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【资源】Cell-of-Origin for Human Prostate Cancer Identified for First Time 已有1人参与
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ScienceDaily (July 29, 2010) — UCLA scientists have identified for the first time a cell-of-origin for human prostate cancer, a discovery that could result in better predictive and diagnostics tools and the development of new and more effective targeted treatments for the disease. The researchers, from UCLA's Jonsson Comprehensive Cancer Center, proved that basal cells found in benign prostate tissue could become human prostate cancer in mice with suppressed immune systems, a finding that bucks conventional wisdom. It had been widely believed that luminal cells found in the prostate were the culprits behind prostate cancer because the resulting malignancies closely resembled luminal cells, said Dr. Owen Witte, a Jonsson Cancer Center member and director of the UCLA Broad Stem Cell Research Center. "Certainly the dominant thought is that human prostate cancer arose from the luminal cells because the cancers had more features resembling luminal cells," said Witte, senior author of the study and a Howard Hughes Medical Institute Investigator. "But we were able to start with a basal cell and induce human prostate cancer and now, as we go forward, this gives us a place to look in understanding the sequence of genetic events that initiates prostate cancer and defining the cell signaling pathways that may be at work fueling the malignancy, helping us to potentially uncover new targets for therapy." The study appears July 30, 2010 in the peer-reviewed journal Science. The researchers took healthy tissue from prostate biopsies and separated the cells based on their surface marker expression into groups of luminal cells and groups of basal cells. Using viral vectors as vehicles, they then expressed altered genes known to cause cancer into both cell populations and placed the cells in mice to see which developed cancer, said Andrew Goldstein, a UCLA graduate student and first author of the study. "Because of the widespread belief that luminal cells were the root of human prostate cancer, it would have been those cells examined and targeted to treat the disease," said Goldstein. "This study tells us that basal cells play an important role in the prostate cancer development process and should be an additional focus of targeted therapies." In normal prostate tissue, basal cells have a more stem cell-like function, Goldstein said, meaning they proliferate more to re-grow human prostate tissue. Luminal cells don't proliferate as much, but rather produce major proteins that are important for reproduction. Something is going awry in the basal cells that results in cancer and Witte and Goldstein plan to study those cells to uncover the mechanisms that result in malignancy. Currently, there is a dearth of knowledge about how prostate cancer develops to treat it effectively in a targeted way, as Herceptin targets an out-of-control production of growth factor receptors in breast cancer cells. The major targeted therapy used for prostate cancer is directed at the androgen receptor and it is not always effective, Witte said. The new human-in-mouse model system developed in the study -- created by taking healthy human prostate tissue that will induce cancer once it is placed in mice instead of taking malignant tissue that is already cancerous and implanting it -- can now be used to evaluate the effectiveness of new types of therapeutics. By using defined genetic events to activate specific signaling pathways, researchers can more easily compare therapeutic efficacy. The new model, by deconstructing tissue and then reconstructing it, also will aid in analyzing