Saunus Jodi M, McCart Reed Amy E, Lim Zhun Leong, Lakhani Sunil R
The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland 4029, Australia.
QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
Int J Mol Sci. 2017 Jan 13;18(1):152. doi: 10.3390/ijms18010152.
Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely-held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management.
脑转移是乳腺癌在独特微环境中高度进化的表现形式，使其在面对新的外在压力时具有非凡的适应性。随着人口老龄化，其发病率不断上升，并且使用了更新的疗法来稳定全身转移性疾病负担，疗效各异。从历史上看，人们普遍认为脑转移对循环治疗无反应，因为血脑屏障（BBB）会限制药物摄取。然而，新出现的数据开始描绘出一幅更为复杂的图景，即大脑充当了休眠、亚临床增殖的庇护所，这些增殖最初受到血脑屏障的保护，但随着肿瘤成熟和血管通透性增加，随后会面临动态选择压力。在此，我们回顾了绘制乳腺癌脑转移基因组图谱的关键实验方法和具有里程碑意义的研究。这些发现与影响大脑中克隆性生长的因素相关：脑转移适应性所需的内在乳腺肿瘤细胞能力，以及神经微环境，神经微环境最初对侵入细胞具有敌意，但随后被成功的少数细胞改造为肿瘤支持载体。我们还讨论了晚期检测、异常血管灌注和间质液动力学如何支撑脑转移顽固的临床行为，并概述了精准管理背景下的正在进行的临床试验。
