Mechanisms of Inorganic Carcinogenesis

无机致癌机制

• 批准号: 8157181
• 负责人: MICHAEL WAALKES
• 金额: $ 82.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157181
• 关键词: carcinogenesis

Many inorganics are human carcinogens and pose major hazards to after environmental or occupational exposure. Arsenic and cadmium are two of the most important inorganic carcinogens and with arsenic alone over 100 million people world-wide are exposed to clearly unhealthy levels via contaminated drinking water in what is likely the worst mass poisoning in human history. Defining carcinogenic mechanisms will greatly aid in designing prevention or intervention strategies and in assigning appropriate levels of risk to these exposures. The primary goal of the ICS is to define the molecular mechanisms of carcinogenic action of arsenic and cadmium under the project titled Molecular Mechanisms of Inorganic Carcinogenesis. Since they can impact carcinogenicity and potentially provide a means for prevention or intervention, mechanisms of adaptation and acquired tolerance are studied as well. Emphasis is placed on key factors that dictate sensitivity, such as early-life exposure and poor expression of critical adaptive genes. These inorganics attack various targets sites in humans. Arsenic causes skin, urinary bladder, lung, kidney, liver, and prostatic malignancies and likely uterine cancers. Cadmium is primarily associated with human lung, prostatic and kidney cancers and recently pancreatic cancers. All these sites may have distinct differences in mode of action and adaption. Thus, various in vitro and in vivo model systems have been developed to study important molecular targets in targets tissues, with an emphasis on human relevance. These inorganic carcinogens likely have multiple mechanisms that are site and cell specific. A reproducible rodent model where inorganic arsenic acts a complete carcinogen has been developed in which brief in utero arsenic exposure in mice leads to tumors or proliferative lesions of the urogenital system, liver, lung and adrenal in the offspring as adults. The urogenital system lesions include transplacental arsenic-induced or initiated tumors of the ovaries, uterus, vagina, and bladder and proliferative lesions of the kidney. These results are in accord with human studies that indicate the liver, urinary bladder, lung, kidney and uterus are target tissues of arsenic carcinogenesis. Molecular mechanism studies indicate disruption of estrogen signaling by in utero exposure to arsenic contributes to the liver, lung and urogenital system malignancies, in part through aberrant activation of estrogen receptor-a. Indeed, we find that tumors and proliferative lesions of the urogenital system, including the uterus, ovary, vagina and urinary bladder, are greatly enhanced by postnatal exposure to synthetic estrogens like diethylstilbestrol. We also find evidence of aberrant estrogen signaling in arsenic exposed human liver. Further molecular characterization of arsenic-induced in utero tumor initiation is underway, including aberrant gene imprinting, using this model of arsenic carcinogenesis. We hypothesize that arsenic in utero may attack a critical pool of stem cells in target organs and induces aberrant genetic reprograming as part of its carcinogenic mechanism. These studies have important public health implications, including the identification of early life period as a time of very high sensitivity to arsenic. Human data is now emerging that fetal and/or early life exposure to arsenic is clearly carcinogenic. Further study will include prenatal arsenic exposure combined with exposures to urinary bladder and renal tumor promoters in mice to enhance the carcinogenic response to arsenic in these key human target organs. Various in vitro cell transformation model systems have also been developed to study inorganic carcinogenesis. In doing these studies we select cells with relevance to the human targets of arsenic, cadmium or lead carcinogenesis, and use low-level exposures for long periods, which approximates typical human exposures and avoids supra-physiological responses associated with acute high doses that could have limited relevance to the carcinogenic process. A human prostate epithelial cell line has been malignantly transformed with cadmium and arsenic, both potential human prostatic carcinogens. Additional work indicates the arsenic and cadmium transformants both acquire androgen independence, an event associated with a very poor clinical prognosis in prostatic cancer patients, largely through androgen receptor by-pass related mechanisms. Molecular dissection of the events associated with arsenic- or cadmium-induced malignant transformation in this and other human cell lines will continue with a focus of aberrant expression of genes critical to the carcinogenic process. In addition, a human prostate stem cell line has been developed and we have show it is malignantly transformed by arsenic through a combination of selection due to a survival advantage over mature heterogenous populations, and due to aberrant stimulation of self-replication genes typical for stem cells populations. We have further found that malignant transformants induced by arsenic with recruit nearby normal stem cells in transwell experimentation. Similarly, during skin cell transformation, arsenic causes an overabundance of skin cancer stem cells. This creates the distinct possibility that arsenic causes cancer by attack on stem cell populations. Indeed, in a mouse in vivo model of skin cancer, we have found that arsenic in utero causes over production of cancer stem cells in adult skin squamous cell carcinoma apparently by distorting fetal skin stem cell dynamics. Other tumors model systems are now being investogated. Furthermore, we have successfully transformed a human pancreatic ductal cell with cadmium, which fortifies a possible role of cadmium in this deadly disease. In this case it appears that cadmium initially kills back stem cells. However, after this bottle-neck effect the stem cell emerge transformed and capable of malignant behavior. This is consistent with cadmium as a single dose carcinogen. We are now seeing this effect in other lines with cadmium. Many cell biomethylate arsenic using specific methyltransferases S-adenosylmethionine (SAM) as the methyl group donor. We have found that cells that do not biomethylate arsenic cannot induce oxidative DNA damage (ODD). This is a very important finding because many target cells do not biomethylate arsenic but none-the-less become malignantly transformed by the metalloid. This likely indicates multiple mechanisms are operative with arsenic, some of which are genotoxic (ODD) and some of which may not be.

