我国科学家发现导致肿瘤恶化的“罪魁祸首”

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中国科学家近期公布的一项研究成果，将有望给恶性肿瘤的治疗带来新方向。; A/ y% ]+ W% }2 I" t( `
     取得这项研究成果的是中国医学科学院基础医学研究所博士生导师、生理学教授张宏冰及其率领的团队。
1 N7 B4 t9 C/ I     张宏冰告诉记者，一种叫雷帕霉素靶点（mTOR）的蛋白质激酶遭遇多种上游基因突变后，导致其过度活化，从而引起多种肿瘤发生。
# E; W  L2 \& ^      虽然医学界已知肿瘤细胞分化程度越低，恶性程度就越高，治疗越难，病人的预后就越差。但一直以来对肿瘤细胞低分化的机理不甚清楚，因此面对恶性肿瘤时感觉“无能为力”。
: r, p) }: Y' i! R2 W" H7 N) ^2 h2 e     而张宏冰团队的研究则找出了雷帕霉素靶点过度活化导致肿瘤细胞低分化的“通道”。他说，过度活化的雷帕霉素靶点是通过上调NOTCH信号通路来抑制分化，从而造成肿瘤细胞低分化，使肿瘤恶性程度变高。雷帕霉素或NOTCH抑制剂则可以恢复雷帕霉素靶点活化细胞的分化能力，也就是说阻断NOTCH有望治疗雷帕霉素靶点过度活化引起的肿瘤恶化。这一发现为临床诱导肿瘤细胞分化、靶向治疗肿瘤提供了新方向。# m/ ]4 U5 h6 w( `7 n8 j1 L% e
     目前这项研究成果已申请专利，并在国际著名医学期刊《临床研究杂志》（The Journal of Clinical Investigation，JCI）2010年1月刊上发表。

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Title:Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade% o+ `- T+ u5 i  O
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Abstract:The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

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JCI 同期上另一篇文章也证明TSC/Rheb pathway 导致NOTCH信号通路上调，这是在果蝇里做的。
  a1 @5 P0 M( Y0 HThe evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development
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Abstract: Mutations in either of the genes encoding the tuberous sclerosis complex (TSC), TSC1 and TSC2, result in a multisystem tumor disorder characterized by lesions with unusual lineage expression patterns. How these unusual cell-fate determination patterns are generated is unclear. We therefore investigated the role of the TSC in the Drosophila external sensory organ (ESO), a classic model of asymmetric cell division. In normal development, the sensory organ precursor cell divides asymmetrically through differential regulation of Notch signaling to produce a pIIa and a pIIb cell. We report here that inactivation of Tsc1 and overexpression of the Ras homolog Rheb each resulted in duplication of the bristle and socket cells, progeny of the pIIa cell, and loss of the neuronal cell, a product of pIIb cell division. Live imaging of ESO development revealed this cell-fate switch occurred at the pIIa-pIIb 2-cell stage. In human angiomyolipomas, benign renal neoplasms often found in tuberous sclerosis patients, we found evidence of Notch receptor cleavage and Notch target gene activation. Further, an angiomyolipoma-derived cell line carrying biallelic TSC2 mutations exhibited TSC2- and Rheb-dependent Notch activation. Finally, inhibition of Notch signaling using a γ-secretase inhibitor suppressed proliferation of Tsc2-null rat cells in a xenograft model. Together, these data indicate that the TSC and Rheb regulate Notch-dependent cell-fate decision in Drosophila and Notch activity in mammalian cells and that Notch dysregulation may underlie some of the distinctive clinical and pathologic features of TSC.