Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Department of Anatomy and Cell Biology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Oncogene. 2017 Sep 28;36(39):5445-5459. doi: 10.1038/onc.2017.148. Epub 2017 May 22.
Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.
转移是癌症危及生命的特征，是癌症患者死亡的主要原因。肿瘤细胞与内皮细胞之间的串扰对于肿瘤的进展和转移很重要。然而，人们对靠近肿瘤细胞的内皮细胞（EC）在肿瘤进展和转移过程中如何响应肿瘤细胞的机制知之甚少。在这项研究中，我们利用内皮细胞特异性信号转导和转录激活因子 3（STAT3）敲除小鼠来研究 STAT3 在肿瘤进展和转移中的 EC 中的作用。我们发现，EC 中 STAT3 的缺失并不影响原发性 Lewis 肺癌（LLC）肿瘤的生长，但它减少了实验和自发转移模型中的体内 LLC 转移。从机制上讲，STAT3 激活在上皮细胞 MS-1 细胞中上调细胞黏附分子的表达，包括肿瘤细胞条件培养基体外处理的小鼠内皮 MS-1 细胞和荷瘤小鼠的前转移肺中的 E-选择素和 P-选择素，以及体内。我们还发现，E-选择素和 P-选择素至少部分负责 STAT3 诱导的 LLC 细胞通过内皮细胞单层的黏附和侵袭。然而，B16F10 黑色素瘤细胞的肿瘤细胞条件培养基不能在 MS-1 细胞中激活 STAT3。因此，EC STAT3 敲除不会影响 B16F10 黑色素瘤细胞的转移。此外，各种人类癌细胞激活了人内皮细胞（HUVEC）中的 STAT3，导致细胞黏附分子表达增加。总之，我们的研究结果表明，EC 中 STAT3 的激活通过诱导细胞黏附分子促进肿瘤转移，表明 EC 在肿瘤转移过程中对肿瘤细胞的反应中起作用。
