更新于：2024-05-01

CSPG4

chondroitin sulfate proteoglycan 4

更新于：2024-05-01

基本信息

别名

chondroitin sulfate proteoglycan 4、Chondroitin sulfate proteoglycan NG2、CSPG4

+ [9]

简介

Proteoglycan playing a role in cell proliferation and migration which stimulates endothelial cells motility during microvascular morphogenesis. May also inhibit neurite outgrowth and growth cone collapse during axon regeneration. Cell surface receptor for collagen alpha 2(VI) which may confer cells ability to migrate on that substrate. Binds through its extracellular N-terminus growth factors, extracellular matrix proteases modulating their activity. May regulate MPP16-dependent degradation and invasion of type I collagen participating in melanoma cells invasion properties. May modulate the plasminogen system by enhancing plasminogen activation and inhibiting angiostatin. Functions also as a signal transducing protein by binding through its cytoplasmic C-terminus scaffolding and signaling proteins. May promote retraction fiber formation and cell polarization through Rho GTPase activation. May stimulate alpha-4, beta-1 integrin-mediated adhesion and spreading by recruiting and activating a signaling cascade through CDC42, ACK1 and BCAR1. May activate FAK and ERK1/ERK2 signaling cascades.

关联

项与 CSPG4 相关的药物

M4-3-ML2

靶点

CSPG4 x Chondroitin sulfate proteoglycans

作用机制

CSPG4基因调节剂 [+1]

在研机构

Roche Holding AG

原研机构

Roche Holding AG

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

CSPG4-targetedCAR-M(University of Utah)

CSPG4靶向CAR-M(University of Utah)

靶点-

作用机制

CSPG4基因调节剂

在研机构

University of Utah

原研机构

University of Utah

在研适应症

黑色素瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

VT68.2

靶点

CSPG4

作用机制

CSPG4基因调节剂

在研机构

University of Arkansas System

原研机构

University of Arkansas System

在研适应症

三阴性乳腺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 CSPG4 相关的临床试验

NCT06096038 / Recruiting临床1/2期IIT

Administration of T Cells Expressing Chondroitin-Sulfate-Proteoglycan-4 Specific Chimeric Antigen Receptors (CAR) in Subjects With Head and Neck Squamous Cell Carcinoma (HNSCC)

The purpose of this study is to test the safety and tolerability of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the CSPG4 antigen (iC9.CAR-CSPG4 T cells) in patients with head and neck cancer that came back after receiving standard therapy for this cancer. The iC9.CAR-CSPG4 treatment is experimental and has not been approved by the Food and Drug Administration.
How many (dose) of the iC9.CAR. CSPG4 T cells are safe to use in patients without causing too many side effects, and what is the maximum dose that could be tolerated will be investigated. The information collected from the study would help cancer patients in the future.
There are two parts to this study. In part 1, blood will be collected to prepare the iC9.CAR-CSPG4 T cells. Disease fighting T cells will be isolated and modified to prepare the iC9.CAR-CSPG4 T cells. In part 2, the iC9.CAR-CSPG4 T cells are given by infusion after completion of lymphodepletion chemotherapy.
The data from the dose escalation will be used to determine a recommended phase 2 dose (RP2D), which will be decided based on the maximum tolerated dose (MTD). Additionally, recommended phase 2 dose will be tested.
Eligible subjects will receive lymphodepletion chemotherapy standard followed by infusion of iC9-CAR.CSPG4 T cells. After treatment completion or discontinuation, subjects will be followed since involving gene transfer experiments.

开始日期2024-04-05

申办/合作机构

UNC Lineberger Comprehensive Cancer Center

[+2]

100 项与 CSPG4 相关的临床结果

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100 项与 CSPG4 相关的转化医学

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0 项与 CSPG4 相关的专利（医药）

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1,403

项与 CSPG4 相关的文献（医药）

2024-03-01·Cell biochemistry and function

Temporal and differential proteomic profile of molecular mediators associated with chronic and acute wound healing

Article

作者: Zaidi, Midhat Batool ; Khan, Faisal ; Jameel, Fatima ; Khan, Irfan ; Musharraf, Syed Ghulam ; Salim, Asmat

