Trikha P, Sharma N, Pena C, Reyes A, Pécot T, Khurshid S, Rawahneh M, Moffitt J, Stephens J A, Fernandez S A, Ostrowski M C, Leone G
Human Cancer Genetics Program, The Ohio State University, Columbus, OH, USA.
Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
Oncogene. 2016 Jul 14;35(28):3636-46. doi: 10.1038/onc.2015.429. Epub 2015 Nov 9.
The Rb-E2F axis is an important pathway involved in cell-cycle control that is deregulated in a number of cancers. E2f transcription factors have distinct roles in the control of cell proliferation, cell survival and differentiation in a variety of tissues. We have previously shown that E2fs are important downstream targets of a CSF-1 signaling cascade involved in myeloid development. In cancer, tumor-associated macrophages (TAMs) are recruited to the tumor stroma in response to cytokines secreted by tumor cells, and are believed to facilitate tumor cell invasion and metastasis. Using the MMTV-Polyoma Middle T antigen (PyMT) mouse model of human ductal carcinoma, we show that the specific ablation of E2f3 in TAMs, but not in tumor epithelial cells, attenuates lung metastasis without affecting primary tumor growth. Histological analysis and gene expression profiling suggest that E2f3 does not impact the proliferation or survival of TAMs, but rather controls a novel gene expression signature associated with cytoskeleton rearrangements, cell migration and adhesion. This E2f3 TAM gene expression signature was sufficient to predict cancer recurrence and overall survival of estrogen receptor (ER)-positive breast cancer patients. Interestingly, we find that E2f3b but not E2f3a levels are elevated in TAMs from PyMT mammary glands relative to controls, suggesting a differential role for these isoforms in metastasis. In summary, these findings identify E2f3 as a key transcription factor in TAMs, which influences the tumor microenvironment and tumor cell metastasis.
Rb-E2F轴是参与细胞周期调控的重要通路，在多种癌症中失调。E2f转录因子在多种组织的细胞增殖、细胞存活和分化控制中具有不同作用。我们之前已经表明，E2fs是参与髓系发育的CSF-1信号级联的重要下游靶点。在癌症中，肿瘤相关巨噬细胞（TAM）会响应肿瘤细胞分泌的细胞因子而被招募到肿瘤基质中，并被认为有助于肿瘤细胞的侵袭和转移。利用人导管癌的MMTV-多瘤中间T抗原（PyMT）小鼠模型，我们发现，在TAM中特异性敲除E2f3，而非在肿瘤上皮细胞中敲除，可减弱肺转移，而不影响原发肿瘤生长。组织学分析和基因表达谱表明，E2f3不影响TAM的增殖或存活，而是控制与细胞骨架重排、细胞迁移和黏附相关的一种新的基因表达特征。这种E2f3 TAM基因表达特征足以预测雌激素受体（ER）阳性乳腺癌患者的癌症复发和总生存期。有趣的是，我们发现，相对于对照组，PyMT乳腺的TAM中E2f3b而非E2f3a的水平升高，表明这些异构体在转移中具有不同作用。总之，这些发现确定E2f3是TAM中的关键转录因子，其影响肿瘤微环境和肿瘤细胞转移。
