肿瘤细胞治疗研究
英文原题：Molecular Biology of Brain Metastases.
Molecular Biology of Brain Metastases.
脑转移（BMs）常发生于肺癌、乳腺癌和黑色素瘤患者中，是发病和死亡的主要原因。
脑转移（BM）常发生于肺癌、乳腺癌和黑色素瘤患者中，是致病和致死的主要原因。随着神经影像学的进步和癌症患者总生存期的延长，BM 的发病率有所增加。随着立体定向放射外科和导航引导显微外科等局部治疗手段的进步，BM 可以实现长期控制，即使是在多发病灶的病例中也是如此。然而，放射/化疗药物对脑也具有毒性，通常不可逆且具有累积性，且完全治愈 BM 仍然困难。因此，我们必须了解启动和维持 BM 的分子事件，以开发有效的靶向治疗和工具来预防局部和远处治疗失败。BM 最常通过血行播散，血脑屏障（BBB）是播散性肿瘤细胞（DTC）进入脑实质的第一道障碍。然而，DTC 如何跨越 BBB 并定植于相对贫瘠的中枢神经系统组织仍不清楚。即使在成功定居于脑内之后，独特的肿瘤微环境以受限的需氧糖酵解代谢和有限的淋巴细胞浸润为特征。脑器官趋向性，即原发癌某些有利于脑转移的表型，可能源于体细胞突变或表观遗传调控。近期研究揭示，原发癌分泌的外泌体或蛋白水解酶的过表达可以“预适应”脑血管内皮细胞。“转移龛”的概念，即驻留的DTC在增殖前保持休眠并受到保护，免受全身化疗和抗原暴露的影响，得到了全身癌症清除患者BM临床观察以及癌细胞与TIL（肿瘤浸润淋巴细胞）相互作用的实验证据的支持。本综述通过考察创造和维持BM的分子事件，审视了关于BM转移级联的现有研究，以揭示有助于开发有效靶向治疗的线索，从而治疗已形成的BM并预防BM复发。
Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiation/chemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can "pre-condition" brain vasculoendothelial cells. The concept of the "metastatic niche," where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.
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