The underlying pathophysiology of nonhealing chronic wounds is poorly understood due to the changes occurring at the gene level and the complexity arising in their proteomic profile. Here, we elucidated the temporal and differential profile of the normal and diabetic wound-healing mediators along with their interactions and associated pathways. Skin tissues corresponding to normal and diabetic wounds were isolated at Days 0, 3, 6, and 9 representing different healing phases. Temporal gene expression was analyzed by quantitative real-time PCR. Concurrently, differential protein patterns in the wound tissues were identified by Nano LC-ESI-TOF mass spectrometry and later confirmed by Western blot analysis. Gene ontology annotation, protein-protein interaction, and protein pathway analysis were performed using DAVID, PANTHER, and STRING bioinformatics resources. Uniquely identified proteins (complement C3, amyloid beta precursor protein, and cytoplasmic linker associated protein 2) in the diabetic wound tissue implied that these proteins are involved in the pathogenesis of diabetic wound. They exhibit enhanced catalytic activity, trigger pathways linked with inflammation, and negatively regulate wound healing. However, in the normal wound tissue, axin 1, chondroitin sulfate proteoglycan 4, and sphingosine-1-phosphate receptor were identified, which are involved in proliferation, angiogenesis, and remodeling. Our findings demonstrate the correlation between elevated gene expression of tumor necrosis factor-α, interleukin (IL)-1β, and identified mediators: aryl hydrocarbon receptor nuclear translocator, 5'-aminolevulinate synthase 2, and CXC-family, that inflicted an inflammatory response by activating downstream MAPK, JAK-STAT, and NF-κB pathways. Similarly, in normal wound tissue, the upregulated IL-4 and hepatocyte growth factor levels in conjunction with the identified proteins, serine/threonine-protein kinase mTOR and peroxisome proliferator-activated receptor gamma, played a significant role in the cellular response to platelet-derived growth factor stimulus, dermal epithelialization, and cell proliferation, processes associated with the repair mechanism. Furthermore, Western blot analysis indicated elevated levels of inflammatory markers and reduced levels of proliferative and angiogenic factors in the diabetic wound.

2024-02-22·Stem cells translational medicine

Agrin Inhibition in Enteric Neural Stem Cells Enhances Their Migration Following Colonic Transplantation.

Article

作者: Jessica L Mueller ; Rhian Stavely ; Richard A Guyer ; Ádám Soos ; Sukhada Bhave ; Chris Han ; Ryo Hotta ; Nandor Nagy ; Allan M Goldstein

Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.

2024-02-01·The Journal of biological chemistry

Chondroitin sulfate modification of CSPG4 regulates the maintenance and differentiation of glioma initiating cells via integrin-associated signaling.

Article

作者: Akiko Niibori-Nambu ; Yoshimune Yamasaki ; Daiki Kobayashi ; Kiyohiko Angata ; Atsushi Kuno ; Orasa Panawan ; Atit Silsilivanit ; Hisashi Narimatsu ; Norie Araki

Glioma stem/initiating cells (GSC/GIC) and their niches are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanisms of GIC maintenance/differentiation, we performed a unique integrated proteogenomics utilizing GIC clones established from patient tumors having the potential to develop glioblastoma. After the integration and extraction of the transcriptomics/proteomics data, we found that chondroitin sulfate proteoglycan 4 (CSPG4) and its glyco-biosynthetic enzymes were significantly upregulated in GICs. Glyco-qPCR array revealed that chondroitin sulfate (CS) biosynthetic enzymes, such as xylosyltransferase 1 (XYLT1) and CHST11, were significantly downregulated during serum-induced GIC differentiation. Simultaneously, the CS modification on CSPG4 was characteristically decreased during the differentiation, and also downregulated by XYLT1 knockdown. Notably, the CS-degradation on CSPG4 by ChondroitinaseABC treatment dramatically induced GIC differentiation, which was significantly inhibited by the addition of CS. GIC growth and differentiation ability were significantly suppressed by CSPG4 knockdown, suggesting that CS-CSPG4 is an important factor in GIC maintenance/differentiation. To understand the molecular function of CS-CSPG4, we analyzed its associating proteins in GICs and found that CSPG4, but not CS-CSPG4, interacts with integrin αV during GIC differentiation. This event sequentially upregulates integrin-ERK signaling, which can be inhibited by cyclic-RGD integrin αV inhibitor. These results indicate that CS-CSPG4 regulates the GIC microenvironment for GIC maintenance/differentiation via the CS moiety which controls integrin signaling. This study demonstrates a novel function of CS on CSPG4 as a niche factor, so-called "glyco-niche" for GICs, and suggests that CS-CSPG4 could be a potential target for malignant glioma.

