Rb TS inhibition dedifferentiates astrocytes leading to Astrocytoma initiation

胶质母细胞瘤是人类最常见的脑部恶性肿瘤，目前尚无有效的治疗方法。一些研究表明神经前体细胞和干细胞是胶质母细胞瘤发展的靶点。在这里，我们展示了一种新的机制，通过这种机制，分化的星形胶质细胞可以转化为祖细胞状态，并作为GBM的起源细胞。使用成人可诱导的HGA GEMM，其中Rb肿瘤抑制(TS)与Kras激活一起被取消，我们证明了Rb TS在体外和体内的成年星形胶质细胞中的失活，将它们转化为祖细胞，产生一种肿瘤前状态，容易发生GBM进展。Rb TS失活后，皮质星形胶质细胞去分化为表达增殖和祖细胞标志物的细胞，同时抑制分化标志物的表达。这些去分化的细胞能够形成球体，自我更新，并可以在实验中诱导成多谱系分化。需要将星形胶质细胞转化为祖细胞样细胞，以创造肿瘤通过Kras激活而进展为更高级别疾病的易感性。Kras本身既不足以促进肿瘤的发生，也不足以诱导祖细胞的特性。因此，靶细胞群可能取决于星形胶质细胞对内稳态过程中出现的随机事件的特异性。一些星形胶质细胞在损伤后增殖，Rb网络的改变可以产生前体细胞群，容易在Kras途径中第二次攻击并进展为HGA。这一过程也为启动癌症的细胞的起源提供了一种机制，即使在癌症治疗后，启动细胞也可以传播癌症。由于Rb网络已知在大多数实体癌中发生改变，我们的结果可能表明在广泛的癌症中肿瘤起始的新机制。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--文摘内容取消RB肿瘤抑制通过驱动祖细胞程序启动分化的星形胶质细胞的GBM。正在准备中

Glioblastoma is the most common human brain malignancy, and as yet there is no effective treatment. Several studies have implicated neural progenitor and stem cells as targets for glioblastoma development. Here we demonstrate a novel mechanism by which differentiated astrocytes can be converted into progenitor state and act as cells of origin in GBM. Using adult inducible HGA GEMMs where Rb tumor suppression (TS) is abrogated along with Kras activation we demonstrate that Rb TS inactivation in adult astrocytes in vitro and in vivo, converts them into progenitor cells generating a pretumorigenic state that is susceptible to GBM progression. Upon Rb TS inactivation, cortical astrocytes dedifferentiated into cells expressing proliferation and progenitor markers while suppressing the expression of differentiation markers. These "dedifferentiated" cells were capable of forming spheres, self renewed and could be experimentally driven into multilineage differentiation. Conversion of astrocytes to progenitor-like cells was required to create susceptibility for the tumor to progress to a higher grade disease by Kras activation. By itself Kras was not sufficient either for tumorigenesis or for induction of progenitor properties. Thus the target cell population may depend on the specificity of astrocytes to stochastic events that arise during homeostasis. Some astrocytes proliferate in response to injury, alteration in Rb network can generate a progenitor population, susceptible for a second hit in the Kras pathway and progression into HGA. This process also provides a mechanism for origination of cancer-initiating cells which can propagate the cancer even after a cancer treatment. With the Rb network known to be altered in majority solid cancers our results may indicate novel mechanism for tumor initiation in a broad spectrum of cancers. Adhikari, A. Sullivan, T, and T. Van Dyke. Abrogation of Rb tumor suppression initiates GBM from differentiated astrocytes by driving a progenitor cell program. In preparation