人胚胎干细胞来源的内皮细胞对乳腺癌肺转移灶形成的抑制作用

Pulmonary metastasis is one of the most important causes of death of breast cancer patients. Gene therapy provides new chances for these patients, and it is most important to choose the appropriate cellular vehicles. In our preliminary research, we found that after intravenous injection, human embryonic stem cell-derived endothelial cells (hESC-ECs) can aggregate at the pulmonary metastases of breast cancer, and inhibit the formation of macrometastases. In this project, we plan to investigate the mechanism of the inhibition effects of hESC-ECs on the formation of lung metastases of breast cancer. First, through animal experiments and 3-D model, we plan to demonstrate that hESC-ECs can inhibit the colonization of breast cancer cells in lung, thus inhibiting the formation of macrometastases. Second, via investigating the proportion of breast cancer stem cells and carrying out functional experiments, we can prove the inhibition of hESC-ECs on the stemness of breast cancer cells, which lead to the prevention of colonization. Third, we will also analyze the molecular mechanism of the inhibition effects of breast cancer stemness by hESC-ECs. The predicted outcome of this project will provide scientific evidences for the usage of hESC-ECs as gene therapy vehicles in breast cancer pulmonary metastasis, and also supply new approaches for the treatment of metastatic breast cancer.

肺转移目前已成为乳腺癌患者的重要死因。基因治疗为这部分患者提供了新的可能，而选择一种合适的细胞载体尤为关键。我们通过前期研究已证明：人胚胎干细胞来源的内皮细胞（hESC-ECs）经静脉注射后能够富集于乳腺癌肺转移灶，且对宏观转移灶的形成起到明显的抑制作用。本项目拟在此基础上，探讨hESC-ECs对乳腺癌肺转移灶的形成发挥抑制作用的深层机制：⑴在动物水平上和体外三维培养条件下，证明hESC-ECs能够抑制乳腺癌细胞在肺部的克隆形成能力，从而抑制肺部转移灶的形成；⑵通过检测乳腺癌干细胞的比例和功能性实验，证明hESC-ECs能够抑制乳腺癌细胞干性，进而抑制其在肺部的克隆形成能力；⑶ 分析明确hESC-ECs抑制乳腺癌细胞干性的具体分子机制。本项目将为hESC-ECs作为乳腺癌肺转移基因治疗载体提供进一步的科学依据，为制订转移性乳腺癌的治疗策略提供新思路。

在本项目中，我们探讨了：⑴ 人胚胎干细胞来源的内皮细胞（hESC-ECs）对乳腺癌细胞在肺部转移灶的影响；⑵ hESC-ECs对乳腺癌细胞干性的影响；⑶ 分析明确hESC-ECs抑制乳腺癌细胞干性的具体分子机制。我们的工作揭示：人胚胎干细胞来源的内皮细胞（hESC-ECs）能够通过抑制乳腺癌细胞的干性，进而显著抑制共注射的乳腺癌细胞在小鼠肺部形成转移灶的能力；并发现hESC-ECs和乳腺癌细胞进行共培养后乳腺癌细胞中干细胞相关分子ID家族蛋白（Inhibitor of DNA binding proteins）的表达水平得到明显下调，且一系列参与胆固醇合成的酶的表达水平均存在不同程度的下调。本项目证明人胚胎干细胞来源的内皮细胞 hESC-ECs 能够抑制乳腺癌肺转移灶形成，为未来hESC-ECs作为乳腺癌肺转移基因治疗载体走向临床应用提供了更多的科学依据。