Cancer cell & microenvironment最新文献

英文中文

STAT5 activation in B-cell acute lymphoblastic leukemia: damned if you do, damned if you don’t b细胞急性淋巴细胞白血病中STAT5的激活:做也罢，不做也罢

Cancer cell & microenvironment

Pub Date : 2016-02-22 DOI: 10.14800/ccm.1186

Zhengqi Wang, K. Bunting

A significant role of the microenvironment in leukemogenesis is beginning to emerge. The leukemia cell microenvironment consists of not only the stromal and endothelial cell components but also the normal hematopoietic cells. Signal transducer and activator of transcription 5 (STAT5) is a latent transcription factor that is normally transiently activated by phosphorylation in response to microenvironmental signals. In hematopoietic cells, persistently activated STAT5 via aberrant receptor signaling, Janus kinases (JAKs), or intracellular tyrosine kinases is a bona fide driver of leukemogenesis. However, active IL-7/STAT5 signaling also protects the early B-cell genome by suppressing error-prone recombination and vulnerability to transformation. Along these lines, we have reported that lymphocyte development from transplanted STAT5-deficient fetal liver cells was blocked at the pre-pro-B-cell stage but when combined with transgenic Myc and Bcl-2 promoted faster initiation of B-ALL. Furthermore, inflammatory responses may also be involved in leukemia initiation in both pediatric and adult patients which are associated with decreased phosphorylation of STAT5. Likewise, additional targeted agents continue to be developed for precision medicine that prominently suppress signaling pathways. A common theme of all of these perturbations is potential risk for dysregulating hematopoiesis through general transcriptional modulation. Here we discuss the potential for STAT5 inhibition as a double edged sword in certain hematologic disorders, such as early B-cell lymphoblastic leukemias. Considering the rapid pace of understanding of the pre-leukemic decrease in poly-clonality that precedes leukemia, the functional changes associated with microenvironmental influences are thus of potential clinical significance.

微环境在白血病发生中的重要作用开始显现。白血病细胞微环境不仅包括基质细胞和内皮细胞成分，还包括正常造血细胞。信号换能器和转录激活因子5 (STAT5)是一种潜在的转录因子，通常在响应微环境信号时被磷酸化而瞬间激活。在造血细胞中，通过异常受体信号、Janus激酶(JAKs)或细胞内酪氨酸激酶持续激活STAT5是白血病发生的真正驱动因素。然而，活跃的IL-7/STAT5信号也通过抑制易出错的重组和易转化来保护早期b细胞基因组。沿着这些思路，我们已经报道了移植的缺乏stat5的胎儿肝细胞的淋巴细胞发育在前-前b细胞阶段被阻断，但当与转基因Myc和Bcl-2联合使用时，促进了B-ALL的更快启动。此外，炎症反应也可能参与儿童和成人患者的白血病起始，这与STAT5磷酸化降低有关。同样，更多的靶向药物继续被开发用于精准医学，显著抑制信号通路。所有这些扰动的一个共同主题是通过一般转录调节对造血功能失调的潜在风险。在这里，我们讨论STAT5抑制在某些血液疾病(如早期b细胞淋巴细胞白血病)中作为双刃剑的潜力。考虑到对白血病前多克隆性减少的快速理解，微环境影响相关的功能变化因此具有潜在的临床意义。

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引用次数: 7

Sugars and cell adhesion: the role of ST6GalNAc1 in prostate cancer progression 糖和细胞粘附:ST6GalNAc1在前列腺癌进展中的作用

Cancer cell & microenvironment

Pub Date : 2016-02-08 DOI: 10.14800/CCM.1174

J. Munkley, D. Elliott

O-linked glycans become altered in cancer cells, leading to changes in cell adhesive properties and contributing to metastasis. But the mechanisms driving these changes and how these carbohydrate groups are involved in tumour spread remain poorly understood. We recently identified the sialyltransferase gene ST6GalNAc1 as a novel androgen-regulated gene in prostate cancer. Expression of ST6GalNAc1 in prostate cancer cells induced expression of the cancer-associated sTn antigen, reduced cell adhesion, and dramatically inhibited the formation of stable tumour masses in vivo after orthotopic transplantation experiments in mice. Although ST6GalNAc1 is significantly upregulated in primary prostate carcinoma tissue, there is a striking downregulation of this gene in metastatic prostate tissue, suggesting an important yet transient role for ST6GalNAc1 in prostate cancer progression. Here we discuss mechanistically how changes in sialylation could alter prostate tumour cell behaviour and contribute to cancer cell dissemination.

