Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (H.G.R., M.W.M., E.M.C., S.A.M., P.L.K., E.M.B.).
Harvard Medical School, Boston, MA (H.G.R., I.C.B., P.L.K., I.A., A.A.S., E.M.B.).
Arterioscler Thromb Vasc Biol. 2024 Sep;44(9):2024-2037. doi: 10.1161/ATVBAHA.124.321189. Epub 2024 Jul 25.
In addition to their fundamental roles in preserving vascular integrity, platelets also contribute to tumor angiogenesis and metastasis. However, despite being a reservoir for angiogenic and metastatic cytokines, platelets also harbor negative regulators of tumor progression. Angpt1 (angiopoietin-1) is a cytokine essential for developmental angiogenesis that also protects against tumor cell metastasis through an undefined mechanism. Although activated platelets release Angpt1 from α-granules into circulation, the contributions of platelet Angpt1 to tumor growth, angiogenesis, and metastasis have not been investigated.
Using cytokine arrays and ELISAs, we first compared platelet Angpt1 levels in breast and melanoma mouse tumor models to tumor-free controls. We then assessed tumor growth and metastasis in mice lacking megakaryocyte and platelet Angpt1 (Angpt1). The spontaneous metastasis of mammary-injected tumor cells to the lungs was quantified using RT-PCR (reverse transcription-polymerase chain reaction). The lung colonization of intravenously injected tumor cells and tumor cell extravasation were determined using fluorescent microscopy and flow cytometry.
Platelet Angpt1 is selectively upregulated in the PyMT (polyoma middle tumor antigen) breast cancer mouse model, and platelets are the principal source of Angpt1 in blood circulation. While primary tumor growth and angiogenesis were unaffected, Angpt1 mice had both increased spontaneous lung metastasis and tumor cell lung colonization following mammary or intravenous injection, respectively. Although platelet Angpt1 did not affect initial tumor cell entrapment in the lungs, Angpt1 mice had increased tumor cell retention and extravasation. Serum from Angpt1 mice increased endothelial permeability and reduced VE (vascular endothelial)-cadherin expression at endothelial junctions compared with serum from control mice (Angpt1).
Platelets provide an intravascular source of Angpt1 that restrains tumor metastasis by preserving the lung microvasculature to limit tumor cell extravasation.
血小板除了在维持血管完整性方面发挥基本作用外，还促进肿瘤血管生成和转移。然而，尽管血小板是血管生成和转移细胞因子的储存库，但它们也含有肿瘤进展的负调控因子。Angpt1（血管生成素 1）是一种对发育血管生成至关重要的细胞因子，它通过未定义的机制防止肿瘤细胞转移。尽管激活的血小板将 Angpt1 从α-颗粒释放到循环中，但血小板 Angpt1 对肿瘤生长、血管生成和转移的贡献尚未被研究。
我们首先使用细胞因子阵列和 ELISA 比较了乳腺癌和黑色素瘤小鼠肿瘤模型与无肿瘤对照的血小板 Angpt1 水平。然后，我们评估了缺乏巨核细胞和血小板 Angpt1（Angpt1）的小鼠的肿瘤生长和转移。通过 RT-PCR（逆转录-聚合酶链反应）定量测量乳腺注射肿瘤细胞的自发性转移到肺部。通过荧光显微镜和流式细胞术确定静脉注射肿瘤细胞的肺定植和肿瘤细胞的血管外渗。
血小板 Angpt1 在 PyMT（多瘤中瘤抗原）乳腺癌小鼠模型中选择性地上调，血小板是血液循环中 Angpt1 的主要来源。虽然原发性肿瘤生长和血管生成不受影响，但 Angpt1 小鼠在乳腺或静脉注射后分别出现自发性肺转移和肿瘤细胞肺定植增加。虽然血小板 Angpt1 不影响初始肿瘤细胞在肺部的捕获，但 Angpt1 小鼠的肿瘤细胞保留和血管外渗增加。与对照小鼠（Angpt1）的血清相比，Angpt1 小鼠的血清增加了内皮通透性并降低了血管内皮钙黏蛋白在血管内皮连接处的表达。
血小板提供了 Angpt1 的血管内来源，通过维持肺微血管来限制肿瘤细胞的血管外渗，从而抑制肿瘤转移。