项与 CSPG4 相关的新闻（医药）

2023-04-25

·World Pharma News

Study shows promising results for immunotherapy targeting skin cancer

A new class of immunotherapy shows promising results for fighting the most aggressive form of skin cancer. The study, published today in Nature Communications by researchers from King's College London and Guys and St Thomas NHS Foundation Trust, investigates whether a novel antibody can target and treat melanomas. The results show that the antibody activates the immune response to fight cancer and slows melanoma growth in mice. Malignant melanoma is the most aggressive type of skin cancer with poor survival rates for half of patients within five-years of diagnosis. Although there has been substantial progress in developing immunotherapies (drugs which stimulate the bodys own natural defence system to attack cancer), many patients tumours do not respond. This drug could benefit those patients with melanoma who do not respond to existing treatment. Many existing immunotherapies used in cancer treatment belong to the antibody type called IgG. However, researchers at Kings College London and Guy's and St Thomas' have developed an IgE antibody which can utilise the patients own immune system to attack cancer in a different way. Researchers developed an IgE antibody specific for a marker on the surface of human melanoma cells, called chondroitin sulfate proteoglycan 4 (CSPG4) found on up to 70% of melanomas. Immunotherapies currently available draw broadly upon the immune systems defences, however this new antibody was designed to target immune responses specifically towards melanoma cells. The researchers showed that CSPG4 IgE could attach to and activate immune cells found in melanoma patient blood to kill human melanoma cancer cells. CSPG4 IgE treatment slowed cancer growth in mice implanted with human immune cells, including cells from patients with melanoma. An allergy test conducted with patient blood found that CSPG4 IgE did not activate white blood cells called basophils, indicating that the therapy may be safe to take. Dr Heather Bax, Postdoctoral Research Fellow from St. John's Institute of Dermatology, King's College London, said: "We have shown that an immune response can be triggered by IgE immunotherapy for melanoma and that this applies to human melanomas and to melanoma patient immune responses. Our findings replicate existing observations for MOv18 IgE, the firstanti-cancer IgE, which targets ovarian cancer, and supports development of IgE therapies for other solid tumors." Professor Sophia Karagiannis, from St. John's Institute of Dermatology, Kings College London, said: "Four in ten people with advanced melanoma do not respond to available treatments. Our findings show that the human immune system reacts differently in the presence of drugs based on IgE antibodies and points to the potential of applying IgE to mount an effective response against melanoma. This opens up the possibility of this new class of drugs to benefit different patient groups and a new frontier in the battle against cancer." Professor James Spicer, from Kings College London and a Consultant at Guys and St Thomas' NHS Foundation Trust, said: "We have recently completed the first ever trial testing an IgE therapy for cancer (MOv18 IgE), and are excited about the prospect of a whole new class of antibody drugs in oncology. The collaboration between the King's College London and Guy's and St Thomas' research groups is close and ever more productive." The first IgE antibody (MOv18 IgE) generated at Kings College London has been trialled for ovarian cancer with results expected to be published later in 2023. Epsilogen Ltd owns rights to both CSPG4 IgE and MOv18 IgE. Epsilogen was spun out from Kings College London in 2017 and has attracted venture capital financing from multiple investors. Chauhan, J., Grandits, M., Palhares, L.C.G.F. et al. Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4. Nat Commun 14, 2192, 2023. 10.1038/s41467-023-37811-3

