Eileen Shiuan1,2, Ashwin Inala1, Shan Wang3,4, Wenqiang Song3,4, Victoria Youngblood5, Jin Chen3,4,6,7, Dana M Brantley-Sieders4,6. 1. Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA. 2. Medical Scientist Training Program, Vanderbilt University, Nashville, TN, 37232, USA. 3. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN, 37212, USA. 4. Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 5. School of Nursing, Duke University, Durham, NC, 27710, USA. 6. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. 7. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
Abstract
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. Copyright:
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-A1host 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-A1impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies. Copyright:
Authors: Steven Daniel Funk; Alexandra C Finney; Arif Yurdagul; Christopher B Pattillo; A Wayne Orr Journal: Cell Signal Date: 2018-05-21 Impact factor: 4.315
Authors: Dana M Brantley-Sieders; Wei Bin Fang; Donna J Hicks; Guanglei Zhuang; Yu Shyr; Jin Chen Journal: FASEB J Date: 2005-09-15 Impact factor: 5.191
Authors: Natasha L Friend; Duncan R Hewett; Vasilios Panagopoulos; Jacqueline E Noll; Kate Vandyke; Krzysztof M Mrozik; Stephen Fitter; Andrew C W Zannettino Journal: FASEB Bioadv Date: 2020-08-05