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按照经典致癌理论,肿瘤是致癌病毒感染导致细胞恶性增生的结果,如EB病毒引起鼻咽癌、人乳头瘤病毒引起宫颈癌。因此,当初的观点是致癌病毒基因组(包括癌基因)整合到人的染色体上导致细胞癌变。
后来,一项惊人的发现迫使人们改变了原来的看法:人类基因组上早就存在病毒癌基因的同源序列,被称为“原癌基因”。换句话说,人们不再把致癌病毒感染当做肿瘤发生的必要条件。
不过,人们仍然坚信,肿瘤发生必定是肿瘤抑制基因(抑癌基因)发生突变,不能抑制原癌基因异常表达导致的细胞癌变。比如,肿瘤抑制基因BRCA1/BRCA2突变会让妇女罹患乳腺癌,因为BRCA失活将使DNA损伤难以修复。
可是,后来发现幽门螺杆菌感染完全不涉及癌基因,却能通过诱发十二指肠溃疡最终发展成胃癌。于是,肿瘤抑制基因突变也不再成为致癌的先决条件,让人们从此开始认真思考炎症如何致癌的问题。
当前,炎症致癌犹如一个“黑箱”,知道原因和结果,但不知道中间过程。真正让肿瘤起源研究发生一场“革命”的是表观遗传学时代的到来,它为肿瘤成因的研究注入了新的活力。
从“炎”到“癌”很可能是表观遗传模式(染色体DNA/组蛋白共价修饰)从量变到质变的过程!它既可以解释基因突变,也可以解释染色体不稳定,这意味着教科书上有关肿瘤成因的陈旧而过时的概念必须改写,而且它正在把人们的目光引向一个令人豁然开朗的全新场景!
另一个让人刮目相看的领域是“诺贝尔级”研究:诱导胚胎干细胞(ESC)转变成多能干细胞(iPSC),而实现这一转变的竟然是几个癌基因编码的转录因子,被称为“山中伸弥因子”(Yamanaka factors)!有人认为iPSC就是肿瘤干细胞(CSC),目前尚无定论。
以下将就最近几年内有关肿瘤成因研究方面的最新研究进展作一个粗略回顾,力图把分散在顶尖学术期刊上的肿瘤起源问题的相关报道作一个初步梳理,希望抛砖引玉,供感兴趣的同行们参考。
表观遗传因素如何促进肿瘤形成?
Cell最近(Cell,2014,156:663-677)发表的一篇文章宣称,小鼠体内重编程的提前终止可以通过改变表观遗传调控导致肿瘤发生。它由此得出几个结论:重编程因子的瞬时表达可导致肿瘤发生;因重编程失败诱发的肿瘤出现表观遗传调节改变;重编程失败相关肾脏肿瘤类似于Wilms瘤;肾脏肿瘤来源的多能干细胞(iPSC)可产生非瘤性肾脏细胞。
也就是说,iPSC分化出肿瘤细胞只涉及表观遗传模式改变,而无需发生不可逆的遗传转化。不过,目前还不清楚这种癌变的特异性表观遗传模式,只能理解为癌变后表观遗传模式异常。至于表观遗传模式异常的原因,很可能是DNA甲基转移酶(甲基化酶)功能异常或失活,源于编码基因突变或酶分子修饰。
以下是该文题目及摘要:
Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation
Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer.
感染性炎症——细菌致癌
Science在2012年发表的一篇快报(Science,2012,338:120-123)探讨了大肠杆菌性肠炎与结肠癌及直肠癌的关系,结论是肠炎是微生物群落诱导癌症的关键因素。这篇文章的新意在于不仅证实了大肠杆菌感染与结直肠癌的关系,而且首次发现只有含“基因毒性岛”(genotoxic island)的大肠杆菌才能诱发结直肠癌。也就是说,过去认为只要是慢性炎症就能致癌的观点不全面,为特殊病原体所致炎症才能致癌的观点提供了新证据。
所谓“基因毒性岛”是指大肠杆菌基因组中的聚酮合酶基因(pks)编码序列。最新研究发现,如果把这个pks基因删除掉,尽管肠炎依旧,但致癌性和侵润性减弱。因此,结直肠癌归根结底还是由肠道细菌感染产生的聚酮类化合物诱发的。不过,聚酮合酶及聚酮类化合物如何参与炎症向癌症的转化还不清楚。这个实验是在一种特殊的小鼠中完成的,它们的抗炎症细胞因子——白细胞介素10(IL-10)基因被敲除,从而导致肠道菌群改变,大肠杆菌菌株占绝对优势,使偶氮甲烷处理小鼠的侵润性结直肠癌发生率大增。
在另一项研究中还发现,这种pkc+大肠杆菌属于肠粘膜结合细菌,它们在炎性肠病(IBD)及肠炎相关结直肠癌(CRC)患者肠道中所占比例极高。这个结果印证了在小鼠中得出的上述结论。在正常人中,pkc+毒性大肠杆菌仅有20%,IBD患者体内的毒性大肠杆菌则占40%,而结直肠癌患者体内的毒性大肠杆菌高达66.7%。同时,毒性大肠杆菌占优势的肠道中,非毒性菌群(如粪肠球菌)的比例同步减少。
下面是这篇文章题目和摘要:
Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota
Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that impacts the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10–deficient (Il10−/−) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)–treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10−/− mice, without altering intestinal inflammation. Mucosa-associated pks+ E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.