许多无机药物是人类致癌物，对环境或职业暴露构成了重大危害。砷和镉是最重要的两种无机致癌物中的两个，仅全球范围内有超过1亿人的砷通过被污染的饮用水暴露在人类历史上最严重的大规模中毒，这显然是不健康的水平。定义致癌机制将极大地有助于设计预防或干预策略，并为这些暴露措施分配适当水平的风险。 ICS的主要目的是定义砷和镉在该项目中的致癌作用的分子机制，称为无机致癌的分子机制。由于它们可以影响致癌性，并有可能提供预防或干预的方法，因此也研究了适应性和获得的耐受性的机制。重点放在决定灵敏度的关键因素上，例如早期暴露和关键适应基因的表达不佳。这些无机物质攻击了人类的各种目标站点。砷会导致皮肤，膀胱，肺，肾脏，肝脏和前列腺恶性肿瘤以及可能的子宫癌。镉主要与人类肺，前列腺和肾脏癌以及最近的胰腺癌有关。所有这些站点在作用方式和适应方式上可能有明显的差异。因此，已经开发出各种体外和体内模型系统来研究目标组织中的重要分子靶标，重点是人类相关性。这些无机致癌物可能具有多种位点和细胞特异性机制。一种可再现的啮齿动物模型，其中已经开发出一种完整的致癌物，在该模型中，在小鼠的子宫砷暴露中的简短导致泌尿生殖系统，肝脏，肺，肺和肾上腺的肿瘤或增生性病变，成人作为成人。泌尿生殖器系统病变包括卵巢，子宫，阴道和膀胱肿瘤的移植砷诱导或引发的肿瘤，以及肾脏的增殖性病变。这些结果与表明肝脏，膀胱，肺，肾脏和子宫的人体研究是一致的，这是砷癌发生的靶组织。分子机制研究表明，在子宫内暴露于砷中，雌激素信号传导破坏了砷，肺和泌尿生殖系统恶性肿瘤，部分原因是雌激素受体A的异常激活。实际上，我们发现泌尿生殖系统的肿瘤和增生性病变，包括子宫，卵巢，阴道和膀胱，通过产后暴露于二乙基替尔贝特罗（如二乙基替代）的合成雌激素会大大增强。我们还发现砷暴露的人肝脏中异常雌激素信号传导的证据。使用这种砷癌变模型，包括异常基因印记，包括异常基因印记，包括砷诱导的砷诱导的进一步分子表征。我们假设子宫中的砷可能会攻击目标器官中的干细胞的关键池，并引起异常的遗传重编程，作为其致癌机制的一部分。这些研究具有重要的公共卫生影响，包括将早期生命时期鉴定为对砷敏感的时期。现在，人类数据正在出现，胎儿和/或早期生命暴露于砷显然是致癌的。进一步的研究将包括产前砷暴露，以及在小鼠中对膀胱和肾肿瘤启动子的暴露，以增强这些主要人类靶心器官对砷的致癌反应。还开发了各种体外细胞转化模型系统来研究无机癌变。在进行这些研究时，我们选择了与砷，镉或癌症的人类靶标相关的细胞，并长期使用低级暴露，这近似于典型的人类暴露，并避免了与急性高剂量相关的超级生理学反应，这些反应可能与急性高剂量相关，这些反应可能限制与致癌过程相关。人类前列腺上皮细胞系已被镉和砷（均为潜在的人类前列腺致癌物）恶化。其他工作表明，砷和镉转化子都获得了雄激素独立性，这一事件与前列腺癌患者的临床预后非常差有关，主要是通过雄激素受体旁路相关的机制。在该和其他人类细胞系中与砷或镉诱导的恶性转化相关的事件的分子解剖将继续以对致癌过程至关重要的基因表达的重点。此外，已经开发了人类前列腺干细胞系，我们已经证明，由于与成熟的异质种群的生存优势相结合，砷通过砷的结合而恶意转化，并且由于对干细胞种群典型的自我复制基因的异常刺激。我们进一步发现，在Transwell实验中，砷引起的恶性转化因子在附近的正常干细胞附近。同样，在皮肤细胞转化期间，砷会导致皮肤癌干细胞的过度。这产生了一种明显的可能性，即砷通过对干细胞群体的攻击引起癌症。实际上，在小鼠的体内皮肤癌模型中，我们发现子宫内的砷在成年皮肤鳞状细胞癌中的产生而导致癌细胞的产生显然是通过扭曲胎儿皮肤干细胞动力学而导致的。其他肿瘤模型系统现在正在投资。此外，我们已经成功地将人类胰管细胞与镉转化为镉，这在这种致命的疾病中可能起到了可能的作用。在这种情况下，镉似乎最初会杀死后部干细胞。然而，在这种瓶颈后，干细胞出现了并能够转变为恶性行为。这与镉作为单剂量致癌一致。现在，我们正在与镉的其他线中看到这种效果。许多细胞生物甲基化砷都使用特异性甲基转移酶S-腺苷甲硫氨酸（SAM）作为甲基供体。我们发现，不生物甲基化砷的细胞不能诱导氧化性DNA损伤（奇数）。这是一个非常重要的发现，因为许多靶细胞没有生物甲基化砷，但仍会被金属遗物变形。这可能表明多种机制具有砷的操作，其中一些是遗传毒性（奇数），其中一些可能不是。

