COX-2 Induces Breast Cancer Stem Cells via EP4/PI3K/AKT/NOTCH/WNT Axis

被引：113

作者：

Majumder, Mousumi ^{[1
]}

Xin, Xiping ^{[1
]}

Liu, Ling ^{[1
]}

Tutunea-Fatan, Elena ^{[2
]}

Rodriguez-Torres, Mauricio ^{[1
]}

Vincent, Krista ^{[1
,4
]}

Postovit, Lynne-Marie ^{[1
,4
]}

Hess, David ^{[2
,5
]}

Lala, Peeyush K. ^{[1
,3
]}

机构：

[1] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, 1151 Richmond St, London, ON N6A 5C1, Canada

[2] Univ Western Ontario, Schulich Sch Med & Dent, Physiol & Pharmacol, London, ON, Canada

[3] Univ Western Ontario, Schulich Sch Med & Dent, Oncol, London, ON, Canada

[4] Univ Alberta, Dept Oncol, Edmonton, AB, Canada

[5] Robarts Res Inst, Krembil Ctr Stem Cell Biol, London, ON, Canada

来源：

STEM CELLS | 2016年 / 34卷 / 09期

关键词：

Breast cancer; Cyclo-oxygenase-2; EP4; Stem-like cell; NOTCH/WNT; PROSTANOID RECEPTORS; CYCLOOXYGENASE-2; GROWTH; EP4; ANGIOGENESIS; EXPRESSION; LYMPHANGIOGENESIS; INHIBITORS; MIGRATION; TARGET;

D O I：

10.1002/stem.2426

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG) E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH/WNT signaling. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 cell lines resulted in: increased migration/invasion/proliferation, epithelial-mesenchymal transition (EMT), elevated SLCs (spheroid formation), increased ALDH activity and colocalization of COX-2 and SLC markers (ALDH1A, CD44, beta-Catenin, NANOG, OCT3/4, SOX-2) in spheroids. These changes were reversed with COX-2-inhibitor or EP4-antagonist (EP4A), indicating dependence on COX-2/EP4 activities. COX-2 over-expression or EP4-agonist treatments of COX-2-low cells caused up-regulation of NOTCH/WNT genes, blocked with PI3K/AKT inhibitors. NOTCH/WNT inhibitors also blocked COX-2/EP4 induced SLC induction. Microarray analysis showed up-regulation of numerous SLC-regulatory and EMT-associated genes. MCF-7-COX-2 cells showed increased mammary tumorigenicity and spontaneous multiorgan metastases in NOD/SCID/IL-2R gamma-null mice for successive generations with limiting cell inocula. These tumors showed up-regulation of VEGF-A/C/D, Vimentin and phospho-AKT, down-regulation of E-Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF-7-COX-2 cells also showed increased lung colonization in NOD/SCID/GUSB-null mice, an effect reversed with EP4-knockdown or EP4A treatment of the MCF-7-COX-2 cells. COX-2/EP4/ALDH1A mRNA expression in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. In situ immunostaining of human breast tumor tissues revealed colocalization of SLC markers with COX-2, supporting COX-2 inducing SLCs. High COX-2/EP4 mRNA expression was linked with reduced survival. Thus, EP4 represents a novel SLC-ablative target in human breast cancer.

引用

页码：2290 / 2305

页数：16

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