o -链聚糖在癌细胞中发生改变，导致细胞粘附特性的改变并促进转移。但是驱动这些变化的机制以及这些碳水化合物群如何参与肿瘤扩散仍然知之甚少。我们最近发现唾液转移酶基因ST6GalNAc1是前列腺癌中一个新的雄激素调节基因。在小鼠原位移植实验中，前列腺癌细胞中表达ST6GalNAc1可诱导肿瘤相关sTn抗原的表达，降低细胞粘附，显著抑制体内稳定肿瘤块的形成。尽管ST6GalNAc1在原发性前列腺癌组织中显著上调，但在转移性前列腺组织中却显著下调，这表明ST6GalNAc1在前列腺癌进展中起着重要但短暂的作用。在这里，我们讨论了唾液化如何改变前列腺肿瘤细胞的行为和促进癌细胞传播的机制。

引用次数: 12

Complete response of severe idiopathic thrombocytopenic purpura after resection of bulky chromophobe renal cell carcinoma 大体积嫌色性肾细胞癌切除后严重特发性血小板减少性紫癜的完全缓解

Cancer cell & microenvironment

Pub Date : 2016-01-18 DOI: 10.14800/CCM.1158

S. Maekawa, M. Nagata, H. Watanabe, Keina Nozaki, A. Takahashi, S. Minowada, Y. Homma

Idiopathic thrombocytopenic purpura (ITP) associated with renal cell carcinoma (RCC) is relatively rare. In almost all of these case reports, patients affected with ITP developed differentially-involved cancer, because resection of cancer could not improve thrombocytopenia and the treatment of ITP needed to be continued after surgery. We report the case of a 48-year-old woman with massive renal cell carcinoma, measuring approximately 20 × 14 × 14 cm, who presented with severe thrombocytopenia: platelet count, 2000 cells/µl. After confirming normal bone-marrow, she received high-dose dexamethasone and intravenous gamma globulin, which rose the platelet count to normal levels. She then underwent left radical nephrectomy. The pathological examination revealed chromophobe RCC. After the resection, the platelet count was maintained within the normal range without any treatments. The current case is the first report of chromophobe RCC causative of severe ITP and the second case who achieved a sustained complete remission of ITP after cancer surgery alone; moreover our case is only one patient without other causes of ITP.

特发性血小板减少性紫癜(ITP)合并肾细胞癌(RCC)是相对罕见的。在几乎所有这些病例报告中，ITP患者发展为差异受累的癌症，因为切除癌症不能改善血小板减少症，ITP的治疗需要在手术后继续进行。我们报告一例48岁的女性肾癌，体积约20 × 14 × 14厘米，表现为严重的血小板减少:血小板计数，2000个细胞/µl。在确认骨髓正常后，她接受了大剂量地塞米松和静脉注射丙种球蛋白，使血小板计数恢复到正常水平。然后她接受了左肾根治性切除术。病理检查为嫌色性肾细胞癌。切除后，未经任何治疗，血小板计数维持在正常范围内。目前的病例是第一例引起严重ITP的恐色性RCC报告，也是第二例仅在癌症手术后ITP持续完全缓解的病例;此外，我们的病例只是一个没有其他原因的ITP患者。

