Denoyer Delphine, Kusuma Nicole, Burrows Allan, Ling Xiawei, Jupp Lara, Anderson Robin L, Pouliot Normand
Metastasis Research Laboratory, Peter MacCallum Cancer Centre , Melbourne, VIC , Australia .
Growth Factors. 2014 Apr;32(2):63-73. doi: 10.3109/08977194.2014.894037. Epub 2014 Mar 6.
Tumor intrinsic and extrinsic factors are thought to contribute to bone metastasis but little is known about how they cooperate to promote breast cancer spread to bone. We used the bone-metastatic 4T1BM2 mammary carcinoma model to investigate the cooperative interactions between tumor LM-511 and bone-derived soluble factors in vitro. We show that bone conditioned medium cooperates with LM-511 to enhance 4T1BM2 cell migration and invasion and is sufficient alone to promote survival in the absence of serum. These responses were associated with increased secretion of MMP-9 and activation of ERK and AKT signaling pathways and were partially blocked by pharmacological inhibitors of MMP-9, AKT-1/2 or MEK. Importantly, pre-treatment of 4T1BM2 cells with an AKT-1/2 inhibitor significantly reduced experimental metastasis to bone in vivo. Promotion of survival and invasive responses by bone-derived soluble factors and tumor-derived LM-511 are likely to contribute to the metastatic spread of breast tumors to bone.
肿瘤内在和外在因素被认为与骨转移有关，但对于它们如何协同促进乳腺癌扩散至骨却知之甚少。我们使用骨转移性4T1BM2乳腺癌模型在体外研究肿瘤LM-511与骨源可溶性因子之间的协同相互作用。我们发现骨条件培养基与LM-511协同作用可增强4T1BM2细胞的迁移和侵袭能力，并且在无血清条件下单独就足以促进细胞存活。这些反应与MMP-9分泌增加以及ERK和AKT信号通路的激活相关，并且被MMP-9、AKT-1/2或MEK的药理学抑制剂部分阻断。重要的是，用AKT-1/2抑制剂预处理4T1BM2细胞可显著减少体内实验性骨转移。骨源可溶性因子和肿瘤源LM-511对存活和侵袭反应的促进作用可能有助于乳腺肿瘤向骨的转移扩散。
