Chang Jian, Vacher Jean, Yao Bing, Fan Xiaofeng, Zhang Bixiang, Harris Raymond C, Zhang Ming-Zhi
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
Oncotarget. 2015 Oct 20;6(32):33500-11. doi: 10.18632/oncotarget.5589.
Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ mice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment.
结直肠癌（CRC）仍然是发病和死亡的主要原因。尽管CRC发生和发展的潜在因素是多方面的，但肿瘤与宿主的相互作用，尤其是与髓样细胞的相互作用，起着重要作用。越来越多的证据表明，环氧化酶衍生的前列腺素是CRC发生和生长的重要介质。尽管使用非选择性非甾体抗炎药（NSAIDs）或COX-2选择性药物的预防试验已显示出前景，但这些药物的胃肠道或心血管副作用限制了它们的应用。参与CRC发病机制的主要前列腺素是PGE2。由于髓样细胞表达高水平的PGE2受体亚型EP4，我们在髓样细胞中选择性地敲除EP4，并在肠道腺瘤性息肉病小鼠模型ApcMin/+小鼠中研究腺瘤形成。选择性髓样细胞缺失EP4的ApcMin/+小鼠的腺瘤数量和大小均受到显著抑制，同时mTOR和ERK激活也相应降低。对EP4受体的基因抑制或药物抑制均导致巨噬细胞/树突状细胞出现抗肿瘤的M1表型。因此，髓样细胞中PGE2介导的EP4信号传导促进肿瘤发生，这表明EP4是CRC化学预防或治疗的一个潜在有吸引力的靶点。