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引用次数: 1

Opioids and cancer recurrence: A brief review of the literature 阿片类药物与癌症复发:文献综述

Cancer cell & microenvironment

Pub Date : 2016-01-18 DOI: 10.14800/CCM.1159

J. Cata, D. Bugada, M. Marchesini, M. Gregori, M. Allegri

Opioids are the most commonly used analgesics during and after cancer surgery and in patients with advanced malignancies who suffer from moderate to severe pain. It has been suggested that opioids can promote cancer progression through different mechanisms including a direct effect on malignant cells, stimulation of angiogenesis and immunosuppression. In contrast, other studies have shown that opioids have anticancer effects. The results of clinical studies remain controversial with some evidence indicating that a high expression of the mu opioid receptor is an independent factor of tumor progression while other studies indicate that the administration of opioids perioperatively is associated with cancer recurrence. Unfortunately, all those clinical studies are retrospective and suffer from significant confounding variables and biases. To date, there is no solid evidence to suggest the avoidance of opioids in cancer patients with moderate to significant with the goal of reducing cancer recurrence. Some authors have suggested the use of spinal administration of opioids in order to reduce systemic effects. Careful use of opioids should be advise to reduce side effects or hyperalgesia in relation to specific needs of the patients.

阿片类药物是癌症手术期间和之后以及患有中度至重度疼痛的晚期恶性肿瘤患者最常用的镇痛药。研究表明，阿片类药物可以通过不同的机制促进癌症的进展，包括对恶性细胞的直接作用、刺激血管生成和免疫抑制。相比之下，其他研究表明阿片类药物具有抗癌作用。临床研究结果仍存在争议，一些证据表明mu阿片受体的高表达是肿瘤进展的独立因素，而其他研究表明围手术期给药阿片与癌症复发有关。不幸的是，所有这些临床研究都是回顾性的，并且存在显著的混杂变量和偏差。迄今为止，没有确凿的证据表明中度至重度癌症患者避免阿片类药物的目的是减少癌症复发。一些作者建议使用脊柱给药阿片类药物，以减少全身影响。应建议谨慎使用阿片类药物，以减少与患者的特殊需要相关的副作用或痛觉过敏。

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引用次数: 13

Multifunctional polymer vesicles for cancer stem cells-targeted drug/siRNA therapy 用于癌症干细胞靶向药物/siRNA治疗的多功能聚合物囊泡

Cancer cell & microenvironment

Pub Date : 2016-01-11 DOI: 10.14800/CCM.1145

Qiuming Liu, Jianzhong Du

Cancer stem cells (CSCs) are responsible for origin, growth, recurrence, and metastasis of tumor, and are closely linked to the failure of chemotherapy due to their self-renewal and multilineage differentiation capability with an innate resistance to cytotoxic agents. We have recently reported a novel EpCAM (epithelial cell adhesion molecule)-monoclonal-antibody-labeled CSCs-targeting, noncytotoxic and pH-sensitive block copolymer vesicle as a nanocarrier of anticancer drug and siRNA (to overcome CSCs drug resistance by silencing the expression of oncogenes). This vesicle shows high delivery efficacy of both doxorubicin hydrochloride (DOX·HCl) and siRNA to the CSCs. Furthermore, the DOX or siRNA loaded CSCs-targeting vesicles exhibited much better CSCs killing and tumor growth inhibition capabilities with much lower toxicity to normal cells (IC 50,DOX decreased by 80%) compared with non-CSCs-targeting vesicles. Overall, these vesicles have significant implications for overcoming CSCs chemo-resistance in cancer chemotherapy.

肿瘤干细胞(Cancer stem cells, CSCs)与肿瘤的起源、生长、复发和转移有关，由于其自我更新和多谱系分化能力以及对细胞毒性药物的先天抗性，与化疗的失败密切相关。我们最近报道了一种新的EpCAM(上皮细胞粘附分子)-单克隆抗体标记的CSCs靶向，无细胞毒性和ph敏感的嵌段共聚物囊泡作为抗癌药物和siRNA的纳米载体(通过沉默癌基因的表达来克服CSCs的耐药性)。该囊泡显示盐酸阿霉素(DOX·HCl)和siRNA对CSCs的递送效率高。此外，与非CSCs靶向囊泡相比，负载DOX或siRNA的CSCs靶向囊泡表现出更好的CSCs杀伤和肿瘤生长抑制能力，对正常细胞的毒性低得多(IC 50,DOX降低80%)。总之，这些囊泡对于克服肿瘤化疗中CSCs的化疗耐药具有重要意义。

引用次数: 1

The role of miR-139-5p and miR-206 in non-small cell lung cancer (NSCLC) by targeting c-Met miR-139-5p和miR-206靶向c-Met在非小细胞肺癌(NSCLC)中的作用

