Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells
Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells
复制标题
DOI：
10.1158/0008-5472.can-06-4174
复制
发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
--
作者：
Sinha, Pratima;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
慢性炎症与癌症之间的因果关系已被假设多年，临床观察和实验室实验支持炎症导致肿瘤发生和进展的假设。然而，这种关系背后的确切机制尚不清楚。我们最近报道，促炎细胞因子白介素-lo 会诱导骨髓源性抑制细胞 (MDSC) 的积累和保留，这种细胞常见于许多癌症患者和实验动物中，是适应性和先天免疫的有效抑制剂。这一发现使我们推测炎症通过诱导 MDSC 导致癌症，MDSC 抑制免疫监视，从而允许癌前细胞和恶性细胞不受控制地持续存在和增殖。我们现在报道宿主MDSC具有前列腺素E2（PGE2）受体，并且E-前列腺素受体激动剂（包括PGE2）诱导骨髓干细胞分化为Gr1（+）CD11b（+）MDSC，而受体拮抗剂则阻止分化。与野生型小鼠相比，接种自发转移性 BALB/c 衍生 4T1 乳腺癌的 BALB/c EP2 敲除小鼠肿瘤生长延迟，MDSC 数量减少，表明 PGE2 通过 EP2 受体部分介导 MDSC 诱导。用环氧合酶 2 抑制剂 SC58236 治疗携带 4T1 肿瘤的野生型小鼠，可延迟原发性肿瘤生长并减少 MDSC 积累，进一步表明 PGE2 诱导 MDSC 并为减少这种促肿瘤细胞群提供治疗方法。
A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-lo, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.