内皮细胞中mTORC1的组成性激活通过VEGF自分泌信号导致淋巴管肉瘤的发生和进展。
Constitutive Activation of mTORC1 in Endothelial Cells Leads to the Development and Progression of Lymphangiosarcoma through VEGF Autocrine Signaling.
作者信息
Sun Shaogang, Chen Song, Liu Fei, Wu Haige, McHugh Jonathan, Bergin Ingrid L, Gupta Anita, Adams Denise, Guan Jun-Lin
机构信息
Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
Cancer Cell. 2015 Dec 14;28(6):758-772. doi: 10.1016/j.ccell.2015.10.004.
Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.
血管肉瘤/淋巴管肉瘤是一种预后较差的罕见恶性肿瘤。我们构建了一种可诱导内皮细胞特异性缺失Tsc1的小鼠模型，以研究淋巴管肉瘤中的mTORC1信号传导。Tsc1缺失增加了新生小鼠的视网膜血管生成，并在成年小鼠中导致从血管畸形到血管肿瘤的内皮增殖性病变。淋巴管肉瘤的发生和维持需要持续的mTORC1信号传导。在肿瘤细胞中可见VEGF表达增加，阻断自分泌VEGF信号传导可消除血管肿瘤的发生和生长。我们还发现人类血管肉瘤样本中mTORC1激活与VEGF、HIF1α和c-Myc表达之间存在显著相关性。这些研究证明了淋巴管肉瘤中mTORC1异常激活的关键机制，并验证了该小鼠作为进一步研究的有价值模型。
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