企业邮箱
天下生命科学前沿动态周报（四十）
（1.17-1.23/2011）
一竞技国际集团:陶国新
主要内容：血管内皮细胞能够渗透抑制肿瘤生长和转移的物质 ；从皮肤细胞直接诱导出软骨细胞 ；IRF5双向调理免疫反应 ；母体的干细胞解决胎儿细胞移植问题 ；有数癌症的奇异基因型 ；Ras效应物转换决议差别的细胞运气。
焦点动态：血管内皮细胞能够渗透抑制肿瘤生长和转移的物质。
1. 血管内皮细胞能够渗透抑制肿瘤生长和转移的物质
【动态】
美国MIT的科学家发明血管内皮细胞能够渗透抑制肿瘤生长和转移的物质。血管内皮细胞已往曾被以为主要是调理往返组织的血液运输 ，厥后发明它们还能控制血管缩短和扩张 ，甚至更主要的作用象通过释放细胞因子和大分子糖卵白复合物来调理凝血、组织修复、炎症和疤痕形成。MIT科学家的这项最新研究显示血管内皮细胞的渗透物在体外细胞生长试验和老鼠试验都能够抑制肿瘤细胞的生长和侵袭力。在数百种渗透物中 ，他们找到对此起主要作用的两种：大分子糖卵白-基底膜聚糖和细胞因子白介素IL-6。当内皮细胞渗透大宗基底膜聚糖和少少IL-6时能有用抑制癌细胞的侵袭 ，反之无效。MIT已经允许Pervasis Therapeutics公司使用此项手艺 ，该公司妄想在人体举行测试。
【点评】
该发明增进了对内皮细胞的心理作用以及肿瘤生长的调控机制的熟悉 ，同时也拓展了癌症的细胞移植疗法的思绪。
【参考论文】Sci Transl Med 19 January 2011: Vol. 3, Issue 66, p. 66ra5
Stromal Endothelial Cells Directly Influence Cancer Progression
Joseph W. Franses, Aaron B. Baker, Vipul C. Chitalia and Elazer R. Edelman
Cancer growth and metastasis are regulated in part by stromal cells such as fibroblasts and immune cells within the tumor microenvironment. Endothelial cells (ECs) are also ubiquitous within tumors because tumors are vascular, and yet, the impact of tumor-resident ECs is less well understood. Through paracrine regulation, ECs modulate a diverse spectrum of pathophysiologic processes in normal and hyperplastic tissues. We hypothesized that ECs offer similar paracrine regulatory control of cancer biology. Indeed, secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling. EC perlecan silencing significantly changed this regulatory relationship, eliminating the ability of ECs to inhibit cancer cell invasiveness via increased interleukin-6 secretion. Moreover, implanting ECs embedded within porous matrices slowed adjacent xenograft tumor growth and prevented architectural degeneration, with a concomitant reduction in proliferative and tumorigenic markers. Finally, lung carcinoma cells pretreated with intact EC-conditioned media, but not media conditioned with perlecan-silenced ECs, exhibited reduced micrometastatic burden after tail vein injection. These findings add to an emerging appreciation of EC-regulatory effects that transcend their structural roles and pave the way for improved characterization and control of EC-cancer cross-talk interactions for diagnosis, prognosis, and treatment of cancer.