免疫疗法并购

2023-04-06

·生物探索

Cell Res | 王皞鹏/吴海涛/许琛琦/宋献民合作开发CAR-T理性设计平台

嵌合抗原受体(CAR)的强化信号，即CAR在没有肿瘤抗原刺激的情况下自发激活，被认为是控制CAR-T疗效的关键事件。然而，自发CAR信号背后的分子机制仍然难以捉摸。2023年3月8日，上海科技大学生命科学与技术学院王皞鹏课题组联合复旦大学附属眼耳鼻喉科医院吴海涛团队、中科院分子细胞科学卓越创新中心许琛琦实验室，以及上海市第一人民医院宋献民课题组在Cell Research 上发表了题为 “Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness”的研究论文，并被杂志列为精选论文（Featured Article）。该研究阐明了CAR-T细胞中基底信号形成的机制，开发了基于基底信号调控的CAR理性设计（rational design）平台，为推进CAR-T细胞治疗实体瘤提供了新策略。CAR-T细胞治疗是通过在T细胞上表达嵌合型抗原受体（Chimeric Antigen Receptor, CAR），使其在患者体内识别并杀伤肿瘤细胞的一种肿瘤免疫疗法。CAR-T疗法在血液肿瘤的治疗中展现出显著的效果，多种CAR-T细胞产品也已获批上市，但其在治疗实体瘤方面一直疗效不佳，其中一个重要原因是CAR-T 细胞容易功能耗竭。如何解决功能耗竭这一难题是实体肿瘤CAR-T治疗中的热点与难点。近期研究发现，多数实体肿瘤CAR受体在无肿瘤抗原刺激时，仍然会产生一种持续的基底信号（tonic signal），而这种基底信号，会持续刺激CAR-T细胞，导致CAR-T细胞功能耗竭。同时，近期临床研究也表明，基底信号的过度不足也会影响CAR-T细胞的持续和疗效。因此，了解基底信号形成和维持的机制可以帮助设计高持续、抗耗竭的CAR-T细胞，提高CAR-T疗效。目前，领域内对CAR的基底信号的研究匮乏，基底信号是如何形成的、基底信号又是如何影响CAR- T疗效等一系列重要科学问题尚待解决。图一：CAR受体表面电荷的分布（临床中常见的10种CAR的设计。其中蓝色：正电荷基团；红色：负电荷基团）在该项研究中，研究人员首次揭示了CAR受体表面正电荷斑块（PCP）介导的静电作用是基底信号的重要发生机制（图一）。研究人员发现，大多数靶向实体瘤的CAR-T细胞往往会因为基底信号强度过高导致自发耗竭，如GD2、CSPG4 CAR等，可以通过提高盐离子浓度或者缩小PCP的方法来减弱实体瘤CAR-T细胞的基底信号，提高它们的体内生存优势。然而，某些治疗血液肿瘤的CAR-T细胞会因为基底信号强度不足导致持续能力不够，如CD19、CD22 CAR等，设计者又可以通过增大PCP的方法来增强该类CAR-T细胞的基底信号，增强它们的体内持续能力。图二. CAR-T基底信号的产生机制与调控方法（基底信号过弱导致体内持续性不足，可以通过增加PCP的方法提高基底信号强度进而改善其活力；基底信号过强导致T细胞耗竭，可以通过缩小PCP或增加盐离子浓度的方式减弱基底信号进而促进其活性；PCP,正电荷斑块；ion,盐离子）研究人员提出的理性设计概念能为CAR的结构设计提供评价指导和功能预测，大大加速CAR-T的研发效率和进程，进而推动肿瘤尤其是实体瘤CAR-T治疗研究领域的发展进步(图二)。在该项目中，复旦大学附属眼耳鼻喉科医院陈健、上海科技大学博士研究生邱士真及上海科技大学博士李文涛（已毕业）为论文共同第一作者。王皞鹏研究员、吴海涛教授、许琛琦研究员和宋献民教授为共同通讯作者。上海科技大学范高峰课题组、中科院分子细胞科学卓越创新中心柳欣课题组参与研究。本文转载自“iNature”公众号校对|风立宵End 往期精选围观 ‍张锋团队最新研究：可将蛋白递送至任何指定人类细胞，或打破基因治疗困局热文恢复80%头发生长！礼来斑秃治疗新药在中国获批热文研究发现，这种“升级版”辅酶Q10能逆转HIV引起的器官损伤热文为什么甜食让人难以抗拒？人体实验显示甜食改变我们的大脑热文中国首份中重度卵巢过度刺激综合征发病率报告出炉！点击“阅读原文”，了解更多~

