Inhibition of vasculogenic mimicry and angiogenesis by an anti-egfr igg1-human endostatin-p125a fusion protein reduces triple negative breast cancer metastases

Seung Uon Shin, Hyun Mi Cho, Rathin Das, Hava Gil-Henn, Sundaram Ramakrishnan, Ahmed Al Bayati, Stephen F. Carroll, Yu Zhang, Ankita P. Sankar, Christian Elledge, Augustin Pimentel, Marzenna Blonska, Joseph D. Rosenblatt

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody– endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.

Original languageEnglish
Article number2904
JournalCells
Volume10
Issue number11
DOIs
StatePublished - 27 Oct 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Funding

JDR has received funding support from the Dawn Arnall and the Roland Arnall Foundation, Morgan Pressel Foundation, Steven Dwoskin, Saul Gilinski, Bruce and Anne Rhodes, and the Sylvester Comprehensive Cancer Center. JDR has also received funding from DoD (W81XWH-11-10597, W81XWH-11-1-0598), Florida Department of Health Bankhead Coley Cancer Research Program (09BR-02). R.D. is a principal investigator, and J.D.R. and S.-U.S. are academic co-investigators on NCI/SBIR 1R43CA195882-01A1 and NIH SBIR grant 1R44 CA 265690-01A1 awarded to Synergys Biotherapeutics. MB has received support from Florida Department of Health, Bankhead-Coley Cancer Research Program: 20B14. HGH has received funding from Israel Cancer Research Fund (grant number 20-101-PG), the Israel Cancer Association (grant number 20210071), and the Israel Science Foundation (grant number 2142/21). H.G.-H. and J.D.R. have received joint funding from Professor Moshe I. Meidar, Hilit-Meidar Alfi Ph.D., Eyal Alfi, Liad Meidar.

FundersFunder number
Bankhead-Coley Cancer Research Program20B14
Dawn Arnall
Morgan Pressel Foundation
NIH SBIR1R44 CA 265690-01A1
Roland Arnall Foundation
Sylvester Comprehensive Cancer Center
U.S. Department of DefenseW81XWH-11-1-0598, W81XWH-11-10597
National Cancer Institute20210071
Israel Cancer Research Fund20-101-PG
Small Business Innovation Research1R43CA195882-01A1
Florida Department of Health09BR-02
Israel Science Foundation2142/21

    Keywords

    • EGFR
    • Endostatin
    • Triple negative breast cancer
    • Vasculogenic mimicry

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