Lee Hyunsook, Kang Kyu-Tae
Department of Pharmacy, College of Pharmacy, Duksung Women's University, Seoul, Korea.
Duksung Innovative Drug Center, Duksung Women's University, Seoul, Korea.
J Lipid Atheroscler. 2021 Jan;10(1):111-122. doi: 10.12997/jla.2021.10.1.111. Epub 2021 Jan 18.
Triple negative breast cancer (TNBC) is one subtype of breast cancer. It is characterized by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Compared with non-TNBC, TNBC is more aggressive, of higher grade, and frequently metastatic with poor prognosis, which is correlated with upregulated microvascular density. Endothelial colony-forming cells (ECFCs) mediate neovascularization, which is the crucial contributor to cancer growth and metastasis. The present study aimed to determine whether angiogenic responses of ECFCs are regulated differently by TNBC compared with non-TNBC.
MDA-MB-231 and MCF7 cells were utilized for TNBC and non-TNBC, respectively. Bone-marrow-derived human ECFCs were treated with a conditioned medium (CM) of cancer cells to investigate the paracrine effect on angiogenesis. Also, ECFCs were co-cultured with cancer cells to evaluate the angiogenic effect of direct cell-to-cell interaction. Angiogenic responses of ECFCs were evaluated by proliferation, migration, and tube formation. Gene expression profiles of pro-angiogenic factors were also analyzed.
Migration and tube formation of ECFCs were increased by treatment with CM of MDA-MB-231, which correlated with a higher gene expression profile of pro-angiogenic factors in MDA-MB-231 compared to MCF7. Interestingly, ECFCs co-cultured with MDA-MB-231 showed further increase of tube formation, suggesting synergic mechanisms between the paracrine effect and direct interaction between the cells.
The angiogenic potential of ECFCs was enhanced by TNBC through both direct and indirect mechanisms. Therefore, the investigation of signaling pathways to regulate ECFC-mediated angiogenesis will be important to the discovery of anti-angiogenic therapies to treat TNBC patients.
三阴性乳腺癌（TNBC）是乳腺癌的一种亚型。其特征是缺乏雌激素受体、孕激素受体和人表皮生长因子受体2。与非三阴性乳腺癌相比，三阴性乳腺癌侵袭性更强、分级更高，且常发生转移，预后较差，这与微血管密度上调有关。内皮祖细胞（ECFCs）介导新血管形成，这是癌症生长和转移的关键因素。本研究旨在确定与非三阴性乳腺癌相比，三阴性乳腺癌对ECFCs血管生成反应的调节是否不同。
分别使用MDA-MB-231和MCF7细胞代表三阴性乳腺癌和非三阴性乳腺癌。用癌细胞条件培养基（CM）处理骨髓来源的人ECFCs，以研究其对血管生成的旁分泌作用。此外，将ECFCs与癌细胞共培养，以评估细胞间直接相互作用的血管生成作用。通过增殖、迁移和管腔形成评估ECFCs的血管生成反应。还分析了促血管生成因子的基因表达谱。
用MDA-MB-231的CM处理可增加ECFCs的迁移和管腔形成，这与MDA-MB-231中促血管生成因子的基因表达谱高于MCF7相关。有趣的是，与MDA-MB-231共培养的ECFCs管腔形成进一步增加，表明旁分泌作用与细胞间直接相互作用之间存在协同机制。
三阴性乳腺癌通过直接和间接机制增强了ECFCs的血管生成潜力。因此，研究调节ECFCs介导的血管生成的信号通路对于发现治疗三阴性乳腺癌患者的抗血管生成疗法具有重要意义。
