陈淑娴
[EMBO rep., 2018]cGAS-STING通路在癌症发生以及肿瘤治疗中的作用
2021-4-12 21:43
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Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches

Authors: Li Teng Khoo & Liuh-Yow Chen*


这是一篇年份较近的阐述cGAS-STING通路和癌症发生以及靶向治疗思路的文章,讲的比较完善,以下是博主精读自翻,作为初学者,如有不正确的地方欢迎指正~


The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway mediates anti-microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self-DNA from tumors and by-products of genomic instability also activates the cGAS–STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists alone and in combination with conventional cancer treatment or immune checkpoint targeting. On the other hand, for cancers lacking the cGAS–STING pathway and thus a regular innate immunity response, oncolytic virus therapy has been shown to have therapeutic potential. We here review and discuss the dichotomous roles of the cGAS–STING pathway in cancer development and therapeutic approaches.

Cyclic guanosine monophosphate–adenosine monophosphate ——环状一磷酸鸟苷-一磷酸腺苷(cyclic GMP-AMP, cGAMP,GMP-AMP)合酶(cGAS)-干扰素基因激活因子(STING)通路介导了抗微生物的天然免疫,通过促使I型IFN以及炎症因子的合成,through DNA的识别。最近的研究表明肿瘤细胞的自身DNA以及基因组的不稳定产物也会激活cGAS-STING通路,或促进或抑制肿瘤的发育。靶向STING的激动剂的运用,并结合其他肿瘤治疗方法,可以被研究。另外,对于没有cGAS-STING通路的癌症,可以运用溶瘤病毒疗法。


Introduction

Innate immunity is the first line of host defense against various pathogenic infections [1]. It is based on recognition of pathogenassociated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoid acidinducible gene I (RIG-I)-like receptors, or cytosolic DNA sensors [2,3]. The cGAS–STING pathway is an important cytosolic DNA sensing pathway that activates expression of type I IFNs and other inflammatory cytokines to induce innate immunity for anti-microbial effects in response to viral and bacterial DNA [4,5]. Recent studies suggest that the cGAS–STING pathway is also involved in modulating cancer formation. Tumor-derived DNA, such as DNA of dead tumor cells, micronuclei, cytoplasmic chromatin fragments, and free telomeric DNA, can activate the cGAS–STING pathway and induce cell senescence, inflammation, and anti-tumor immunity, which can have divergent effects on tumorigenesis [6–12]. Hence, in this review, we highlight recent findings regarding how the cGAS–STING pathway is activated in response to tumor-derived DNA and its subsequent effects in terms of suppressing and promoting tumorigenesis. We then describe the approaches for developing anti-cancer interventions using STING agonists and targeting the vulnerabilities associated with loss of the cGAS–STING pathway.


The cGAS–STING pathway

Studies revealed that STING is an essential signal adaptor that mediates cytosolic DNA-induced innate immune responses [13–16] (Fig 1). It was shown that STING directly senses the bacterial cyclic dinucleotides (CDNs) c-di-AMP, c-di-GMP, and 3030-cGMP-AMP (3030–cGAMP) [17–19] (Fig 1), which have two 30-50 phosphodiester linkages, to activate host immune responses. Furthermore, an endogenous cGAMP with a 20-50 and a 30-50 phosphodiester linkage [19–23], designated 2030-cGAMP, is produced by cGAS upon engaging with cytosolic DNA [24], thereby establishing a signaling cascade of cGAS–STING [4,25]. 

Structural studies revealed that dsDNA binding leads to conformational changes of cGAS and promotes cGAS catalytic activity for cGAMP production [21,26]. Binding of cGAMP to a small pocket of the STING dimer [19,20,23,27] promotes translocation of STING from the endoplasmic reticulum (ER) via the Golgi apparatus to perinuclear microsomes [28,29]. Here, STING recruits and activates TANK-binding kinase 1 (TBK1) and interferon regulatory transcription factor 3 (IRF3) through serial phosphorylation events [30,31]. NF-jB is also activated by STING in a TBK1-dependent manner in response to cytosolic dsDNA and collaborates with IRF3 to mediate dsDNA-induced gene expression of type I IFN [4,25,32]. 

