STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.
STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.
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DOI：
10.1371/journal.pone.0005821
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发表时间：
2009-06-08
期刊：
影响因子：
3.7
通讯作者：
Weichselbaum RR
中科院分区：
文献类型：
--
作者：
Khodarev NN;Roach P;Pitroda SP;Golden DW;Bhayani M;Shao MY;Darga TE;Beveridge MG;Sood RF;Sutton HG;Beckett MA;Mauceri HJ;Posner MC;Weichselbaum RR
传统上，IFN/STAT 1信号传导与抗病毒应答和促凋亡肿瘤抑制功能有关。组成性激活的IFN/STAT 1通路的新功能表明与侵袭性肿瘤表型相关。我们假设，组成型过表达该途径的肿瘤克隆由于对STAT 1依赖性细胞毒性的抵抗力而优先被宿主微环境选择，并表现出转移能力增强以及对遗传毒性应激的抵抗力增强。在这里，我们报告说，克隆的B16 F1肿瘤生长在同基因C57 BL/6小鼠的肺部表现出可变的IFN/STAT 1通路表达的转录水平。通过肺微环境选择组成型过表达IFN/STAT 1途径（STAT 1H基因型）的肿瘤细胞。STAT 1H肿瘤细胞还表现出相对于亲本B16 F1对IFN-γ（IFNγ）、电离辐射（IR）和多柔比星的抗性以及IFN/STAT 1途径的低表达（STAT 1 L基因型）。STAT 1的稳定敲除逆转了侵袭性表型，并降低了肺定植和对遗传毒性应激的抗性。我们的研究结果确定了一个由肿瘤间质相互作用激活的途径，从而选择促转移和治疗耐药的肿瘤克隆。针对IFN/STAT 1信号通路的新疗法可能提供一种有效的策略来治疗侵袭性肿瘤克隆或使其对常规癌症疗法敏感，并可能预防远处器官定植。
Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1H genotype) are selected by the lung microenvironment. STAT1H tumor cells also demonstrate resistance to IFN-gamma (IFNγ), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1L genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.
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DOI：
10.1038/newbio242148a0
发表时间：
1973-01-01
期刊：
NATURE-NEW BIOLOGY
影响因子：
--
作者：
FIDLER, IJ
通讯作者：
FIDLER, IJ
影响因子：
11.2
作者：
Dunn, GP;Sheehan, KCF;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
56.9
作者：
Chin, YE;Kitagawa, M;Fu, XY
通讯作者：
Fu, XY
影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD
影响因子：
4
作者：
Khodarev, NN;Yu, JQ;Weichselbaum, RR
通讯作者：
Weichselbaum, RR