Cancer cell & microenvironment

Pub Date : 2016-01-11 DOI: 10.14800/CCM.1157

Chengcao Sun, Shu-Jun Li, Dejia Li

Increasing evidences have confirmed that ectopic miRNAs are key regulatory factors in various types of cancers. Both hsa-miRNA-206 (miR-206) and hsa-miRNA-139-5p (miR-139-5p) have been demonstrated that possess anticancer properties in a variety of tissues and organs. In our recent investigations, we discovered miR-139-5p and miR-206 played a crucial role in lung cancer progression. There were extremely low levels of miR-206 and miR-139-5p in NSCLC (non-small cell lung cancer) cell lines as well as expression of them were inhibited in lung cancer tissues, respectively. Moreover, we found that miR-206 through targeting 3′-UTR（3'-untranslated region ）of Bcl-2 and c-Met mRNA that promoted cell apoptosis as well as suppressed non-small cell lung cancer SK-MES-1 and A549 cells colony formation, growth, invasion and metastasis. The analogical phenomenon was also discovered in miR-139-5p that targeted tumorigenic c-Met, which contributed to promotion of apoptosis and inhibition of cell proliferation and migration in non-small cell lung cancer.

越来越多的证据证实，异位mirna是各种类型癌症的关键调控因子。hsa-miRNA-206 (miR-206)和hsa-miRNA-139-5p (miR-139-5p)已被证明在多种组织和器官中具有抗癌特性。在我们最近的研究中，我们发现miR-139-5p和miR-206在肺癌进展中起着至关重要的作用。miR-206和miR-139-5p在NSCLC(非小细胞肺癌)细胞系中表达水平极低，在肺癌组织中表达受到抑制。此外，我们发现miR-206通过靶向Bcl-2和c-Met mRNA的3' -UTR(3'-未翻译区)促进细胞凋亡，抑制非小细胞肺癌SK-MES-1和A549细胞的集落形成、生长、侵袭和转移。在靶向致瘤性c-Met的miR-139-5p中也发现了类似的现象，这有助于促进非小细胞肺癌细胞凋亡，抑制细胞增殖和迁移。

引用次数: 0

Immune dysfunction induced by myeloid-derived suppressor cells in lymphoma 淋巴瘤中髓源性抑制细胞诱导的免疫功能障碍

Cancer cell & microenvironment

Pub Date : 2016-01-11 DOI: 10.14800/CCM.1111

Narges Seyfizadeh

Lymphoma cancer cells have strongly orchestrated interactions with immune cells and also other surrounding stromal cells in tumor microenvironment. Myeloid derived suppressor cells (MDSC) is believed to have major role in induction of immune suppressive effects in tumor microenvironment. This heterogeneous population of immature myeloid cells influence on immune cells function by indirectly Treg differentiation and directly oxidative stress induction and nutrient depletion in tumor milieu. Our understanding of the role of MDSCs in tumor microenvironment suggests novel immunotherapeutic approaches and need to be more explored. In this article we briefly discuss the main MDSCs immune dysfunction mechanisms with more focus in lymphoma.

淋巴瘤细胞在肿瘤微环境中与免疫细胞和其他周围基质细胞有强烈的相互作用。髓源性抑制细胞(Myeloid derived suppressor cells, MDSC)被认为在肿瘤微环境中具有诱导免疫抑制作用的重要作用。这种异质的未成熟骨髓细胞群体通过间接Treg分化和直接氧化应激诱导和肿瘤环境中的营养消耗来影响免疫细胞功能。我们对MDSCs在肿瘤微环境中的作用的理解提示了新的免疫治疗方法，需要更多的探索。在本文中，我们简要讨论了主要的MDSCs免疫功能障碍机制，并重点讨论了淋巴瘤。

引用次数: 4

Preoperative anemia, blood transfusion, and neutrophil-to-lymphocyte ratio in patients with stage i non-small cell lung cancer. i期非小细胞肺癌患者术前贫血、输血和中性粒细胞与淋巴细胞比值。

