The Molecular Profile of Prostate Tumors in Smokers

吸烟者前列腺肿瘤的分子特征

• 批准号: 8349092
• 负责人: Stefan Ambs
• 金额: $ 6.39万
• 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/8349092
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aggressive behavior; Alkaloids; B-Lymphocytes; Blood; Blood specimen; Burn injury; Cancer Patient; Cancerous; Carcinogens; Cell Survival; Cells; Characteristics; Chemicals; Cigarette; Clinical; Collaborations; Contracts; DNA Damage; Data; Data Set; Development; Disease; Distant Metastasis; Epidemiologic Studies; Epithelium; Exhibits; Extraprostatic; Gene Expression; Genes; Goals; Harvest; Hepatocyte Growth Factor; Human; Immune; Immunohistochemistry; Institution; Interleukin-8; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mammalian Cell; Mediating; Mediator of activation protein; Medical; Metastatic Prostate Cancer; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Nicotine; Nitrosamines; Oncogenic; Organ; Pathway interactions; Patients; Pattern; Physiological; Plasma; Plasma Cells; Process; Production; Prostate; Prostatic Neoplasms; Public Health; Relative (related person); Research; Residual state; Resources; Role; Sampling; Signal Pathway; Smoker; Smoking; Smoking Status; Tobacco; Tobacco smoke; Tobacco smoking; Transcript; Tumor Necrosis Factor-Beta; Urology; Validation; Water; angiogenesis; cancer cell; case control; cigarette smoke-induced; design; follow-up; mortality; non-smoker; population based; receptor; research study; tumor; tumor progression

We are pursuing the hypothesis that prostate tumors from current, past, and never smokers exhibit differences in their gene expression profiles that are consistent with distinct oncogenic molecular alterations in tumors of current smokers. We are also exploring the effects of nicotine in human prostate cancer cells and TRAMP mice, and are evaluating whether those resemble smoking-associated alterations in prostate tumors. This research is aimed at identifying the mechanisms by which cigarette smoking induces prostate cancer progression, and to define the specific role of nicotine in this process. This proposal combines novelty with a high-impact concept. If we find that nicotine induces disease metastasis, the results could have significant public health implications. Tobacco smoke contains numerous chemicals, including many that are DNA-damaging and carcinogenic. Nitrosamines that are produced from the alkaloid nicotine during post-harvest processing and the burning process of cigarettes are an important group of carcinogens in tobacco smoke. Recently, nicotine and nitrosamines were found to activate signaling pathways in non-neuronal mammalian cells by receptor-mediator mechanisms. Several of these pathways are cancer-related and promote cell survival, angiogenesis, and metastasis. For example, nicotine activates the Akt pathway, which is a key pathway in the development and progression of many cancers, including prostate cancer. In addition, nicotine can reach high nanomolar steady-state concentrations in the blood of current smokers that may activate a signaling pathway in organs other than lung if the appropriate receptors are expressed by the target cells. We collected 67 prostate tumors from 16 current, 28 past, and 23 never smokers for the study, which we obtained from the NCI CPCTR, our resource contract, and Johns Hopkins Medical Institutions. The clinical characteristics of these tumors are similar among current, past, and never smokers. In a pilot, we analyzed the gene expression profiles of tumors from 9 current, 21 past, and 17 never smokers. This analysis revealed a very distinct signature that differentiated tumors from current smokers from those of never and past smokers. Because the first dataset contained tumors from only 9 current smokers, additional prostate tumors were collected at the Department of Urology, Johns Hopkins Medical Institutions (in collaboration with Jun Luo and William Isaacs) and combined with the existing samples to increase the statistical power of our study to identify additional genes that are differentially expressed between current and never/past smokers. The comparison of tumors from current and never smokers yielded 98 transcripts encoding 73 differentially expressed genes. A second comparison, current versus past/never smokers, resulted in a shorter list of only 70 transcripts encoding 40 differentially expressed genes. Likely a residual effect of smoking on the tumor gene signature in past smokers, this study yielded fewer genes when the current and combined past/never smokers were compared. Many of the differentially expressed genes have known immune-regulatory functions. The list also contained interleukin 8 (IL-8), and several others of the differentially genes were found to have an association with hepatocyte growth factor (HGF). The latter is intriguing because both nicotine and HGF activate common pathways, e.g., the PI3 kinase-Akt axis. Some of our observations are preliminary and will need further validation. Nevertheless, the data show that a current smoking status generates a gene signature in prostate tumors that could reveal the mechanism by which smoking causes the metastatic spread of prostate cancer. These observations are being followed up with additional research. We evaluated the relative abundance and expression pattern of IL-8 in prostate tumors from current, former, and never smokers by immunohistochemistry, and also analyzed plasma samples from prostate cancer cases (n = 97) and matched population-based controls (n = 87) with known smoking status to find out whether patients with prostate cancer who are current smokers have higher IL-8 levels in their blood than former or never smokers, or than population-based controls. Immunohistochemistry revealed that IL-8 is expressed by the tumor epithelium and by plasma cell-like immune cells in the prostate of current smokers. The analysis of plasma samples from cases and controls showed that IL-8 is increased in blood samples of prostate cancer patients who are current smokers when compared to former and never smokers among cases and population-based controls. Furthermore, current smokers among population-based controls did not have the same increased IL-8 plasma concentrations that current smoking cases had, indicating that active smoking may lead to increased IL-8 in prostate tumors that can be detected in the blood of these patients. This increased production of IL-8 may also promote the more aggressive behavior of prostate tumors in current smokers, leading to more metastases in this patient group, as found by epidemiological studies. Currently, we are evaluating plasma for lymphotoxin levels to see whether lymphotoxin is increased in the plasma of current smokers who are also prostate cancer patients. We are following up on a recent observation that B cells in prostate tumors can accelerate prostate cancer progression by a lymphotoxin-mediated mechanism. Lastly, we have started to analyze gene expression profiles from the cancerous prostate of TRAMP mice that received physiological concentrations of nicotine for 12 weeks, or tap water only. This experiment is designed to compare the nicotine-induced profiles with the gene expression profiles in prostate tumors from current smokers. It is our hypothesis that these two datasets have a common signature.

