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.

许多无机物是人类致癌物，在环境或职业接触后会造成重大危害。砷和镉是两种最重要的无机致癌物，仅砷一项，全世界就有超过 1 亿人通过受污染的饮用水接触到明显不健康的水平，这可能是人类历史上最严重的大规模中毒事件。定义致癌机制将极大地有助于设计预防或干预策略以及为这些暴露分配适当的风险水平。 ICS 的主要目标是在名为“无机致癌作用的分子机制”的项目下确定砷和镉致癌作用的分子机制。由于它们可以影响致癌性并可能提供预防或干预手段，因此还研究了适应和获得性耐受的机制。重点放在决定敏感性的关键因素上，例如生命早期的暴露和关键适应性基因的表达不良。这些无机物攻击人体的各个目标部位。砷会导致皮肤癌、膀胱癌、肺癌、肾癌、肝癌、前列腺癌以及可能的子宫癌。镉主要与人类肺癌、前列腺癌和肾癌以及最近的胰腺癌有关。所有这些位点在作用方式和适应方面可能有明显的差异。因此，已经开发了各种体外和体内模型系统来研究靶组织中的重要分子靶点，重点是人类相关性。这些无机致癌物可能具有多种特定部位和细胞的机制。已经开发出一种可重复的啮齿动物模型，其中无机砷完全致癌，在该模型中，小鼠在子宫内短暂接触砷会导致成年后代的泌尿生殖系统、肝脏、肺和肾上腺出现肿瘤或增殖性病变。泌尿生殖系统病变包括经胎盘砷诱发或引发的卵巢、子宫、阴道和膀胱肿瘤以及肾脏的增殖性病变。这些结果与人体研究一致，表明肝脏、膀胱、肺、肾和子宫是砷致癌的靶组织。分子机制研究表明，子宫内接触砷会破坏雌激素信号传导，从而导致肝脏、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。事实上，我们发现泌尿生殖系统（包括子宫、卵巢、阴道和膀胱）的肿瘤和增殖性病变因产后接触己烯雌酚等合成雌激素而大大增强。我们还在砷暴露的人类肝脏中发现了异常雌激素信号的证据。砷诱导的子宫内肿瘤发生的进一步分子表征正在进行中，包括使用砷致癌模型的异常基因印记。我们假设子宫内的砷可能会攻击靶器官中关键的干细胞库，并诱导异常的基因重编程，作为其致癌机制的一部分。这些研究具有重要的公共卫生意义，包括确定生命早期是对砷非常敏感的时期。现在出现的人类数据表明，胎儿和/或生命早期接触砷显然会致癌。进一步的研究将包括产前砷暴露与小鼠膀胱和肾肿瘤促进剂的暴露相结合，以增强这些关键人类靶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致癌作用。在进行这些研究时，我们选择与砷、镉或铅致癌作用的人类目标相关的细胞，并长期使用低水平暴露，这接近典型的人类暴露，并避免与急性高剂量相关的超生理反应，这些反应可能会导致与致癌过程的相关性有限。人类前列腺上皮细胞系已被镉和砷恶性转化，这两种物质都是潜在的人类前列腺致癌物。其他工作表明砷和镉转化体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相关，主要是通过雄激素受体旁路相关机制。对该人类细胞系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剖析将继续关注对致癌过程至关重要的基因的异常表达。此外，人类前列腺干细胞系已经开发出来，并且我们已经证明，由于相对于成熟异源细胞群的生存优势，以及由于干细胞典型的自我复制基因的异常刺激，它可以通过组合选择而被砷恶性转化。细胞群。我们进一步发现，在transwell实验中，砷诱导的恶性转化体会招募附近的正常干细胞。同样，在皮肤细胞转化过程中，砷会导致皮肤癌干细胞过多。这就产生了砷通过攻击干细胞群而导致癌症的明显可能性。事实上，在小鼠皮肤癌体内模型中，我们发现子宫内的砷显然是通过扭曲胎儿皮肤干细胞动力学而导致成人皮肤鳞状细胞癌中癌症干细胞的过度产生。其他肿瘤模型系统目前正在研究中。此外，我们成功地用镉转化了人类胰腺导管细胞，这强化了镉在这种致命疾病中可能发挥的作用。在这种情况下，镉似乎最初会杀死干细胞。然而，在这种瓶颈效应之后，干细胞发生了转变并能够产生恶性行为。这与镉作为单剂量致癌物是一致的。我们现在在其他含镉产品线中看到了这种效应。许多细胞使用特定的甲基转移酶 S-腺苷甲硫氨酸 (SAM) 作为甲基供体来生物甲基化砷。我们发现，不将砷生物甲基化的细胞不能诱导氧化性 DNA 损伤 (ODD)。这是一个非常重要的发现，因为许多靶细胞不会将砷生物甲基化，但仍然会被类金属恶性转化。这可能表明砷具有多种作用机制，其中一些具有基因毒性（ODD），而另一些可能则不然。

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.