Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.
Medical Scientist Training Program, Vanderbilt University, Nashville, TN, 37232, USA.
F1000Res. 2020 Mar 30;9:217. doi: 10.12688/f1000research.22689.2. eCollection 2020.
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. 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type ( ), heterozygous ( ), or knockout ( ) 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. While primary tumor growth did not differ between , , and mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. mice had reduced lung colonization of 4T1 cells compared to littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in mice had reduced proliferation compared to those in controls. 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.
传统上治疗癌症的方法是专注于消除肿瘤细胞，而最近这一方法被进一步细化，纳入了对肿瘤微环境的考虑，其中包括宿主基质细胞。Ephrin-A1 是一种参与黏附和迁移的细胞表面蛋白，已被证明在癌细胞中具有肿瘤抑制作用。然而，其在宿主中的作用尚未得到充分研究。在这里，我们研究了 Ephrin-A1 宿主缺失如何影响乳腺癌小鼠模型中的癌症生长和转移。将 4T1 细胞原位植入乳腺脂肪垫或尾静脉注射到 Ephrin-A1 野生型（）、杂合型（）或敲除型（）小鼠体内。测量肿瘤生长、肺转移和手术后肿瘤复发情况。流式细胞术和免疫组织化学（IHC）用于分析原发肿瘤和荷瘤肺中的各种细胞群体。尽管 Ephrin-A1 缺失对肿瘤生长没有影响，但原发性肿瘤复发和肺转移明显减少。敲除型小鼠比野生型对照在尾静脉注射后 24 小时就减少了 4T1 细胞在肺中的定植。此外，与野生型对照相比，Ephrin-A1 缺失型小鼠的肺转移灶中肿瘤细胞增殖减少。我们的研究表明，Ephrin-A1 宿主缺失不会影响原发性肿瘤的生长，但会通过为癌细胞定植和生长提供不利的转移环境来影响转移。阐明宿主 Ephrin-A1 影响癌症复发和转移的机制可能为新的治疗策略提供新的思路。
