfasst von: Yismeilin R. Feliz-Mosquea
Ashley A. Christensen
Adam S. Wilson
Brian Westwood
Jasmina Varagic
Giselle C. Meléndez
Anthony L. Schwartz
Qing-Rong Chen
Lesley Mathews Griner
Rajarshi Guha
Craig J. Thomas
Marc Ferrer
Maria J. Merino
Katherine L. Cook
David D. Roberts
David R. Soto-Pantoja
Publikationsdatum: 28.07.2018
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4884-x

Neu im Fachgebiet Onkologie

25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

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

Abstract

Background

Methods

Results

Conclusions

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Springer Medizin

Abstract

Background

Methods

Results

Conclusions

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