how the cells change during cancer progression. "There are very few examples of taking benign cells and turning them into cancer experimentally," Goldstein said. "We usually study cancer cell lines created from malignant tumors. This study resulted in the creation of a novel model system that is highly adaptable, such that we can test any cellular pathway and its interactions with other genes known to induce cancer, and we can start with any type of cell as long as it can be reproducibly purified." In this system, Witte and Goldstein know the "history" of the cells that became cancer, unlike the cancer cells lines used in other work. "We know those cells are malignant, but we don't know how they got there," Goldstein said. "By starting with healthy cells and turning them into cancer, we can study the cancer development process. If we understand where the cancer comes from, we may be able to develop better predictive and diagnostic tools. If we had better predictive tools, we could look earlier in the process of cancer development and find markers that are better than the current PSA test at catching disease early, when it is more treatable." Rising PSA levels can indicate the presence of cancer that is already developing in the prostate. However, now that it is known that basal cells are one root of human prostate cancers, scientists can study pre-malignant basal cells and uncover what they express that the healthy ones don't, perhaps revealing a new marker for early detection, Goldstein said. Also, a therapy directed at the pre-malignant basal cells about to become malignant could provide a way to prevent the cancer before it becomes dangerous. This year alone, more than 217,000 men will be diagnosed with prostate cancer. Of those, more than 32,000 will die from their disease. The study was funded by a Prostate Cancer Foundation Challenge Award, the Howard Hughes Medical Institute and the Department of Defense. |
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首次发现前列腺癌细胞来源 今日科学2010年7月29日报道，UCLA科学家们首次发现了人前列腺癌的细胞来源，该发现可能更好地成为前列腺癌预测和诊断工具，并可开发新的和更加有效的靶向治疗方法。 来自于UCLA's Jonsson 综合癌症中心的研究人员采用免疫系统抑制的小鼠，证明了良性前列腺组织中的基底细胞可能变成前列腺癌，该研究发现颠覆了传统观点。Jonsson癌症中心成员，也是UCLA组干细胞研究中心主任Owen Witte博士说现在人们广泛认为前列腺腔上皮细胞是前列腺癌细胞来源，因为恶性上皮非常类似于腔上皮细胞。 “人前列腺癌起源于腔上皮细胞的观点为主是因为前列腺癌细胞特征更加类似于腔上皮细胞，”该项研究的高级作者，Howard Hughes医学研究所调查人员Witte说。“但是我们能从一个基底细胞开始并诱导出人前列腺癌，现在，随着我们继续努力，必将给我们提供了一个理解诱发前列腺癌发生的遗传学时间的顺序和定义可促使恶性转化的细胞信号途径的机会，有助于我们可能揭示新的治疗靶点。” 该项研究以同行评论的方式发表在2010年7月30日的《科学》杂志上。 研究人员采用前列腺活检的健康组织，根据它们的表面标记物表达将这些细胞分为腔细胞和基底细胞组。使用病毒载体作为赋形剂，然后他们将已知的能致癌的基因导入这2组细胞中，并将这些细胞注入小鼠细胞中观察哪个发展为癌。UCLA研究生和本研究的第一作者Andrew Goldstein说。 “由于人们普遍认为腔细胞是前列腺癌的细胞来源，所以这些细胞被检查和靶向治疗这种疾病，”Goldstein说：“这项研究告诉我们基底细胞在前列腺癌发展进程中发挥重要作用，应该成为靶向治疗的另一个焦点。” 在正常前列腺组织中，基底细胞具有更多的干细胞样功能，Goldstein说，意味着这些细胞可以增生并重新生长为前列腺组织。腔细胞虽然不增生，但可产生主要蛋白对再生具有重要作用。有时候基底细胞发生差错可导致癌，Witte和Goldstein计划研究这些细胞并揭示其发展为癌的机制。 Witte said.Witte说，目前还缺乏前列腺癌应如何更有效的靶向治疗，虽然赫赛汀可靶向乳腺癌细胞中生长因子受体的失控性产生。前列腺癌的主要靶向治疗是直接针对雄激素受体，而且它不是总是有效的。 本研究中发展了一种新的人鼠模型，该模型是采用可诱发癌的健康人前列腺组织，将其注入小鼠中，而不是采用已经成为癌的恶性前列腺癌组织种植到小鼠中。现在使用该模型能评估新的治疗方法的有效性。能够使用明确的遗传学事件活化特异性信号途径，研究人员较能容易比较不同治疗方法的有效性。这种新的模型通过破坏组织和重构组织，也将有助于分析在癌症进展过程中这些细胞是如何变化的。 “有一些较少的例子是采用良性细胞，采用实验方法将这些细胞变为癌细胞，”Goldstein说：“我们通常研究恶性肿瘤的癌细胞系，而本研究可导致一种高度可适应性的新的动物模型系统，采用这种系统我们能检测任何细胞途径和与其他已知的能诱导癌症的其他基因的相互作用。只要能够可重复性纯化，我们能从任何一种类型细胞开始。” 在这个系统中，Witte和Goldstein知道变成癌的细胞的历史，不想过去在其他工作中使用的癌细胞系。 “我们知道这些细胞是恶性的，但我们不知道他们如何到达那里的，”Goldstein说。“通过从健康细胞开始，将它们变为癌细胞，我们能研究癌症发展过程。如果我们理解了癌症起源于哪里，我们可以能够开发出更好的预测和诊断工具。如果我们有较好的预测工具，我们能在癌症发展过程中较早看到，发现比目前PSA检测更好的标记物早期诊断，从而达到更好的治疗。” PSA增高能预测前列腺癌的存在，然后，现在知道基底细胞是前列腺癌的来源，科学家们能研究癌前基底细胞，揭示它们在正常健康人不表达的东西，或许能发现早期检测的新的标记物，Goldstein说。而且，针对将变为恶性的癌前基底细胞的治疗能提供一种预防癌症的方法。 每年大约有217,000名男性被诊断为前列腺癌，其中有32,000人死于该病。 这项研究由前列腺癌基金会挑战资金、霍华德休斯医学研究所和国防部资金资助。 |
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