Murdoch Craig, Lewis Claire E
Tumor Targeting Group, Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield S10 2RX, United Kingdom.
Int J Cancer. 2005 Dec 10;117(5):701-8. doi: 10.1002/ijc.21422.
Monocytes are recruited into tumors from the circulation along defined chemotactic gradients and they then differentiate into tumor-associated macrophages (TAMs). Recent evidence has shown that large numbers of TAMs are attracted to and retained in avascular and necrotic areas, where they are exposed to tumor hypoxia. At these sites, TAMs appear to undergo marked phenotypic changes with activation of hypoxia-inducible transcription factors, dramatically upregulating the expression of a large number of genes encoding mitogenic, proangiogenic and prometastatic cytokines and enzymes. As a consequence, high TAMs density has been correlated with increased tumor growth and angiogenesis in various tumor types. Since hypoxia is a hallmark feature of malignant tumors and hypoxic tumor cells are relatively resistant to radio- and chemotherapy, these areas have become a target for novel forms of anticancer therapy. These include hypoxia-targeted gene therapy in which macrophages are armed with therapeutic genes that are activated by hypoxia-responsive promoter elements. This restricts transgene expression to hypoxic areas, where the gene product is then released and acts on neighboring hypoxic tumor cells or proliferating blood vessels. In this way, the responses of macrophages to tumor hypoxia can be exploited to deliver potent antitumor agents to these poorly vascularized, and thus largely inaccessible, areas of tumors.
单核细胞沿特定趋化梯度从循环系统募集到肿瘤中，随后分化为肿瘤相关巨噬细胞（TAM）。最近的证据表明，大量TAM被吸引并滞留在无血管和坏死区域，在那里它们会暴露于肿瘤缺氧环境。在这些部位，TAM似乎会发生显著的表型变化，缺氧诱导转录因子被激活，大量编码促有丝分裂、促血管生成和促转移细胞因子及酶的基因表达显著上调。因此，在各种肿瘤类型中，高TAM密度与肿瘤生长和血管生成增加相关。由于缺氧是恶性肿瘤的一个标志性特征，且缺氧肿瘤细胞对放疗和化疗相对耐药，这些区域已成为新型抗癌治疗的靶点。这些治疗方法包括缺氧靶向基因治疗，即巨噬细胞携带由缺氧反应性启动子元件激活的治疗基因。这将转基因表达限制在缺氧区域，基因产物随后在该区域释放，并作用于邻近的缺氧肿瘤细胞或增殖的血管。通过这种方式，可以利用巨噬细胞对肿瘤缺氧的反应，将强效抗肿瘤药物递送至肿瘤中这些血管化不良且因此在很大程度上难以到达的区域。
