CXCR4/CXCL12 在肿瘤中的研究进展

研究表明趋化因子及其受体在胚胎发育、干细胞迁移以及各种免疫反应中发挥重要作用,是许多生理及病理过程中细胞运动的重要因素。趋化因子受体CXCR4是一个由352个氨基酸构成的、7次跨膜的G蛋白偶联受体。趋化因子CXCL12为其特异性受体。研究发现,CXCR4/CXCL12在多种肿瘤中都有表达,在肿瘤的生长、血管生成、转移等方面发挥着重要作用。与正常组织相比,肿瘤组织及转移灶CXCR4高表达。因此,对CXCR4/CXCL12轴在肿瘤病生理中的作用机制进行进一步研究,很可能为肿瘤的治疗及对肿瘤转移的预防提供一个新的思路。我们现在就对其在肿瘤病生理中的作用做一综述。     

趋化因子SD-1及其受体CXCR4在卵巢癌中的研究进展

基质细胞衍生因子-1(Stromal cell derived factor-1,SDF-1)是CXC趋化因子家族的重要成员,系统命名为CXCL12,能与它的唯一受体CXC趋化因子受体-4(CXC chemokine receptor-4,CXCR4)形成CXCL12-CXCR4生物学轴,CXCL12-CXCR4生物学轴在肿瘤生长、侵袭、转移过程中发生重要作用。到目前为止,已发现CXCL12-CXCR4在卵巢癌、胰腺癌、肝癌等多种肿瘤组织中表达。然而,国内目前还没有关于CXCL12-CXCR4与卵巢癌关系的相关综述,本文将从趋化因子CXCL12及其受体CXCR4,CXCL12/CXCR4轴与卵巢癌细胞系实验研究,CXCL12-CXCR4轴与卵巢癌的临床研究,CXCL12/CXCR4与卵巢癌预后,CXCL12/CXCR4与卵巢癌治疗展望等五个方面对CXCL12-CXCR4生物轴与卵巢癌的关系,及其在卵巢癌治疗中的应用展开综述。     

靶向CXCL12/CXCR4轴在肿瘤治疗中的作用

远处转移是恶性肿瘤预后不良的主要原因之一。CXCL12/CXCR4信号通路与多种肿瘤的发展及转移、血管生成、免疫逃逸密切相关,阻断该信号通路可抑制肿瘤的进展和转移。靶向CXCR4的拮抗剂表现出良好的治疗前景,部分已应用于临床中。靶向CXCL12的核酸适配体开发以及可靶向调控CXCL12/CXCR4表达的mi RNA和si RNA的研究也有一些新的进展,这些为肿瘤靶向治疗提供了新思路。     

CXCL12/CXCR4轴的表达和功能研究进展

CXCL12/CXCR4(CXC ligand 12/CXC receptor 4)轴不仅在趋化、细胞迁徙方面起作用,还参与细胞增殖、分化、干细胞的归巢、炎症反应、免疫调节、内分泌调节及提高痛觉敏感性等多种生命活动中。CXCR4在许多类型的肿瘤中有高表达,并且对于这些类型的肿瘤的远处转移有十分明显的促进作用。在干细胞归巢方面,间充质干细胞中CXCR4表达普遍不高,通过病毒载体过表达CXCR4于间充质干细胞,用于移植治疗损伤或炎症性疾病,取得了十分不错的成效,并引起了广泛关注。在免疫调节方面,研究者发现CXCL12/CXCR4轴也参与到其中。本文对CXCL12/CXCR4轴的生物学功能进行了综述。     

趋化因子CXCL12及其受体CXCR4在胶质瘤中的研究进展

CXCL12是趋化因子家族成员之一,是能够特异性结合其受体CXCR4发挥趋化性作用的细胞因子。最初,CXCL12及CXCR4被发现于炎症细胞,参与机体炎症、免疫等病理反应。接下来的几年中发现,它在机体发育、成熟过程中也有重要作用。如今,大量研究表明它与肿瘤的生长、侵袭及转移密切相关。据报道,在乳腺癌、肺癌、卵巢癌等二十余种肿瘤组织中发现CXCL12及CXCR4的表达,其中也包括中枢系统肿瘤-胶质瘤。CXCL12/CXCR4参与胶质瘤生长过程的多个步骤,包括肿瘤增殖、侵袭、转移等。有实验指出,转移灶的CXCR4表达水平较原发灶高,CXCR4有可能成为抑制胶质瘤生长、转移的重要靶目标。     

趋化因子CXCL12 及其受体CXCR4 在胶质瘤中的研究进展

CXCL12是趋化因子家族成员之一,是能够特异性结合其受体CXCR4发挥趋化性作用的细胞因子。最初,CXCL12及CXCR4被发现于炎症细胞,参与机体炎症、免疫等病理反应。接下来的几年中发现,它在机体发育、成熟过程中也有重要作用。如今,大量研究表明它与肿瘤的生长、侵袭及转移密切相关。据报道,在乳腺癌、肺癌、卵巢癌等二十余种肿瘤组织中发现CXCL12及CXCR4的表达,其中也包括中枢系统肿瘤-胶质瘤。CXCL12/CXCR4参与胶质瘤生长过程的多个步骤,包括肿瘤增殖、侵袭、转移等。有实验指出,转移灶的CXCR4表达水平较原发灶高,CXCR4有可能成为抑制胶质瘤生长、转移的重要靶目标。     