细胞疗法免疫疗法

2023-03-07

·生物谷

PNAS：科学家识别出人类神经退行性疾病发生期间小胶质细胞增生的新型细胞来源

来自中科院脑科学与智能技术卓越创新中心等机构的科学家们通过研究发现，Cspg4高水平表达的小胶质细胞或许是神经退行性疾病发生过程中小胶质细胞增生的新型细胞来源。小胶质细胞在诸如帕金森疾病和阿尔兹海默病等多种神经退行性疾病的致病过程中扮演着关键角色，在病理性刺激下，小胶质细胞就会“监视者”的角色过渡到过度活化的表型，然而，增殖的小胶质细胞以及其在神经退行性疾病的发病机制中所扮演的关键角色，研究人员并不清楚。近日，一篇发表在国际杂志Proceedings of the National Academy of Sciences上题为“Cspg4high microglia contribute to microgliosis during neurodegeneration”的研究报告中，来自中科院脑科学与智能技术卓越创新中心等机构的科学家们通过研究发现，Cspg4高水平表达的小胶质细胞或许是神经退行性疾病发生过程中小胶质细胞增生的新型细胞来源，而且研究者还揭示了这类小胶质细胞的分子特征和功能，其会在神经退行性疾病中表现出高水平的增殖，这或许就提供了人类神经退行性疾病新型发病机制。有研究证据强烈表明，小胶质细胞在包括阿尔兹海默病在内的多种神经退行性疾病发生过程中扮演着关键角色，一旦受到病理性刺激时，小胶质细胞就会快速被激活并迁移到受损的大脑部位，而活化的小胶质细胞在神经性炎症、蛋白质沉积和吞噬作用中发挥着重要角色，这些细胞的异常激活被认为会明显促进人类神经退行性疾病的开启和进展。有研究结果表明，小胶质细胞能被用来进行神经退行性疾病的早期诊断和治疗，然而，在神经退行性疾病发生期间小胶质细胞被激活的起源目前研究人员还不清楚，从传统上来讲，大脑中激活的小胶质细胞来源于其自身和骨髓衍生的前体细胞，而理解其起源对于控制失调的小胶质细胞的活性非常必要。科学家识别出人类神经退行性疾病发生期间小胶质细胞增生的新型细胞来源。图片来源：Proceedings of the National Academy of Sciences (2023). DOI:10.1073/pnas.2210643120 文章中，研究人员识别出了表达硫酸软骨素蛋白聚糖4（Cspg4，也称之为神经/胶质抗原2）的小胶质细胞或许是神经变性期间具有增殖潜力的一类特殊的小胶质细胞群。研究者发现，在帕金森疾病小鼠模型中Cspg4+小胶质细胞的比例会增加，而对Cspg4+小胶质细胞进行转录组学分析后，研究者发现，Cspg4高水平表达的小胶质细胞亚群会展现出特殊的转录组学特征，其主要特点是直系同源的细胞周期基因的富集以及负责机体神经性炎症和吞噬作用的基因表达水平降低，其基因特征或许与已知的疾病相关的小胶质细胞不同。静止的Cspg4高水平表达的小胶质细胞的增值是由病理性的α-突触核蛋白所诱发的，当在剔除了内源性小胶质细胞的成年个体的大脑中进行移植后，Cspg4高水平表达的小胶质细胞移植物则会表现出相比Cspg4-对照个体更高的存活率。而相一致的是，研究者在阿尔兹海默病患者的大脑中也检测到了Cspg4高水平表达的小胶质细胞，同时阿尔兹海默病动物模型中也会表现出该细胞群的扩张。综上，本文研究结果表明，Cspg4高水平表达的小胶质细胞或许是机体神经变性期间小胶质细胞增生的新型细胞来源，这或许就为后期科学家们开发治疗人类神经退行性疾病的新型疗法提供了新的线索和路径。（生物谷Bioon.com）原始出处： Ya-jing Liu,Yu Ding,Yan-qing Yin,et al. Cspg4high microglia contribute to microgliosis during neurodegeneration, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2210643120