Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been show...

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Main Authors: Eileen Shiuan, Ashwin Inala, Shan Wang, Wenqiang Song, Victoria Youngblood, Jin Chen, Dana M. Brantley-Sieders
Format: Article
Language:English
Published: F1000 Research Ltd 2020-03-01
Series:F1000Research
Online Access:https://f1000research.com/articles/9-217/v1
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spelling doaj-d77f234c236642d4b20c33c4c9dc82702020-11-25T03:56:13ZengF1000 Research LtdF1000Research2046-14022020-03-01910.12688/f1000research.22689.125051Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]Eileen Shiuan0Ashwin Inala1Shan Wang2Wenqiang Song3Victoria Youngblood4Jin Chen5Dana M. Brantley-Sieders6Medical Scientist Training Program, Vanderbilt University, Nashville, TN, 37232, USAProgram in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USAVeterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, 37212, USAVeterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, 37212, USASchool of Nursing, Duke University, Durham, NC, 27710, USADivision of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USADivision of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USABackground: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.https://f1000research.com/articles/9-217/v1
collection DOAJ
language English
format Article
sources DOAJ
author Eileen Shiuan
Ashwin Inala
Shan Wang
Wenqiang Song
Victoria Youngblood
Jin Chen
Dana M. Brantley-Sieders
spellingShingle Eileen Shiuan
Ashwin Inala
Shan Wang
Wenqiang Song
Victoria Youngblood
Jin Chen
Dana M. Brantley-Sieders
Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
F1000Research
author_facet Eileen Shiuan
Ashwin Inala
Shan Wang
Wenqiang Song
Victoria Youngblood
Jin Chen
Dana M. Brantley-Sieders
author_sort Eileen Shiuan
title Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
title_short Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
title_full Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
title_fullStr Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
title_full_unstemmed Host deficiency in ephrin-A1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
title_sort host deficiency in ephrin-a1 inhibits breast cancer metastasis [version 1; peer review: 2 approved]
publisher F1000 Research Ltd
series F1000Research
issn 2046-1402
publishDate 2020-03-01
description Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.
url https://f1000research.com/articles/9-217/v1
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