Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma
Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma
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DOI：
10.1101/gad.1890510
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发表时间：
2010-08-15
影响因子：
10.5
通讯作者：
Furnari, Frank
中科院分区：
文献类型：
--
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
人实体瘤在组织学、遗传学和基因表达水平上通常具有肿瘤细胞和正常细胞的显著异质性。虽然目前的努力集中在理解肿瘤细胞和周围正常细胞之间的异型相互作用，但对肿瘤内异质肿瘤细胞之间的相互作用知之甚少。在多形性胶质母细胞瘤（GBM）中，表皮生长因子受体基因（EGFR）扩增和突变（EGFRvIII/Delta EGFR）是总是以异质性方式表达的标志性发病事件。引人注目的是，尽管其比野生型EGFR（wtEGFR）更大的生物活性，但表达两种扩增受体的个体GBM肿瘤通常表达wtEGFR，其丰度远高于Delta EGFR病变。我们假设，较小的Delta EGFR表达亚群增强了整个肿瘤细胞群的致瘤性，从而维持了两种受体形式在不同细胞中表达的异质性。使用神经胶质瘤细胞以及永生化鼠星形胶质细胞的混合物，我们证明了由Delta EGFR驱动的旁分泌机制是招募wtEGFR表达细胞加速体内增殖的主要手段。我们确定了表达Delta EGFR的人神经胶质瘤组织、神经胶质瘤细胞系、神经胶质瘤干细胞和永生化小鼠Ink 4a/Arf（-/-）星形胶质细胞也各自表达IL-6和/或白血病抑制因子（LIF）细胞因子。这些细胞因子激活gp 130，进而激活邻近细胞中的wtEGFR，导致肿瘤生长速率增加。激活IL-6、LIF或gp 130可解除这种细胞间的相互作用，并有效地减弱肿瘤生长的增强作用。这些发现支持了这样的观点，即较小的肿瘤细胞群可以有效地驱动整个肿瘤块的加速生长，从而积极地维持肿瘤块内的肿瘤细胞异质性。基因不同的癌细胞之间的这种相互作用可以提供新的治疗干预点。
Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/Delta EGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the Delta EGFR lesion. We hypothesized that the minor Delta EGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by Delta EGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express Delta EGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.