Through the detection of cytosolic DNA and initiating the production of type I IFNs and inflammatory cytokines, the cGAS– STING pathway is essential for host defense against various DNA viruses and retroviruses [28,33,34]. Likewise, STING is activated by the secondary messengers c-di-AMP and c-di-GMP released from intracellular bacterial pathogens (such as Listeria monocytogenes and Francisella tularensis) to trigger host production of type I IFNs [17,35–37]. Apart from pathogen detection, the cGAS–STING pathway also detects self-DNA and thereby promotes inflammatory autoimmune diseases [38,39] and is implicated in the development of cancer, as will be discussed next.

研究表明STING是一个重要的信号调节因子,介导胞质DNA促使的天然免疫应答。已有研究证明STING可以直接感知到细菌的环二核苷酸(cyclic dinucleotides,CDNs),包括环二单磷酸腺苷(c-di-AMP)、环二鸟苷酸(c-di-GMP)、3'3'环鸟苷酸,有着3'-5'磷酸双酯键,可以激活宿主免疫应答。另外,还有一种cGAMP有着2'-5'以及3'-5'的磷酸双酯键,名为2'3'环鸟苷酸,它是由cGAS在结合胞质DNA后产生的,由此就有了一条cGAS-STING的串联通路。

*环二核苷酸(CDN)在原核生物和真核生物中均被认为是第二信使。到目前为止,在自然生物中已鉴定出四个CDN。在哺乳动物细胞中,CDN可以激活干扰素基因的刺激物(STING),从而导致I型干扰素促炎细胞因子的诱导。表明CDNs可用于免疫治疗中的肿瘤和感染性疾病。

对结构的研究表明,与双链DNA结合后,cGAS的构象会发生改变,由此激发了cGAS的催化作用去催化cGAMP的产生。当cGAMP与STING二聚体结合时,会促使STING从内质网上通过高尔基体移位到核周微粒体中。在这里,STING会通过一系列的磷酸化反应,招募并激活TANK-binding kinase1(TBK1,TANK结合激酶1)以及interferon regulatory transcription factor 3(IRF3,干扰素调节转录因子3)。STING也会通过TBK1依赖型机制去激活NF-kB,从而来响应双链DNA,NF-kB会与IRF3合作去介导双链DNA激发的I型IFN的产生。

通过胞质DNA的检测以及I型干扰素和炎症因子的产生,cGAS-STING通路在受到DNA侵害时发挥了重要作用。同样地,STING也会被从细菌中释放出的第二信使们如c-di-AMP以及c-di-GAMP激活,来诱导I型干扰素的合成。除去病原体的探测之外,cGAS-STING通路也会探测自身DNA,并且引发自身炎症免疫疾病,并且也会和癌症相关,这在后面会讲述到。

*微粒体是细胞被匀浆破碎时, 内膜系统的膜结构破裂后自己重新封闭起来的小囊泡(主要是内质网和高尔基体)

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Involvement of the cGAS–STING pathway in host immunosurveillance of cancer

Activation of the host cGAS–STING pathway contributes to antitumor immunity (Fig 2). Cross-presentation of tumor antigens by dendritic cells (DCs) to CD8+ T cells is critical for anti-tumor immunity. Priming of CD8+ T cells against immunogenic tumors involves type I IFN production by DCs [40,41]. It has been shown that in the tumor microenvironment, IFN-b expression in DCs is STING-dependent and correlates with the uptake of tumor-derived DNA by DCs [6]. CD8+ T-cell activation and tumor rejection are defective in mice lacking STING. In addition, the anti-tumorigenic role of STING has been observed in a colitis-associated cancer mouse model induced by azoxymethane/dextran sodium sulfate (AOM/DSS) [42]. AOM triggers DNA damage and induces expression of inflammatory cytokine genes via STING-dependent signaling. Upon AOM/DSS treatment, STING-deficient mice are prone to colitis, polyp formation, and tumor development [42]. Moreover, cGAS and STING are required for tumor regression by radiation and immune checkpoint inhibitor therapies in mice [43,44]. These findings show that defective innate immune-sensing of tumor DNA in host bone marrow-derived DCs that lack cGAS or STING impairs the generation of tumor-infiltrating CD8+ T cells. Thus, activation of the host cGAS–STING pathway and type I IFN induction in DCs promotes cross-presentation of tumor antigens to activate T cells for tumor control.

