Abstract：
The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.
摘要：
调节乳腺癌细胞（BCC）在软脑膜（LM）内转移和增殖的分子机制知之甚少。这限制了有效疗法的发展。在这项工作中,我们表明，小鼠体内的BCC可以通过沿着连接椎骨或颅骨骨髓和脑膜的血管的腔外迁移侵入LM，绕过血脑屏障.该过程取决于BCC通过表达神经元寻路分子整联蛋白α6与血管基底膜层粘连蛋白的接合。一旦进入LM，BCCs与血管周脑膜巨噬细胞共定位并诱导其表达前存活神经营养因子神经胶质源性神经营养因子（GDNF）。鞘内GDNF阻断，巨噬细胞特异性GDNF消融，或从BCC中删除GDNF受体神经细胞粘附分子（NCAM）会抑制LM内的乳腺癌生长。这些数据表明整联蛋白α6和GDNF信号轴是针对乳腺癌LM转移的新治疗靶标。
