Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	EGFR endostatin vasculogenic mimicry triple negative breast cancer Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d368352d13854fed8120ade6326d597c
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spelling	oai:doaj.org-article:d368352d13854fed8120ade6326d597c2021-11-25T17:08:45ZInhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases10.3390/cells101129042073-4409https://doaj.org/article/d368352d13854fed8120ade6326d597c2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2904https://doaj.org/toc/2073-4409Triple 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.Seung-Uon ShinHyun-Mi ChoRathin DasHava Gil-HennSundaram RamakrishnanAhmed Al BayatiStephen F. CarrollYu ZhangAnkita P. SankarChristian ElledgeAugustin PimentelMarzenna BlonskaJoseph D. RosenblattMDPI AGarticleEGFRendostatinvasculogenic mimicrytriple negative breast cancerBiology (General)QH301-705.5ENCells, Vol 10, Iss 2904, p 2904 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGFR endostatin vasculogenic mimicry triple negative breast cancer Biology (General) QH301-705.5
spellingShingle	EGFR endostatin vasculogenic mimicry triple negative breast cancer Biology (General) QH301-705.5 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 Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
description	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.
format	article
author	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
author_facet	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
author_sort	Seung-Uon Shin
title	Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
title_short	Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
title_full	Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
title_fullStr	Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
title_full_unstemmed	Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
title_sort	inhibition of vasculogenic mimicry and angiogenesis by an anti-egfr igg1-human endostatin-p125a fusion protein reduces triple negative breast cancer metastases
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d368352d13854fed8120ade6326d597c
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Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases

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