我们正在追求这样的假设：从当前，过去和从未吸烟的前列腺肿瘤在其基因表达谱上表现出差异，这些肿瘤与当前吸烟者肿瘤中明显的致癌分子改变一致。我们还正在探索尼古丁在人前列腺癌细胞和流浪汉小鼠中的影响，并评估那些类似于吸烟相关的前列腺肿瘤的改变。这项研究旨在确定吸烟引起前列腺癌进展的机制，并确定尼古丁在此过程中的特定作用。该建议将新颖性与高影响力的概念相结合。如果我们发现尼古丁诱导疾病转移，结果可能会产生重大的公共卫生影响。烟草烟雾含有许多化学物质，包括许多损害DNA和致癌的化学物质。在收获后加工和香烟燃烧过程中由生物碱尼古丁产生的硝基胺是烟草烟雾中的一组重要的致癌物。最近，发现尼古丁和亚硝胺通过受体介导机制激活非神经哺乳动物细胞中的信号通路。这些途径中的几种与癌症有关，并促进细胞存活，血管生成和转移。例如，尼古丁激活AKT途径，AKT途径是许多癌症（包括前列腺癌）发育和发展的关键途径。此外，如果靶细胞表达适当的受体，尼古丁可以在当前吸烟者血液中达到高纳摩尔稳态浓度，这些烟碱可能会激活肺部以外的器官中的信号传导途径。我们从16个当前，28个过去和23名从未吸烟的研究中收集了67个前列腺肿瘤，我们从NCI CPCTR，我们的资源合同和Johns Hopkins医疗机构获得了这项研究。这些肿瘤的临床特征在当前，过去和从未吸烟的人中相似。在飞行员中，我们分析了9个当前，21个过去和17名从未吸烟的肿瘤的基因表达谱。该分析表明，一个非常不同的签名，将目前的吸烟者与从未和过去的吸烟者的吸烟者区分了肿瘤。由于第一个数据集仅包含来自9名吸烟者的肿瘤，因此在泌尿外科，约翰·霍普金斯医学机构（与Jun Luo和William Isaacs合作）中收集了其他前列腺肿瘤，并与现有样品结合在一起，以增加我们研究的统计能力，以识别当前和过去/从未/以前的烟雾中差异表达的其他基因。来自当前和从未吸烟者的肿瘤的比较产生了98个编码73个差异表达基因的转录本。第二个比较，当前与过去/从未吸烟，导致了仅编码40个差异表达基因的70个转录本的较短列表。在过去的吸烟者中，吸烟对肿瘤基因特征的残留作用可能是当比较当前和过去/永不吸烟者时产生的基因较少。许多差异表达的基因具有已知的免疫调节功能。该列表还包含白介素8（IL-8），发现其他几个基因与肝细胞生长因子（HGF）有关联。后者很有趣，因为尼古丁和HGF都激活了公共途径，例如PI3激酶-Akt轴。我们的一些观察是初步的，需要进一步验证。然而，数据表明，当前的吸烟状况会在前列腺肿瘤中产生基因特征，这可能揭示了吸烟引起前列腺癌转移扩散的机制。这些观察结果正在进行其他研究。我们通过免疫组织化学评估了来自当前，以前的和从未吸烟的前列腺肿瘤中IL-8的相对丰度和表达模式，还分析了来自前列腺癌病例的血浆样本（n = 97）（n = 97）（n = 97）（n = 97），基于人群的对照（n = 87）（n = 87）（n = 87），以较高的吸烟或烟熏量是否具有烟雾或烟雾的患者，或者是烟熏的人，或者是烟熏的人，或者是烟熏级别或烟熏级别。控件。免疫组织化学表明，IL-8是由肿瘤上皮和浆细胞样细胞在当前吸烟者的前列腺中表达的。对病例和对照组的血浆样品的分析表明，与案例和基于人群的对照组相比，前列腺癌患者的血液样本中IL-8增加了，这些患者是目前吸烟者的血液样本。此外，目前基于人群的对照中的吸烟者的IL-8血浆浓度与当前吸烟病例相同，这表明积极吸烟可能导致前列腺肿瘤中可以在这些患者血液中检测到的IL-8。通过流行病学研究发现，IL-8的产生增加也可能促进当前吸烟者中前列腺肿瘤的更具侵略性行为，从而导致该患者组的转移量更多。目前，我们正在评估淋巴毒素水平的血浆，以查看当前也是前列腺癌患者的吸烟者的血浆中淋巴毒素是否增加。我们正在关注最近的观察结果，即前列腺肿瘤中的B细胞可以通过淋巴毒素介导的机制加速前列腺癌的进展。最后，我们已经开始分析来自流浪汉小鼠的癌性前列腺的基因表达谱，这些小鼠接受了生理浓度的尼古丁12周或仅自来水。该实验旨在将尼古丁诱导的特征与当前吸烟者的前列腺肿瘤中的基因表达谱进行比较。我们的假设是这两个数据集具有共同的签名。