Department of Cancer Biology, Cancer Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Semin Cancer Biol. 2011 Apr;21(2):107-12. doi: 10.1016/j.semcancer.2010.12.009. Epub 2010 Dec 16.
More than 40% of patients with lung cancer and breast cancer develop brain metastasis. With improved local control and therapy of metastasis to visceral organs, the morbidity and mortality due to late diagnosed brain metastasis are projected to rise. The median survival for untreated patients is 1-2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy. The development of a relevant mouse model for the establishment and growth of brain metastasis has advanced our understanding of the biology and therapy of this most feared consequence of cancer. Injection of murine or human tumor cells into the internal carotid artery of mice produces experimental metastases in specific regions of the brain that are not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of metastatic tumor cells to exploit homeostatic mechanisms and proliferate. Immunohistochemical and morphometric analyses demonstrate that the density of blood vessels within experimental metastases in brains of mice or in clinical specimen of human lung cancer brain metastases is lower than that in the adjacent tumor-free brain parenchyma. However, brain metastasis-associated blood vessels are dilated and contain numerous dividing endothelial cells. Immunohistochemical analysis also reveals that tumor cells located less than 100 μm from a blood vessel are viable, whereas more distant tumor cells undergo apoptosis. Tumor cells within brain metastasis produce VEGF which induces permeability in adjacent vessels. The BBB in metastases that are larger than 0.25 mm in diameter is leaky. Metastases in the brain are resistant to chemotherapeutic drugs. The venerable "seed and soil" hypothesis suggests that the outcome of metastasis depends on the interaction between unique tumor cells and the specific organ microenvironment. The demonstration that activated astrocytes whose physiological role is to protect neurons from toxic substances can be exploited by tumor cells for protection from chemotherapeutic drugs suggests new approaches to the treatment of this fatal disease.
超过 40%的肺癌和乳腺癌患者会发生脑转移。随着局部控制和内脏器官转移治疗的改善，由于晚期诊断出脑转移而导致的发病率和死亡率预计将会上升。未经治疗的患者的中位生存时间为 1-2 个月，如果采用手术、放疗和化疗，生存时间可延长至 6 个月。建立和发展与脑转移相关的小鼠模型，促进了我们对这种最令人恐惧的癌症后果的生物学和治疗的理解。将鼠或人肿瘤细胞注入小鼠颈内动脉，可在大脑的特定区域产生实验性转移，这些转移不是由于初始细胞停滞、运动或侵袭模式引起的，而是由于转移性肿瘤细胞能够利用体内平衡机制并增殖。免疫组织化学和形态计量分析表明，在小鼠脑内实验性转移或人肺癌脑转移的临床标本中，转移灶内的血管密度低于相邻的无肿瘤脑实质。然而，脑转移相关血管扩张，并包含大量分裂的内皮细胞。免疫组织化学分析还表明，位于距血管小于 100μm 的肿瘤细胞是存活的，而更远的肿瘤细胞则发生凋亡。脑转移灶内的肿瘤细胞产生 VEGF，诱导邻近血管通透性增加。直径大于 0.25mm 的转移灶中的血脑屏障是渗漏的。脑转移对化疗药物有抵抗力。古老的“种子和土壤”假说表明，转移的结果取决于独特的肿瘤细胞与特定器官微环境之间的相互作用。证明激活的星形胶质细胞（其生理作用是保护神经元免受有害物质的侵害）可以被肿瘤细胞利用来保护它们免受化疗药物的侵害，这为治疗这种致命疾病提供了新的方法。