cGAS-STING通路对抗肿瘤免疫中也有贡献。树突状细胞将肿瘤抗原交叉呈递给CD8+ T细胞。CD8+ T细胞对于抗肿瘤的开始包括DC产生I型IFN。研究表明在肿瘤微环境中,DC中IFN-b的表达时STING依赖型的,并且这与DC摄取来源于肿瘤的DNA有关。在缺少STING蛋白的小鼠中,CD8+ T细胞的活性与肿瘤抵抗是有缺陷的。另外,研究揭示了STING在抗肿瘤发生中的作用,氧化偶氮甲烷(AOM)及右旋糖酐硫酸酯钠(DSS)诱导的结肠炎相关的小鼠模型中,STING发挥了抗肿瘤发生的作用。AOM激发了DNA损伤,并且通过STING信号通路促进了炎症因子的表达。在AOM/DSS诱导后,STING缺陷的小鼠更倾向于患结肠炎,以及形成息肉,并更倾向于罹患肿瘤。另外,在对小鼠辐射以及免疫检查点抑制剂注射,cGAS以及STING会促进肿瘤消退。这些发现表明在缺乏cGAS或STING时会损害CD8+ T细胞的形成。因此,宿主的cGAS-STING通路的激活以及DC中I型IFN的生成促进了给T细胞的肿瘤抗原的交叉呈递,从而对肿瘤进行控制。


Intrinsic activation of the cGAS–STING pathway suppresses cancer development

Recent studies suggest that cytosolic self-DNA activates the cGAS– STING pathway in cancer cells and affects tumor development (Fig 2). Stalled replication forks resulting from dysregulation of DNA replication in cancer cells are processed for repair by the DNA structure-specific endonuclease MUS81 [45]. Cleavage of detrimental DNA structures by MUS81 leads to an accumulation of cytosolic DNA in cancer cells, which promotes type I IFN production through STING [46]. Moreover, DNA damage followed by mitosis progression generates micronuclei due to chromosome mis-segregation in cancer cells [47]. Rupture of the micronuclei envelopes exposes chromatin DNA that is recognized by cGAS and activates the cGAS– STING pro-inflammatory response [7,8].  

最近研究表明肿瘤细胞内的胞质自身DNA会激活cGAS-STING通路,并且影响肿瘤发育。通过结构特异的核酸内切酶(endonuclease)MUS81,肿瘤细胞内因为DNA复制的紊乱而导致的复制叉(replication folks)停滞会被修复。 肿瘤细胞中,MUS81剪切后产生的对机体有害的DNA片段会造成胞质DNA的积累,从而激活STING通路来完成I型IFN的合成。另外,肿瘤细胞中有丝分裂时,染色体分离紊乱造成的DNA损伤会使细胞产生微核(micronuclei),当微核的包膜(envelope)破裂后,暴露的染色体DNA就会被cGAS识别,从而激活cGAS-STING通路去合成炎症因子。

*复制叉(replication fork),有时也称作生长点(growing point),是DNA复制时在DNA链上通过解旋、解链和SSB蛋白的结合等过程形成的Y字型结构。

*微核(英语:Micronucleus)是细胞的染色体发生断裂后,细胞进入下一次分裂时,染色体片段不能随有丝分裂进入子细胞,而在细胞质中形成直径小于主核的、嗜色与主核一致、完全与主核分开的异常的圆形或椭圆形核。微核效应(英语:Micronucleus effect)就是环境中的有毒物导致染色体结构变化或纺锤体功能失调而形成微核的作用。因此,微核试验(英语:Micronucleus test)就是检测某种化学物质对染色体或有丝分裂器损伤的一种基因毒性试验方法。

Activation of the intrinsic cGAS–STING pathway by cytosolic DNA has been suggested to play a role in cellular senescence, a prominent tumor suppression mechanism. Various stress conditions cause cells to enter senescence, a state of irreversible cell cycle arrest [48,49]. Culturing mouse embryonic fibroblasts (MEFs) at ambient atmospheric O2 levels induces cellular senescence. Intriguingly, acceleration of cell proliferation and attenuation of senescent phenotypes occur in MEFs deficient for cGAS [9,10] and STING [10]. In addition, the cGAS–STING pathway also promotes senescence in response to oxidative stress, genotoxic stress, irradiation, and oncogene expression in MEFs and primary human fibroblasts [9,10]. 

