Department of Medicine, Section of Haematology and Medical Oncology, Tulane University Health Science Centre, New Orleans, Louisiana, USA.
Mol Cancer. 2010 Nov 18;9:295. doi: 10.1186/1476-4598-9-295.
Adult human mesenchymal stem cells (hMSC) have been shown to home to sites of carcinoma and affect biological processes, including tumour growth and metastasis. Previous findings have been conflicting and a clear understanding of the effects of hMSCs on cancer remains to be established. Therefore, we set out to investigate the impact of hMSCs on the oestrogen receptor positive, hormone-dependent breast carcinoma cell line MCF-7.
In this study, we show the effects of hMSCs on cancer cells are mediated through a secreted factor(s) which are enhanced by cancer cell-hMSC contact/communication. In addition to enhanced proliferation when in co-culture with hMSCs, MCF-7 cells were found to have increased migration potential in vitro. Inhibition of ER signalling by the pure anti-oestrogen ICI 182,780 decreased the effect of hMSCs on MCF-7 cell proliferation and migration supporting a role for ER signalling in the hMSC/MCF-7 cell interaction. Additionally, hMSCs have been shown to secrete a wide variety of growth factors and chemokines including stromal cell-derived factor-1 (SDF-1). This coupled with the knowledge that SDF-1 is an ER-mediated gene linked with hormone-independence and metastasis led to the investigation of the SDF-1/CXCR4 signalling axis in hMSC-MCF-7 cell interaction. Experiments revealed an increase in SDF-1 gene expression both in vivo and in vitro when MCF-7 cells were cultured with hMSCs. SDF-1 treatment of MCF-7 cells alone increased proliferation to just below that seen with hMSC co-culture. Additionally, blocking SDF-1 signalling using a CXCR4-specific inhibitor decreased hMSC induced proliferation and migration of MCF-7. However, the combined treatment of ICI and AMD3100 reduced MCF-7 cell proliferation and migration below control levels, indicating targeting both the ER and CXCR4 pathways is effective in decreasing the hMSCs induction of MCF-7 cell proliferation and migration.
The sum of these data reveals the relationship between tumour microenvironment and tumour growth and progression. Better understanding of the mechanisms involved in this tumour stroma cell interaction may provide novel targets for the development of treatment strategies for oestrogen receptor positive, hormone-independent, and endocrine-resistant breast carcinoma.
成人间充质干细胞（hMSC）已被证明能归巢至癌组织并影响生物学过程，包括肿瘤生长和转移。先前的研究结果存在冲突，因此需要进一步明确 hMSC 对癌症的影响。因此，我们研究了 hMSC 对雌激素受体阳性、激素依赖性乳腺癌细胞系 MCF-7 的影响。
在这项研究中，我们发现 hMSC 对癌细胞的影响是通过一种分泌因子（s）介导的，这种因子是由癌细胞与 hMSC 的接触/通讯增强的。与 hMSC 共培养时，MCF-7 细胞除了增殖增强外，还具有更强的体外迁移潜力。纯抗雌激素 ICI 182,780 抑制 ER 信号转导，降低了 hMSC 对 MCF-7 细胞增殖和迁移的影响，支持 ER 信号转导在 hMSC/MCF-7 细胞相互作用中的作用。此外，hMSC 已被证明能分泌多种生长因子和趋化因子，包括基质细胞衍生因子-1（SDF-1）。考虑到 SDF-1 是一种与激素不依赖和转移相关的 ER 介导基因，这与 SDF-1/CXCR4 信号轴在 hMSC-MCF-7 细胞相互作用中的作用有关。实验发现，当 MCF-7 细胞与 hMSC 共培养时，SDF-1 基因在体内和体外的表达均增加。单独用 SDF-1 处理 MCF-7 细胞，其增殖作用仅略低于与 hMSC 共培养的水平。此外，使用 CXCR4 特异性抑制剂阻断 SDF-1 信号转导，可降低 hMSC 诱导的 MCF-7 增殖和迁移。然而，联合使用 ICI 和 AMD3100 可将 MCF-7 细胞的增殖和迁移降低至对照水平以下，这表明同时靶向 ER 和 CXCR4 通路可有效抑制 hMSC 诱导的 MCF-7 细胞增殖和迁移。
这些数据表明了肿瘤微环境与肿瘤生长和进展之间的关系。更好地理解这种肿瘤基质细胞相互作用中的机制，可能为开发针对雌激素受体阳性、激素非依赖性和内分泌耐药性乳腺癌的治疗策略提供新的靶点。