2. 从皮肤细胞直接诱导出软骨细胞
【动态】
日本大阪大学医学院的科学家在一项新的研究中使用了从成年迈鼠皮肤中疏散的成纤维母细胞 ，表达了以前用来与软骨细胞运气决议因子一同诱导细胞多能性的一些卵白 ，生产出具有类似软骨细胞特征的细胞 ，将其注射到老鼠体内能够爆发软骨。临床上透明软骨损伤的修复仍然是个难题 ，该研究用逆转录病毒表达的两种重组因子c-Myc and Klf4连统一种软骨形成因子SOX9将成年迈鼠皮肤的成纤维母细胞在细胞作育中直接诱导形成多角形的软骨细胞 ，不需要经由iPS细胞。这样诱导形成的细胞系皮下注射到裸鼠体内 ，一些形成了肿瘤 ，另一些形成了同质的稳固的透明软骨样组织。研究者相信这可能是迈向发明用患者自身皮肤细胞修复软骨损伤的疗法的主要一步。
【点评】
只管没有使用iPS细胞 ，而是直接从皮肤细胞诱导形成的类软骨细胞 ，在老鼠体内照旧有部分形成了肿瘤。这种使用仅知的少数诱导因子来变换细胞类别的要领现在还很难控制这一转变形成的是康健细胞。
【参考论文】Journal of Clinical Investigation, 2011; DOI: 10.1172/JCI44605
Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors
Kunihiko Hiramatsu, Satoru Sasagawa, Hidetatsu Outani, et al.
Repair of cartilage injury with hyaline cartilage continues to be a challenging clinical problem. Because of the limited number of chondrocytes in vivo, coupled with in vitro de-differentiation of chondrocytes into fibrochondrocytes, which secrete type I collagen and have an altered matrix architecture and mechanical function, there is a need for a novel cell source that produces hyaline cartilage. The generation of induced pluripotent stem (iPS) cells has provided a tool for reprogramming dermal fibroblasts to an undifferentiated state by ectopic expression of reprogramming factors. Here, we show that retroviral expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) induces polygonal chondrogenic cells directly from adult dermal fibroblast cultures. Induced cells expressed marker genes for chondrocytes but not fibroblasts, i.e., the promoters of type I collagen genes were extensively methylated. Although some induced cell lines formed tumors when subcutaneously injected into nude mice, other induced cell lines generated stable homogenous hyaline cartilage–like tissue. Further, the doxycycline-inducible induction system demonstrated that induced cells are able to respond to chondrogenic medium by expressing endogenous Sox9 and maintain chondrogenic potential after substantial reduction of transgene expression. Thus, this approach could lead to the preparation of hyaline cartilage directly from skin, without generating iPS cells.
3. IRF5双向调理免疫反应
【动态】
编码提高mRNA表达的转录因子IRF5的基因多态性与许多自体免疫疾病相关。英国科学家最近发明IRF5卵白在特定白细胞中起到“主开关”的作用 ，决议这些白细胞是增进照旧抑制炎症。炎症反应是机体抵御象熏染和组织损伤等有害刺激的主要手段 ，可是在许多情形下 ，太过发炎自己也会损害机体 ，像类风湿枢纽炎。免疫系统的巨噬细胞既能刺引发炎也能通过释放化学信号改变其他细胞的行为来抑制炎症。而本研究批注IRF5卵白是决议巨噬细胞怎样作用的分子开关。效果显示在巨噬细胞中阻断IRF5卵白的爆发可能会是一种治疗一大群自体免疫疾病的有用要领。另外 ，提升IRF5卵白水平可能有助于治疗免疫系统功效低下。IRF5可能是通过激活那些刺激炎症反应的基因和抑制相反功效的基因来起作用的。IRF5与DNA详细的作用机理还在继续研究中。
【点评】
发明IRF5作为转录阻遏物的新功效 ，协同其已知的转录激活物的作用配合调控巨噬细胞怎样起作用。这增添了对机体免疫调理机制的熟悉。
【参考论文】Nature Immunology, 2011; DOI: 10.1038/ni.1990
IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses
Thomas Krausgruber, Katrina Blazek, Tim Smallie, et al.
Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.