Activation of the cGAS–STING pathway in senescent cells is associated with loss of the nuclear lamina protein lamin B1 and recognition of aberrant cytosolic chromatin fragments by cGAS [10,11]. Accordingly, the cGAS–STING pathway mediates production of type I IFNs and senescence-associated secretory phenotype (SASP) factors to promote senescence [9,10]. Notably, the cGAS– STING pathway also facilitates in vivo production of SASP factors [10,11] and senescence induced by irradiation and oncogenic Ras protein [10]. In addition, the cGAS–STING pathway is required for immune-mediated clearance of senescent hepatocytes induced by oncogenic Ras in mice [10,11].

在细胞衰老中,胞质DNA促进的cGAS-STING通路也承担了重要作用,而这在肿瘤抑制治疗中也很重要。细胞衰老可以由很多中压力造成,而细胞衰老是一种细胞周期不可逆的状态。在大气氧气含量下培育小鼠胚胎成纤维细胞(MEFs)会导致细胞衰老。有趣地是,在小鼠胚胎成纤维细胞中如果有cGAS和STING的缺陷,细胞衰老的表型会减退,并有细胞增殖的促进。另外,在MEFs以及主要的人成纤维细胞,cGAS-STING通路也会在氧化压力、基因毒性压力、辐射以及肿瘤基因的表达会促进细胞的衰老。

衰老细胞中cGAS-STING通路的激活,与核纤层蛋白B1的遗失以及cGAS对异常胞内染色质片段的识别有关。因此,cGAS-STING通路介导了I型IFN、衰老相关联的分泌表型因子(sasp factor)的生成来促进细胞衰老。值得一提的是,cGAS-STING通路也会在辐射以及致癌Ras蛋白处理后,促进体内SASP因子的生成以及细胞衰老。另外,致癌Ras因子处理的小鼠中,cGAS-STING通路在免疫介导的衰老肝细胞的消除也有一定作用。

*核纤层蛋白(英语:Nuclear lamins)也被称为第五类中间纤维(Class V intermediate filaments),是细胞核中提供结构功能和调控转录的纤维蛋白。核纤层蛋白与膜相关蛋白相互交织,形成了核膜内侧下方的核纤层。核纤层蛋白涉及有丝分裂中核膜的解体与重建,以及核孔的定位。

Together, these studies indicate that cGAS–STING pathway activation may suppress cancer development by inducing cellular senescence and by promoting immuno-surveillance. Consequently, disruption of the cGAS–STING pathway may facilitate tumor development. Consistently, cGAS–STING pathway suppression has been observed in colorectal carcinoma, melanoma, and cancer cells lacking telomerase (see below) [12,50,51]. In addition, there is a high mortality rate among gastric cancer patients with low STING expression [52]. Mutation in cGAS or STING is rare in cancer, so the epigenetic and post-translational mechanisms [5] by which cGAS and STING are suppressed remain to be elucidated.

综上所述,这些研究表明cGAS-STING通路的激活可以通过细胞衰老以及免疫监视来抑制癌症的发育。总而言之,如果该通路受到损坏,就会促进肿瘤的发育。在结直肠癌,黑色素瘤以及缺乏端粒酶的癌细胞中都有观察到。另外,胃癌患者如果STING表达量比较低则死亡率就会升高。cGAS或STING的突变在癌症中很少,所以他们在表观遗传以及翻译后的层面上的抑制机制还有待阐述。


