Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus.
复制标题
DOI：
10.1371/journal.pone.0013859
复制
发表时间：
2010-11-05
期刊：
影响因子：
3.7
通讯作者：
Hemminki A
中科院分区：
文献类型：
--
作者：
Ahtiainen L;Mirantes C;Jahkola T;Escutenaire S;Diaconu I;Osterlund P;Kanerva A;Cerullo V;Hemminki A
肿瘤干细胞/起始细胞（CSC/CIC）被认为在恶性组织中以小群体的形式存在。它们对传统的癌症治疗有抗药性，可能是治疗后复发的原因。CIC群体可以被衣壳修饰的溶瘤腺病毒靶向。我们研究了常规治疗耐药非CIC乳腺癌细胞、乳腺癌CD44+/CD24−/低CIC人群和正常乳腺组织CD44+/CD24−/低CIC干细胞对溶瘤腺病毒Ad5/3-Delta24的先天免疫机制。我们比较了模式识别受体对腺病毒的识别，toll样受体（TLR） 2和9以及病毒诱导的I型干扰素（IFN）在这些细胞类型中的应答调节。我们在这些非免疫细胞类型中显示TLR介导的病毒识别。正常组织干细胞具有完整的I型IFN信号。此外，TLR9和TLR2持续存在于识别位点，意味着持续激活。相比之下，乳腺癌CD44+/CD24−/低CIC的先天免疫反应失调，TLR9和辅助因子MyD88的运输受损以及TLR2的缺失导致病毒识别功能失调，对TLR模式识别受体信号传导产生有害影响。此外，CIC通过细胞因子信号通路抑制因子/Tyro3/Axl/Mer受体酪氨酸激酶（SOCS/TAM）通路增加了抑制信号。这些缺陷有助于CIC中I型IFN反应的功能失调诱导，从而允许溶瘤腺病毒。CICs可能是复发或转移性癌症无法治愈的基础，因此是诊断和预后方面以及疾病治疗的重要目标。本研究解决了干细胞先天感染免疫的机制，加深了对干细胞生物学的理解，可能不仅有利于病毒治疗，也有利于一般的免疫治疗。
Cancer stem cells/initiating cells (CSC/CIC), are thought to exist as a small population in malignant tissues. They are resistant to conventional cancer treatments and possibly underlie post-treatment relapse. The CIC population can be targeted with capsid modified oncolytic adenoviruses. We studied the mechanisms of innate immunity to oncolytic adenovirus Ad5/3-Delta24 in conventional treatment resistant non-CIC breast cancer cells, breast cancer CD44+/CD24−/low CIC population and normal breast tissue CD44+/CD24−/low stem cells. We compared virus recognition by pattern recognition receptors for adenovirus, Toll-like receptors (TLR) 2 and 9 and virus induced type I interferon (IFN) response regulation in these cell types. We show TLR mediated virus recognition in these non-immune cell types. Normal tissue stem cells have intact type I IFN signaling. Furthermore, TLR9 and TLR2 reside constantly in recognition sites, implying constant activation. In contrast, breast cancer CD44+/CD24−/low CIC have dysregulated innate immune responses featuring dysfunctional virus recognition caused by impaired trafficking of TLR9 and cofactor MyD88 and the absence of TLR2, having a deleterious impact on TLR pattern recognition receptor signaling. Furthermore, the CIC have increased inhibitory signaling via the suppressor of cytokine signaling/Tyro3/Axl/Mer receptor tyrosine kinase (SOCS/TAM) pathway. These defects in contribute to dysfunctional induction of type I IFN response in CIC and therefore permissivity to oncolytic adenovirus. CICs may underlie the incurable nature of relapsed or metastatic cancers and are therefore an important target regarding diagnostic and prognostic aspects as well as treatment of the disease. This study addresses the mechanisms of innate infection immunity in stem cells deepening the understanding of stem cell biology and may benefit not only virotherapy but also immunotherapy in general.
登录
查看更多内容
影响因子：
12.4
作者：
Kanerva, A;Zinn, KR;Hemminki, A
通讯作者：
Hemminki, A
影响因子：
11.4
作者：
Brendel, C.;Scharenberg, C.;Neubauer, A.
通讯作者：
Neubauer, A.
影响因子：
12.4
作者：
Cerullo, Vincenzo;Seiler, Michael P.;Lee, Brendan
通讯作者：
Lee, Brendan
影响因子：
4.2
作者：
Hakkarainen, Tanja;Sarkioja, Merja;Hemminki, Akseli
通讯作者：
Hemminki, Akseli
影响因子：
82.9
作者：
Heise, C;Hermiston, T;Kirn, D
通讯作者：
Kirn, D