非感染性炎症——肥胖致癌
Cell在2010年发表的一篇文章(Cell,2010,140:197-208)指出,饮食及遗传性肥胖可以通过促进促炎症细胞因子白细胞介素6(IL-6)和肿瘤坏死因子(TNF)表达引起肝炎,后者激活致癌转录因子STAT,最终诱发肝细胞肝癌(HCC)。
以下是该文题目及摘要:
Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression
Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumorpromoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
促炎症细胞因子如何致癌?
Cell子刊在2012年发表的一篇论文(Cancer Cell,2012,22:645-655)首次揭示了白细胞介素15(IL-15)如何诱发大颗粒淋巴细胞白血病的机理。由于IL-15是免疫激活中释放的众多促炎症细胞因子之一,因此其与癌症相关联的发现预示着炎症致癌假说首次在白血病中获得证实。
JMCB于2012年发表的一篇论文(JMCB,2012,4:174-176)认为,缺氧及产能效率与细胞增殖信号传导的错联促进肿瘤细胞快速生长。该文写道:Various proposals have been made regarding the possible drivers of cancer growth such as driver mutations and autonomous growth signaling. While these are clearly relevant, they rely too much on specific types of genomic mutations or molecular abnormalities by chance across different cancer types, which makes the probability for cancer to occur/progress significantly lower than what we have witnessed about the current cancer occurrence rates worldwide, hence making them less probable to be the ultimate drivers of cancer growth。
Induced pluripotency and oncogenic transformation are related processes
Induced pluripotent stem cells (iPSC) have the potential for creating patient-specific regenerative medicine therapies, but the links between pluripotency and tumorigenicity raise important safety concerns. More specifically, the methods employed for the production of induced pluripotent stem cells (iPSC) and oncogenic foci (OF), a form of in vitro produced tumor cells, are surprisingly similar, raising potential concerns about iPSC. To test the hypotheses that iPSC and OF are related cell types and, more broadly, that the induction of pluripotency and tumorigenicity are related processes, we produced iPSC and OF in parallel from common parental fibroblasts. When we compared the transcriptomes of these iPSC and OF to their parental fibroblasts, similar transcriptional changes were observed in both iPSC and OF. A significant number of genes repressed during iPSC formation were also repressed in OF, including a large cohort of differentiation-associated genes. iPSC and OF shared a limited number of genes that were upregulated relative to parental fibroblasts but gene ontology analysis pointed toward monosaccharide metabolism as upregulated in both iPSC and OF. iPSC and OF were distinct in that only iPSCs activated a host of pluripotency-related genes, while OF activated cellular damage and specific metabolic pathways. We reprogrammed OF to produce iPSC-like cells, a process dependent on Nanog. However, the reprogrammed OF (ROF) had reduced differentiation potential compared to iPSC, suggesting that oncogenic transformation leads to cellular changes that impair complete reprogramming. Taken together, these findings support a model in which OF and iPSC are related, yet distinct cell types, and in which induced pluripotency and induced tumorigenesis are similar processes.
EMBO Rep,2014,15:244-253
Dedifferentiation and reprogramming: origins of cancer stem cells
Regenerative medicine aims to replace the lost or damaged cells in the human body through a new source of healthy transplanted cells or by endogenous repair. Although human embryonic stem cells were first thought to be the ideal source for cell therapy and tissue repair in humans, the discovery by Yamanaka and colleagues revolutionized the field. Almost any differentiated cell can be sent back in time to a pluripotency state by expressing the appropriate transcription factors. The process of somatic reprogramming using Yamanaka factors, many of which are oncogenes, offers a glimpse into how cancer stem cells may originate. In this review we discuss the similarities between tumor dedifferentiation and somatic cell reprogramming and how this may pose a risk to the application of this new technology in regenerative medicine.
从历史上看,肿瘤发生的“开关”被认为是主要由遗传机制(基因突变)控制的,而从现状来看,已经过渡到开始寻找肿瘤发生与表观遗传模式(DNA甲基化及组蛋白修饰)变化之间的关系。
尽管从炎症到癌症的机理还有很多细节不清楚,但我们仍然可以勾勒出一个大致的轮廓,或者说提出一个假说:促炎症细胞因子促进氧化应激与硝化应激,二者单独或联合作用,使DNA甲基化酶发生修饰失活或直接导致DNA甲基化酶基因突变,结果正常细胞的DNA甲基化模式向肿瘤细胞的DNA甲基化模式转变。
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