Sensing of free telomeric DNA from ALT by cGAS–STING


A recent study revealed that activation of the cGAS–STING pathway by free cytosolic DNA derived from telomeres may have a tumor suppressive role in the development of cancers using the ALT (alternative lengthening of telomeres) mechanisms for telomere maintenance [12]. Telomeres obscure the ends of linear chromosomes from surveillance by the DNA repair machinery, thereby maintaining genome stability [53,54]. In human somatic cells, telomeres gradually shorten over time due to a lack of telomerase activity, and ultimately, critically short telomeres trigger a DNA damage response, resulting in cell senescence [55]. However, by regaining telomerase expression, telomeres can be maintained in a majority of tumors [56,57]. In the absence of telomerase, cancer cells utilize the ALT mechanisms that are based on homologous recombination (HR) to maintain telomeres [58,59]. ALT is particularly common in tumors of the central nervous system and soft-tissue sarcomas [60]. Accompanying the ALT mechanism, extrachromosomal telomere repeat (ECTR) DNA is generated by spontaneous telomere trimming and telomeric HR in ALT cancer cell lines and in vitro-transformed ALT cells [61–64]. It has been shown that ALT cells can contain ~50% of telomeric DNA in the form of ECTR [65].

最近有研究表明cGAS-STING通路被从端粒发展而来的胞质DNA激活后,可能会在运用ALT(alternative lengthening of telomeres,端粒替代性延长)机制维持端粒长度稳定性的癌细胞中发挥抑制作用。通过DNA修复机制的监察,端粒可以模糊线状染色体的真正末端,因此可以维持基因组的稳定性。在人体细胞中,因为端粒酶的活性被抑制,端粒在一次又一次的复制中不断变短,直到最后非常短的端粒会触发DNA伤害响应,诱导细胞衰老死亡。在没有端粒酶活性的癌症细胞中(通常cancer cell通过激活端粒酶活性来达到无限增殖),细胞会利用ALT机制通过同源重组(HR)来维持端粒长度。ALT在中枢神经系统肿瘤以及软组织毒瘤中普遍存在。伴随ALT机制的是,在ALT癌细胞株和体外转化的ALT细胞中,染色体外端粒重复序列(ECTR) DNA是通过自发的端粒修剪和端粒HR产生的。在ECTR形成过程中,ALT细胞可以包含约50%的端粒DNA。

*端粒替代延长通路(一种基于DNA修复常见通路同源重组的通路,名为alternative lengthening of telomeres, ALT)

*端粒可能使用两种方法通过同源重组来维持其长度。第一种方法中,姐妹端粒之间的不等DNA交换,会产生一个更长的端粒和一个更短的端粒,子细胞会继承这种特殊长度的端粒。继承更长端粒的细胞的增殖能力优于短端粒的细胞。第二种方法中,端粒DNA通过端粒模板来合成。端粒模板有两种来源,一种是姐妹染色体端粒中的现有片段,一种是ALT细胞中发现的、被称为染色体外端粒(extrachromosomal telomeric DNA)的重复DNA游离分子。

Apart from serving as a hallmark of ALT, ECTRs in human fibroblast cells can activate cGAS–STING signaling [12]. Chen et al artificially generated ECTRs in fibroblast cells through ectopically expressing TRF2DB, a dominant-negative mutant form of the telomeric protein TRF2 [63]. TRF2 promotes the formation and stabilization of telomere loop (T-loop) structures, whereas TRF2DB triggers homologous recombination and T-loop excision [63]. ECTRs generated by TRF2DB induce IFN-b expression via the cGAS–STING– TBK1–IRF3 signaling axis and impair cell proliferation [12]. 

However, unlike in human fibroblasts, the presence of ECTRs in ALT cancer cell lines does not elicit type I IFN production nor cause cell growth impairment, even when TRF2DB is expressed [12]. This might be attributed to a universal defect in the cytosolic DNA sensing mechanism in ALT cancer cells due to a lack of STING expression. Analyses of in vitro-derived ALT cell lines demonstrated that inhibition of STING expression, via transcriptional and post-transcriptional controls, is associated with ALT-mediated cell immortalization [12]. 