项目成果

Strain difference of cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 rats.

• DOI: 10.1016/j.tiv.2007.09.013
• 发表时间: 2008-03
• 期刊: Toxicology in vitro : an international journal published in association with BIBRA
• 作者: H. Shimada;A. Yasutake;Takaomi Hirashima;Yasutaka Takamure;T. Kitano;M. Waalkes;Y. Imamura

Potential role of alpha-synuclein and metallothionein in lead-induced inclusion body formation.

α-突触核蛋白和金属硫蛋白在铅诱导的包涵体形成中的潜在作用。

• DOI: 10.1093/toxsci/kfp132
• 发表时间: 2009
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Zuo,Peijun;Qu,Wei;Cooper,RyanN;Goyer,RobertA;Diwan,BhalchandraA;Waalkes,MichaelP
• 通讯作者: Waalkes,MichaelP

Cadmium malignantly transforms normal human breast epithelial cells into a basal-like phenotype.

• DOI: 10.1289/ehp.0900999
• 发表时间: 2009-12
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Benbrahim-Tallaa L;Tokar EJ;Diwan BA;Dill AL;Coppin JF;Waalkes MP
• 通讯作者: Waalkes MP

Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics.

子宫内的砷暴露会加剧成年后的皮肤癌反应，同时导致肿瘤干细胞动力学的扭曲。

• DOI: 10.1158/0008-5472.can-08-2099
• 发表时间: 2008-10-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Waalkes MP;Liu J;Germolec DR;Trempus CS;Cannon RE;Tokar EJ;Tennant RW;Ward JM;Diwan BA
• 通讯作者: Diwan BA

Inorganic arsenic and human prostate cancer.

• DOI: 10.1289/ehp.10423
• 发表时间: 2008-02
• 期刊: ENVIRONMENTAL HEALTH PERSPECTIVES
• 影响因子: 10.4
• 作者: Benbrahim-Tallaa, Lamia;Waalkes, Michael P.
• 通讯作者: Waalkes, Michael P.