Pio Graciella M, Xia Ying, Piaseczny Matthew M, Chu Jenny E, Allan Alison L
Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western University, London, ON, Canada.
London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada.
PLoS One. 2017 May 12;12(5):e0177640. doi: 10.1371/journal.pone.0177640. eCollection 2017.
Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44+CD24- phenotype. In the current study, we tested the hypothesis that these ALDHhiCD44+CD24- breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDHhiCD44+CD24- breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p≤0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p≤0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases.
乳腺癌是女性癌症死亡的主要原因，其中大多数死亡是由癌细胞转移至远处器官所致。乳腺癌最常见的转移部位是骨骼，研究表明，骨骼能提供丰富的微环境，支持乳腺癌细胞的迁移和生长。此外，越来越多的证据表明，成功转移的乳腺癌细胞具有干细胞样表型，包括醛脱氢酶（ALDH）活性高和/或CD44+CD24-表型。在本研究中，我们验证了一个假设，即这些ALDH高表达CD44+CD24-乳腺癌细胞与骨继发性器官微环境中的因子相互作用，以促进转移。具体而言，我们聚焦于骨源性骨桥蛋白及其促进乳腺癌细胞迁移和干细胞样表型的能力。我们的结果表明，在骨髓条件培养基（骨微环境的一种体外模型）中，骨源性骨桥蛋白可促进全部乳腺癌细胞以及ALDH高表达CD44+CD24-乳腺癌细胞的迁移、肿瘤球形成能力和集落形成能力（p≤0.05）。我们还证明，CD44和RGD依赖性细胞表面整合素可促进对骨源性骨桥蛋白的这种功能反应（p≤0.05），可能是通过激活WNK-1和PRAS40相关通路实现的。我们的研究结果表明，可溶性骨源性骨桥蛋白可增强乳腺癌细胞迁移至骨骼并在骨微环境中维持干细胞样表型的能力，这可能有助于骨转移瘤的形成和生长。