除了作为ALT的特点,ECTR在人类成纤维细胞中也可以激活cGAS-STING信号。Chen等人通过异位表达TRF2DB,收集了成纤维细胞中的ECTR。TRF2△B是端粒蛋白TRF2的一种主要的消极型突变体。TRF2促进了T-loop(端粒T环)结构的形成和稳定,然而TRF2DB却会激活同源重组以及T-loop的破裂。TRF2B招募的ECTR会促使IFN-b通过cGAS-STING-TBK1-IRF3通路表达,以此削弱细胞的增殖。

然而,和人体成纤维细胞不同,ALT癌症细胞系中ECTR的存在并不会促进I型IFN的合成,也不会造成癌细胞增殖的抑制,即使TRF2B也表达也都不会。这就可能是因为ALT癌症细胞中,STING表达量下降,导致胞质DNA感知机制的缺陷。体外的ALT细胞系的分析表明,通过转录以及转录后控制STING表达的抑制,会与ALT介导的细胞无限增殖有关。

*T-loop:维持线性染色体的一大挑战在于必须防止DNA末端被检测为DNA损伤。这个问题可以通过端粒来解决,端粒是保护染色体末端的非编码DNA特殊结构。科学家们认为端粒可以保护染色体末端的一种方式是采用套索状的t环结构,该结构可将DNA末端掩埋在端粒中并掩盖它,使其不会被检测为DNA损伤。这些环是由染色体末端端粒向后折叠而形成的,可以缠绕或解开。

Chen et al [12] also showed that ATRX, Daxx, and H3.3 are required for ECTR-induced IRF3 phosphorylation and IFN-b expression in BJ fibroblasts. ATRX–Daxx–H3.3 deficiency in various human cancers and cell lines is highly associated with ALT activity [66–69]. ATRX and Daxx form a histone chaperon complex, which deposits histone variant H3.3 at heterochromatic regions including telomeres [70]. Loss of ATRX causes ALT phenotypes, such as ECTR production, and replication fork stalling, which can promote telomere recombination [71,72]. Based on its role in ECTR sensing, ATRX–Daxx–H3.3 mutations may attenuate IFN-b induction in response to ECTR accumulation during initial ALT development. Following ALT establishment, however a further loss of cGAS or STING expression may be required for cancer cells to tolerate abundant ECTRs that normally impede cell proliferation. 

Chen等人也发现ATRX,Daxx以及H3.3在BJ成纤维细胞中,ECTR促使的IRF3的磷酸化以及IFN-b的表达中非常重要。在很多人类癌症细胞中的ATRX–Daxx–H3.3缺陷斗鱼ALT活性有关。ATRX以及Daxx合成了组蛋白监护复合体,可以在包括端粒在内的异染色质区域沉积组蛋白辩题H3.3。ATRX的缺失会造成ALT的表型,比如ECTR的产生,复制叉的阻滞——可以促进端粒的重组。基于ATRX–Daxx–H3.3对ECTR感知,它们的突变会在ECTR积累后通过促进ALT的发展,减弱IFN-b的合成。ALT机制建成后,就会造成更多的cGAS或者STING的表达,因为癌细胞需要去容纳足够的ECTR去无限增殖。

The mechanism by which ATRX–Daxx–H3.3 senses ECTRs remains to be determined. It is also unknown whether ATRX–Daxx– H3.3 is involved in activation of the cGAS–STING pathway by micronuclei and other cytoplasmic chromatin fragments. It is clear that ECTR generation is associated with ALT development and high levels of ECTRs are present in ALT cells. Thus, ALT cancer can serve as a model to investigate the role of cGAS–STING signaling in tumor formation and the mechanisms leading to inactivation of the cGAS–STING pathway during tumor progression.

ATRX–Daxx–H3.3如何感知ECTR的机制目前还有待阐述。ATRX–Daxx–H3.3是否通过微核或者其他胞质染色质片段参与cGAS-STING通路的激活也是未知的。但ECTR的发生与ALT发展是有关的,ALT细胞中也有非常高水平的ECTR存在。因此,ALT癌症可以作为一个切入点去研究cGAS-STING通路在肿瘤形成中的重要性,ALT也会在肿瘤发生过程中去抑制cGAS-STING通路。


Pro-tumor role of cGAS–STING

As discussed in previous sections, activation of the cGAS–STING signaling pathway upregulates IFN production and exerts anti-tumor roles by mediating innate immune responses [6]. However, other studies revealed that cGAS–STING pathway activation promotes tumor development. Chronic stimulation of the cGAS–STING pathway may induce inflammation-driven carcinogenesis. For example, 7,12-dimethylbenz(a)anthracene (DMBA) is a carcinogen that induces DNA breakage and promotes skin tumorigenesis in mice through STING activation [73]. Nuclear DNA leakage activates STING and induces production of inflammatory cytokines and skin inflammation. Importantly, bone marrow transplant experiments suggest that STING in hematopoietic stem cells plays a significant role in DMBA-induced skin tumorigenesis [73]. Similar roles of the host cGAS–STING pathway have been reported in the induction of tumor growth of Lewis lung carcinoma [74]. 