Cancer cell & microenvironment

Pub Date : 2016-01-04 DOI: 10.14800/CCM.1116

J. Cata, C. Gutierrez, R. Mehran, D. Rice, J. Nates, Lei Feng, A. Rodríguez-Restrepo, F. Martínez, G. Mena, V. Gottumukkala

Perioperative and postoperative blood transfusions (BT), anemia and inflammation are associated with poor survivals in patients with non-small cell lung cancer (NSCLC). This study investigated the impact of perioperative BT on the survival of patients with NSCLC taking into account their preoperative inflammatory status and the presence of anemia. Demographic, perioperative, and survival data for 861 patients with stage I NSCLC was collected retrospectively. The primary endpoints of interest were recurrence-free (RFS) and overall survival (OS). Before and after propensity score matching, univariate and multivariable Cox proportional hazards models were used to evaluate the association between covariates and survival. A neutrophil-to-lymphocyte ratio (NLR) < 5 (hazard ratio [HR]: 0.58, 95% CI: 0.38-0.87; p = 0.009) and normal Hb concentration (HR: 0.72, 95% CI: 0.72; p = 0.022) were independently associated with longer RFS. The administration of blood perioperatively was associated with a trend towards worse RFS (HR: 0.69, 95% CI: 0.47-1.02; p = 0.066). The multivariate analysis also revealed that an NLR < 5 (HR: 0.48, 95% CI: 0.3-0.76; p = 0.001) and the absence of BT (HR: 0.63, 95% CI: 0.4-0.98; p = 0.04) were significantly associated with lower mortality risk. The propensity score matching analysis did not confirm the association between BT and poor RFS (HR: 0.63, 95% CI: 0.35-1.1; p = 0.108) and OS (HR: 0.52, 95% CI: 0.26-1.04; p = 0.06). Inflammation and anemia are common finding in patients with stage 1 NSCLC. After adjusting for these two important confounders, this study confirms that previous reports demonstrating an association between BT and poor survival after NSCLC surgery.

非小细胞肺癌(NSCLC)患者围手术期和术后输血(BT)、贫血和炎症与生存率低相关。本研究考察了围手术期BT对NSCLC患者生存的影响，同时考虑了患者术前炎症状态和贫血的存在。回顾性收集了861例I期NSCLC患者的人口学、围手术期和生存数据。主要研究终点为无复发(RFS)和总生存期(OS)。在倾向评分匹配前后，使用单变量和多变量Cox比例风险模型来评估协变量与生存率之间的关系。中性粒细胞与淋巴细胞比值(NLR) < 5(风险比[HR]: 0.58, 95% CI: 0.38-0.87;p = 0.009)和正常Hb浓度(HR: 0.72, 95% CI: 0.72;p = 0.022)与较长的RFS独立相关。围手术期给血与RFS恶化趋势相关(HR: 0.69, 95% CI: 0.47-1.02;P = 0.066)。多因素分析也显示NLR < 5 (HR: 0.48, 95% CI: 0.3-0.76;p = 0.001)和BT缺失(HR: 0.63, 95% CI: 0.4-0.98;P = 0.04)与较低的死亡风险显著相关。倾向评分匹配分析未证实BT与不良RFS之间存在关联(HR: 0.63, 95% CI: 0.35-1.1;p = 0.108)和OS (HR: 0.52, 95% CI: 0.26-1.04;P = 0.06)。炎症和贫血在1期非小细胞肺癌患者中很常见。在调整了这两个重要的混杂因素后，本研究证实了先前的报道，证实了BT与NSCLC手术后生存率差之间的关联。

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引用次数: 19

Sweet-P inhibition of glucocorticoid receptor β as a potential cancer therapy. 糖皮质激素受体β的Sweet-P抑制作为潜在的癌症治疗方法。

