Small Cell Lung Cancer: Significance of RB Alterations and TTF-1 Expression in its Carcinogenesis, Phenotype, and Biology
Small Cell Lung Cancer: Significance of RB Alterations and TTF-1 Expression in its Carcinogenesis, Phenotype, and Biology
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DOI：
10.1007/s12022-009-9072-4
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Shimoyamada, Hiroaki
中科院分区：
文献类型：
--
作者：
Kitamura, Hitoshi;Yazawa, Takuya;Shimoyamada, Hiroaki
小细胞肺癌（SCLC）表现出高度侵袭性且预后不良。尽管已经进行了大量研究，但其致癌和侵袭性的确切机制仍不清楚。 SCLC 被归类为神经内分泌肿瘤，其遗传特征为 RB 和 TP53 基因的普遍改变。流行病学研究表明大多数SCLC是由吸烟引起的，TP53突变模式与烟雾致癌物诱发的突变模式一致；然而，没有直接证据表明此类致癌物会引起 SCLC 中 RB 的改变。虽然这些改变在 SCLC 致癌过程中的重要性被强烈暗示，但确切的分子机制却很少被阐明。 SCLC 细胞几乎总是表达哺乳动物 achaete-scute 同源物-1 (MASH1) 和甲状腺转录因子-1 (TTF-1)。 MASH1 在神经内分泌分化中发挥着关键作用。 TTF-1是远端气道细胞和肺腺癌的特征标志物，但也在肺外神经内分泌癌中表达。因此，TTF-1很可能在神经内分泌癌的发展中发挥重要作用。最近的研究表明，气道干细胞通过 MASH1 和 Notch 信号转导形成神经内分泌谱系，并且只有 RB 缺失的神经内分泌细胞才会响应 E2F3 选择性增殖，最终转化为神经内分泌癌细胞，这可能与 TP53 基因畸变一致。因此，RB 和 TP53 基因的改变是 SCLC 致癌的核心，而包括 MASH1 和 TTF-1 在内的许多其他因素也有助于 SCLC 的发展和生物学行为。
Small cell lung cancer (SCLC) exhibits highly aggressive behavior and has a poor prognosis. While numerous investigations have been carried out, the exact mechanism of its carcinogenesis and aggressiveness is still unclear. SCLC is categorized as a neuroendocrine neoplasia and has a genetic profile characterized by universal alterations of the RB and TP53 genes. Epidemiological studies indicate the majority of SCLCs to be caused by smoking and the TP53 mutational pattern to be consistent with that evoked by smoke carcinogens; however, there is no direct evidence that such carcinogens induce alterations to RB in SCLC. While the importance of these alterations in the carcinogenesis of SCLC is strongly suggested, the exact molecular mechanism has been only little elucidated. SCLC cells almost always express mammalian achaete-scute homolog-1 (MASH1) and thyroid transcription factor-1 (TTF-1). MASH1 plays a critical role in neuroendocrine differentiation. TTF-1 is a characteristic marker of distal airway cells and pulmonary adenocarcinomas, but is also expressed in extrapulmonary neuroendocrine cancers. Thus, TTF-1 may well play a significant role in the development of neuroendocrine cancers. Recent studies indicate that the airway stem cell is committed to the neuroendocrine lineage through MASH1 and Notch signaling and that only RB-deleted neuroendocrine cells selectively proliferate in response to E2F3, eventually undergoing transformation to neuroendocrine cancer cells, probably in concert with TP53 gene aberrations. Thus, alterations of both the RB and TP53 genes are central to the carcinogenesis of SCLC, while many other factors including MASH1 and TTF-1 contribute to the development and biological behavior of SCLC.