在前面的章节中也提到过,cGAS-STING通路的活性上调了IFN的合成,并且通过介导免疫应答从而发挥了抗肿瘤的作用。然而,其它研究也有证明cGAS-STING通路的活性也会促进肿瘤的发生。cGAS-STING通路的长期刺激可能会促进炎症引导的致癌后果。比如,7,12-二甲基苯并[a]蒽(DMBA)是一种致癌物质,当在小鼠中激活STING后,其可以促使DNA断裂并且引发皮肤癌。核酸DNA的逸出会激活STING,并且促进炎症因子的产生以及皮肤炎症的发生。更重要的是,骨髓移植实验显示,造血干细胞(hematopoietic stem cells )中的STING在DMBA促使的皮肤癌中有重要作用。Lewis肺癌的发生中,cGAS-STING通路也有相同作用。

*DMBA:7,12-二甲基苯并[a]蒽是一种免疫抑制剂和强效的有机致癌物质。在生物实验室中,DMBA常用于癌症模型的造模,即用DMBA诱导细胞组织癌变,可与佛波醇-12-O-十四烷酰-13-乙酸酯联合使用来加速癌症模型的研究。

The cGAS–STING pathway was shown to promote brain metastasis in both cell-autonomous and non-autonomous manners. STING activation in astrocytes mediates brain metastasis of breast and lung cancer cells [75]. Intriguingly, cGAMP is produced in cancer cells and trafficks through carcinoma–astrocyte gap junctions to activate STING in astrocytes. In response to STING activation, inflammatory cytokines and tumor necrosis factor are produced and in turn activate the STAT1 and NF-jB pathways in cancer cells. These paracrine effects support cancer cell growth and confer metastatic brain cell chemo-resistance [75].

cGAS-STING通路已经被证实可以促进肿瘤向大脑的转移,无论是细胞自主或者不自主机制。星形胶质细胞(astrocytes)中STING的激活可以促进乳腺癌以及肺癌细胞向大脑的扩散。有趣的是,癌细胞中会生产cGAMP,并通过癌细胞-星形胶质细胞之间的缝隙连接去激活星形胶质细胞中的STING。为了响应STING的激活,炎症因子以及肿瘤坏死因子会被合成,并且转而在癌细胞中激活STAT1与NF-kB通路。这些副作用促进了癌细胞的生长并且会提高扩散后的癌细胞的化疗耐受。

cGAS–STING activation also mediates metastasis in a cell-autonomous manner. Chromosomal instability (CIN) caused by mis-segregation of chromosomes during cell division is associated with human brain cell metastasis. In metastasis models, CIN promotes micronuclei formation and activates the cGAS–STING pathway, which induces non-canonical NF-jB signaling but not type I IFN signaling [76]. CIN-driven metastasis depends on STING and NF-jB signaling and associates with the induction of epithelial-to-mesenchymal transition and inflammation-related genes [76].

cGAS-STING的激活也会介导细胞自主的扩散,细胞分裂时染色体分离异常导致的染色体不稳定性(Chromosomal instability,CIN)会与人体脑转移(brain metastasis)相关。在脑转移模型中,CIN会促进微核的产生,并且激活cGAS-STING通路,这会促进非典型的(non-canonical)NF-kB信号——这并不会促进I IFN的合成。CIN促使的癌细胞转移取决于STING和NF-kB的信号,并且与上皮细胞间质转化以及炎症相关基因有关。

*脑转移(brain metastasis):统计结果显示,8%~10%的恶性肿瘤患者会发生转移。 发生脑转移的肿瘤以肺癌、乳腺癌、恶性黑色素瘤、消化道肿瘤、肾癌较常见。 其中,肺癌脑转移约占40%,以肺小细胞癌和腺癌居多。 有文献报道,小细胞未分化癌如生存期超过两年者,脑转移率达到80%。

