Department of Medical Pharmacology and SBAUM, School of Medicine, Akdeniz University, Antalya, Turkey.
Breast Cancer Res Treat. 2013 Jun;139(3):677-89. doi: 10.1007/s10549-013-2584-0. Epub 2013 Jun 13.
Breast carcinoma is comprised of heterogeneous groups of cells with different metastatic potential. To develop effective therapeutic strategies targeting metastatic disease, it is crucial to understand the characteristics of breast cancer cells that enable metastasis to distant organs. 4THM breast carcinoma cells are the cells of 4T1 primary tumors that metastasized to the heart. Cells of 4THM tumors which metastasized to liver (4TLM) were previously isolated. Recently macroscopic brain metastasis in 4THM injected animals, were isolated to obtain a brain metastatic cell line (4TBM). Using an orthotopic mouse model differential characteristic of cells metastasized to heart (4THM), liver (4TLM), and brain (4TBM) were compared for ability to metastasize and expression of stem cell markers. We found that 4TLM cells produced significantly more lung and liver metastasis compared to 4TBM and 4THM cells. In vitro, proliferation as well as migration rate of 4TLM cells was also significantly higher than the other cell lines. Remarkably primary tumors formed by 4TLM cells expressed significant amounts of CD34, a marker for mesenchymal malignancies. Markers of epithelial-mesenchymal transition were expressed in all metastatic cells, but the degree of expression differed. Majorities of 4TLM, 4THM, and 4TBM cells were CD44+ CD24- whereas, 12 % of 4TLM cells also expressed membranous CD24. Conditioned mediums of non-metastatic 67NR breast tumors and cancer-associated fibroblasts inhibited growth of highly metastatic 4TLM cells. Malignant cells metastasized to brain were distinguished by membranous E-cadherin expression that was markedly higher in 4TBM cells grown as spheroids suggesting E-cadherin is required for brain metastasis. Differential features of heart, brain, and liver metastatic cells in a syngenic model was shown in this study for the first time. These findings not only provide a model to explore new treatment modalities, but also demonstrate differential features of cancer cells that originally homed to a certain organ, such as liver or brain.
乳腺癌由具有不同转移潜能的异质性细胞群组成。为了开发针对转移性疾病的有效治疗策略，了解使癌细胞转移到远处器官的特征至关重要。4THM 乳腺癌细胞是转移到心脏的 4T1 原发肿瘤的细胞。先前已经分离出转移到肝脏的 4THM 肿瘤（4TLM）的细胞。最近，在注射 4THM 的动物中发现了宏观脑转移，从而获得了脑转移细胞系（4TBM）。使用同源小鼠模型，比较了转移到心脏（4THM）、肝脏（4TLM）和大脑（4TBM）的细胞的差异特征，以评估其转移能力和干细胞标志物的表达。我们发现，与 4TBM 和 4THM 细胞相比，4TLM 细胞产生的肺和肝转移明显更多。在体外，4TLM 细胞的增殖和迁移率也明显高于其他细胞系。值得注意的是，由 4TLM 细胞形成的原发性肿瘤表达了大量的 CD34，这是间充质恶性肿瘤的标志物。上皮-间充质转化标志物在所有转移性细胞中均有表达，但表达程度不同。大多数 4TLM、4THM 和 4TBM 细胞均为 CD44+CD24-，而 4TLM 细胞中有 12%也表达膜性 CD24。非转移性 67NR 乳腺癌肿瘤和癌相关成纤维细胞的条件培养基抑制了高度转移性 4TLM 细胞的生长。转移到大脑的恶性细胞通过膜性 E-钙黏蛋白的表达来区分，该表达在作为球体生长的 4TBM 细胞中明显更高，表明 E-钙黏蛋白是脑转移所必需的。在同种型模型中首次显示了心脏、大脑和肝脏转移性细胞的差异特征。这些发现不仅为探索新的治疗方式提供了模型，而且还证明了最初归巢到特定器官（如肝脏或大脑）的癌细胞的差异特征。