Cancer cell & microenvironment

Pub Date : 2016-01-01 Epub Date: 2016-07-05

Assumpta C Nwaneri, Lucien McBeth, Terry D Hinds

The need for the development of new cancer therapies and push for the design of new targeting techniques is on the rise, and would be useful for cancers that are resistant to current drug treatments. The understanding of the genome has significantly advanced cancer therapy, as well as prevention and earlier detection. This research highlight discusses a potential new type of cancer-targeting molecule, Sweet-P, which is the first of its kind. Sweet-P specifically targets the microRNA-144 binding site in the 3' untranslated region (3' UTR) of the human glucocorticoid receptor β (GRβ), which has been demonstrated to increase expression. GRβ has been shown to be highly expressed in cells from solid tumors of uroepithelial carcinomas, gliomas, osteosarcomas, and hepatocellular carcinomas, as well as in liquid tumor cells from leukemia patients. In non-cancerous diseases, GRβ has been shown to be highly expressed in glucocorticoid-resistant asthma. These maladies brought the need for the development of the Sweet-P anti-GRβ molecule. Sweet-P was shown to repress the migration of bladder cancer cells, and may serve as a new therapeutic for GRβ-related diseases.

开发新的癌症治疗方法和推动设计新的靶向技术的需求正在上升，这将有助于治疗对当前药物治疗有抗药性的癌症。对基因组的了解大大促进了癌症治疗，以及预防和早期发现。本研究重点讨论了一种潜在的新型癌症靶向分子，Sweet-P，这是同类分子中的第一个。Sweet-P特异性靶向人糖皮质激素受体β (GRβ) 3'非翻译区(3' UTR)的microRNA-144结合位点，已被证明可增加表达。GRβ已被证明在尿上皮癌、胶质瘤、骨肉瘤和肝细胞癌等实体瘤细胞以及白血病患者的液体肿瘤细胞中高度表达。在非癌性疾病中，GRβ已被证明在糖皮质激素抵抗性哮喘中高表达。这些疾病带来了开发Sweet-P抗gr β分子的需求。Sweet-P可抑制膀胱癌细胞的迁移，可能成为治疗gr β相关疾病的新方法。

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引用次数: 0

Ascending the PEAK1 toward targeting TGFβ during cancer progression: Recent advances and future perspectives. 在癌症进展过程中瞄准 TGFβ 的 PEAK1 上升：最新进展与未来展望

Cancer cell & microenvironment

Pub Date : 2016-01-01 Epub Date: 2016-01-28 DOI: 10.14800/ccm.1162

Farhana Runa, Yvess Adamian, Jonathan A Kelber

Cancer is the second leading cause of death in the United States. Mortality in patients with solid, epithelial-derived tumors strongly correlates with disease stage and the systemic metastatic load. In such cancers, notable morphological and molecular changes have been attributed to cells as they pass through a continuum of epithelial-mesenchymal transition (EMT) states and many of these changes are essential for metastasis. While cancer metastasis is a complex cascade that is regulated by cell-autonomous and microenvironmental influences, it is well-accepted that understanding and controlling metastatic disease is a viable method for increasing patient survival. In the past 5 years, the novel non-receptor tyrosine kinase PEAK1 has surfaced as a central regulator of tumor progression and metastasis in the context of solid, epithelial cancers. Here, we review this literature with a special focus on our recent work demonstrating that PEAK1 mediates non-canonical pro-tumorigenic TGFβ signaling and is an intracellular control point between tumor cells and their extracellular microenvironment. We conclude with a brief discussion of potential applications derived from our current understanding of PEAK1 biology.

癌症是美国第二大死因。实体瘤、上皮源性肿瘤患者的死亡率与疾病分期和全身转移负荷密切相关。在这类癌症中，细胞在经过连续的上皮-间质转化（EMT）状态时会发生显著的形态和分子变化，其中许多变化对于转移至关重要。虽然癌症转移是一个复杂的级联过程，受细胞自主和微环境影响的调控，但人们普遍认为，了解和控制转移性疾病是提高患者生存率的可行方法。在过去 5 年中，新型非受体酪氨酸激酶 PEAK1 已浮出水面，成为实体瘤和上皮癌中肿瘤进展和转移的核心调控因子。在此，我们回顾了这些文献，并重点介绍了我们最近的研究，该研究表明 PEAK1 介导非经典的促肿瘤生成素 TGFβ 信号传导，是肿瘤细胞与其细胞外微环境之间的细胞内控制点。最后，我们简要讨论了从我们目前对 PEAK1 生物学的了解中得出的潜在应用。

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引用次数: 0

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