*上皮细胞间质转化epithelial-to-mesenchymal,EMT)的激活是癌细胞转移的关键过程,在此过程中,上皮细胞得间充质细胞的特征,细胞运动性和迁移能力增强。 EMT 的特征在于上皮细胞标志物(例如cytokeratins和E-cadherin)缺失,质细胞标志物(例如N-cadherin、vimentin和纤连蛋白)的表达上调。


Targeting the cGAS–STING pathway as a cancer therapy

Oncolytic DNA viruses for cancers lacking an effective cGAS–STING pathway


Concluding remarks and future perspectives(本节为机翻,请见谅)

Recent studies demonstrate that activation of the cGAS–STING pathway by cellular DNA from tumors influences the development of cancer. Although the cGAS–STING pathway is thought to be involved in host immune-mediated tumor control, it remains unclear how tumor-derived DNA is delivered to antigen-presenting cells, and how DNA leaks from the nucleus into the cytosol to activate the cGAS– STING pathway. A better understanding of how the cGAS–STING pathway mediates anti-tumor effects will inform the utilization of STING agonists in cancer therapy. However, given that cGAS–STING pathway activation also associates with tumor metastasis and autoimmune disorders, therapeutic windows and side effects must be considered for the potential use of STING agonists in cancer therapy. Furthermore, it has been shown that an intensified STING response occurs in T cells, but not in MEFs, DCs, or macrophages, and triggers apoptosis [95]. This cell type-specific effect of STING activation suggests that a more detailed understanding of STING signaling responses in different cell types is necessary and crucial for using CDNs in cancer therapy. Moreover, for the cancer cell types that exhibit loss of either cGAS or STING functions (such as colorectal, melanoma, and ALT cancer cells), oncolytic viruses may represent an alternative therapeutic approach. Studies have shown that the cGAS– STING signaling pathway can exhibit cell- and context-dependent anti-tumor and tumorigenic effects. The distinct roles of the cGAS– STING pathway may be determined by differential activation of the downstream IRF3 and NF-jB pathways. Although the underlying mechanisms causing pathway deregulation in cancer cells remain unknown, such alterations may promote immunosuppression in the tumor microenvironment and thereby result in tumorigenesis and metastasis. Accordingly, the dichotomous roles of the cGAS–STING pathway in different cancers must be clearly and better characterized before targeting this pathway as a therapeutic approach.

最近的研究表明,肿瘤细胞DNA激活cGAS-STING通路影响癌症的发展。尽管cGAS - STING通路被认为参与宿主免疫介导的肿瘤控制,但目前尚不清楚肿瘤来源的DNA是如何被运送到抗原提呈细胞的,以及DNA是如何从细胞核渗漏到细胞质中来激活cGAS - STING通路的。更好地了解cGAS-STING通路如何介导抗肿瘤作用,将有助于在癌症治疗中使用STING激动剂。然而,考虑到cGAS-STING通路的激活也与肿瘤转移和自身免疫性疾病相关,在使用STING激动剂治疗癌症时必须考虑治疗窗口和副作用。此外,已有研究表明,T细胞中会发生强烈的STING反应,而mef、DCs或巨噬细胞中不会,并触发细胞凋亡[95]。STING激活的这种细胞类型特异性效应表明,更详细地了解不同细胞类型的STING信号应答对于在癌症治疗中使用cdn是必要和关键的。此外,对于表现出cGAS或STING功能丧失的癌细胞类型(如结直肠癌、黑色素瘤和ALT癌细胞),溶瘤病毒可能是另一种治疗方法。研究表明,cGAS - STING信号通路可表现出细胞和环境依赖的抗肿瘤和致瘤作用。cGAS - STING通路的不同作用可能取决于下游IRF3和NF-kB通路的不同激活。虽然导致肿瘤细胞通路解除的潜在机制尚不清楚,但这种改变可能会促进肿瘤微环境中的免疫抑制,从而导致肿瘤发生和转移。因此,在将cGAS-STING通路作为一种治疗方法之前,必须明确和更好地描述cGAS-STING通路在不同癌症中的两分法作用。


全文完,希望对有需要的人有帮助~



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