4. 母体的干细胞解决胎儿细胞移植问题
【动态】
母亲的干细胞很可能是出生前治疗遗传疾病的要害。美国加州大学的科学家通过一系列老鼠模子试验 ，确定是母亲的免疫反应阻止了胎儿接受移植的造血干细胞 ，而战胜这一反应也很简朴 ，就是移植来自母亲自身的干细胞。这样就提供了一种简朴优质的解决计划使胎儿干细胞移植成为可告竣的目的。第一次有了出生前治疗先天性干细胞障碍的可行战略。
【点评】
胎儿尚不具备的许多身体性能由母亲代庖 ，这是母体对胎儿的� ；� ，也是对自身的� ；�。同时也体现了机体对组成部分包括孕育中的胎儿的统一调控。
【参考论文】Journal of Clinical Investigation, 2011; DOI: 10.1172/JCI44907
Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice
Amar Nijaga, Marta Wegorzewska, Erin Jarvis, et al.
Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell–deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.
5. 有数癌症的奇异基因型
【动态】
美国约翰霍普金斯医学院的科学家的最新研究批注其肿瘤有特定基因编码过失的胰岛细胞癌患者存活时间是没有这类过失的患者的两倍。胰岛细胞癌占所有胰腺癌的或许5% ，每个患有这种少见癌症的患者都有其奇异的遗传编码能够展望疾病的侵袭性与其对特定治疗的敏感性。因此凭证基因类型而不是只凭证器官和细胞种类来划分癌症可能更有用。在这项新研究中 ，在MEN-1, DAXX 和 ATRX三个基因爆发突变的胰岛细胞癌患者确诊后存活至少10年 ，而那些肿瘤没有这三个基因突变的患者凌驾60%死于确诊后5年内。
【点评】
通过基因剖析凭证某些确定联系来辅助诊断癌症或许有用 ，可是这些联系是否有因果关系需要仔细确认 ，不是真正癌症发病缘故原由的就没有理由针对它开发治疗要领。
【参考论文】Science, 2011; DOI: 10.1126/science.1200609
DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors
Y. Jiao, C. Shi, B. H. Edil, et al.
Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.
6. Ras效应物转换决议差别的细胞运气
【动态】
美国国家癌症研究院预计去年美国有凌驾4万3000人诊断为胰腺癌 ，凌驾3万6000人死于胰腺癌。只管遗传学希望批注Ras癌基因在险些所有胰腺癌中都突变 ，可是信号通路网络的重大性阻碍科学家找出潜在的治疗靶点。相关于人类有20多种可与Ras相互作用的下游伙伴 ，蛔虫的此类相互作用关系就很是简朴 ，因而成为退而求其次的研究目的以确定Ras怎样选择伙伴以及后续增进癌症的细胞发育中的要害事务。该研究确立了正常发育中Ras效应物的用途 ，可能会提供一种机明确释在效应物依赖和活化上细胞和癌症类型的差别。
【点评】
以云云低等动物的研究结论做参考 ，研究人的问题 ，有时反而可能会误导 ，细胞运气的决议可能是诸多机制告竣平衡的一个效果。
【参考论文】Developmental Cell, 2011; 20 (1): 84 DOI: 10.1016/j.devcel.2010.12.004
Ras Effector Switching Promotes Divergent Cell Fates in C. elegans Vulval Patterning
Tanya P. Zand, David J. Reiner, Channing J. Der.
The C. elegans vulva is patterned by epidermal growth factor (EGF) activation of Ras to control 1 fate, and 1 fate induces antagonistic Notch-dependent 2 fate. Furthermore, a spatial EGF gradient, in addition to inducing 1 fate, directly contributes to 2 fate via an unknown pathway. We find that in addition to its canonical effector, Raf, vulval Ras utilizes an exchange factor for the Ral small GTPase (RalGEF), such that Ras-RalGEF-Ral antagonizes Ras-Raf pro-1 fate activity. Consistent with its restricted expression pattern, Ral participates in EGF pro-2 activity. Thus, we have delineated a Ras effector-switching mechanism whereby position within the morphogen gradient dictates that Ras effector usage is switched to RalGEF from Raf to promote 2 instead of 1 fate. Our observations define the utility of Ras effector switching during normal development and may provide a possible mechanistic basis for cell and cancer-type differences in effector dependency and activation.