CXCL12/CXCR4轴对NPC调节的研究进展

基质细胞衍生因子1α(SDF-1α/CXCL12)属于趋化因子CXC家族,与其受体CXCR4组成的CXCL12/CXCR4轴,在大脑生理和病理状态下都发挥着重要作用。CXCL12能与神经祖细胞(NPC)表面上的受体CXCR4结合,从而激活CXCR4下游不同的信号通路,参与调节NPC静息、激活、增殖、迁移和分化等活动。在中枢神经系统(CNS)疾病发生后,大脑中CXCL12会激活内源的NPC,促进NPC增殖并迁移至病灶区域,最终分化为神经元并整合入神经系统,促进神经功能恢复。深入理解CNS疾病时期CXCL12/CXCR4轴对NPC调控作用,对内源性和外源性的NPC应用于CNS疾病具有重要意义。现主要对CXCL12/CXCR4轴调控NPC活动的作用机制及相关信号通路进行综述。     

水苏碱调节CXCL12/CXCR4轴对子宫内膜癌细胞增殖、迁移和侵袭的影响

该研究主要探讨水苏碱(STA)对子宫内膜癌(EC)细胞增殖、侵袭和迁移的影响以及对CXCL12/CXCR4轴的调节机制。将EC细胞分为对照组(Control组)、CXCL12/CXCR4抑制剂组(AMD 3100组)、STA-L组(STA-L)、STA-H组(STA-H)、STA-H+CXCL12组。采用CCK-8检测细胞增殖情况;克隆形成实验检测细胞克隆能力;流式细胞术检测细胞凋亡情况; Transwell实验检测细胞的迁移和侵袭能力; Western blot检测细胞中上皮钙黏蛋白(E-cadherin)、波形蛋白(Vimentin)、CXCL12、CXCR4蛋白的表达情况;建立小鼠EC移植瘤模型并观察各组小鼠的肿瘤生长情况。结果发现与Control组相比, AMD 3100组和STA处理组细胞增殖活性、克隆数量、迁移和侵袭数以及Vimentin、CXCL12、CXCR4蛋白表达水平降低,细胞凋亡率和E-cadherin蛋白表达水平升高(P<0.05);与STA-H组相比, STA-H+CXCL12组细胞的增殖活性、克隆数量、迁移和侵袭数以及Vimentin、CXCL12、C...     

CXCR7 的生物学功能及其在肿瘤发生发展中的 作用研究进展

趋化因子受体是一类G 蛋白偶联的7 次跨膜受体,其与配体结合能参与调控多种生理和病理学过程。以往,CXCR4 一直被认为 是趋化因子CXCL12 的唯一受体。然而近年来的研究表明CXCL12 能与另一种新受体CXCR7 结合,并在调控肿瘤转移、血管生成和细 胞粘附等方面起着重要作用,CXCR7 由此成为肿瘤治疗的潜在靶点。介绍CXCR7 的结构、生物学功能以及CXCR7 在肿瘤发生发展中 的作用。     

CXCR4/CXCL12轴与肿瘤发生发展中的作用研究进展

趋化因子受体是一类G蛋白偶联的7次跨膜受体,其与配体结合能参与调控多种生理和病理学过程,CXCR4/CXCL12轴在多种肿瘤中都高表达。本文对该轴生物学功能以及在肿瘤中的表达、增殖、侵袭转移及治疗等方面作一综述,提示此轴可成为抗肿瘤药物治疗的新靶点。     

CXCL12/CXCR4 facilitates perineural invasion via induction of the Twist/S100A4 axis in salivary adenoid cystic carcinoma

The activation of CXCL12/CXCR4 axis participated in the progression of multiple cancers, but potential effect in terms of perineural invasion (PNI) in SACC remained ambiguous. In this study, we identified that CXCL12 substantially expressed in nerve cells. CXCR4 strikingly expressed in tumour cells, and CXCR4 expression was closely associated with the level of EMT-associated proteins and Schwann cell hallmarks at nerve invasion frontier in SACC. Activation of CXCL12/CXCR4 axis could promote PNI and up-regulate relative genes of EMT and Schwann cell hallmarks both in vitro and in vivo, which could be inhibited by Twist silence. After overexpressing S100A4, the impaired PNI ability of SACC cells induced by Twist knockdown was significantly reversed, and pseudo foot was visualized frequently. Collectively, the results indicated that CXCL12/CXCR4 might promote PNI by provoking the tumour cell to differentiate towards Schwann-like cell through Twist/S100A4 axis in SACC.     

In vitro characterization and inhibition of the CXCR4/CXCL12 chemokine axis in human uveal melanoma cell lines

Purpose  

The CXCR4/CXCL12 chemokine axis may play a critical role in guiding CXCR4+ circulating malignant cells to organ specific locations that actively secrete its ligand CXCL12 (SDF-1) such as bone, brain, liver, and lungs. We sought to characterize the presence of the CXCR4/CXCL12 axis in five uveal melanoma (UM) cell lines in vitro. The ability of TN14003, a synthetic peptide inhibitor that targets the CXCR4 receptor complex, to inhibit this axis was also assessed.     

Retracted: Role of CXCL12–CXCR4 axis in ovarian cancer metastasis and CXCL12–CXCR4 blockade with AMD3100 suppresses tumor cell migration and invasion in vitro

Ovarian cancer (OC) is a lethal gynecologic tumor, which brings its mortality to the head. CXCL12 and its receptor chemokine receptor 4 ( CXCR4) have been found to be highly expressed in OC and contribute to the disease progression by affecting tumor cell proliferation and invasion. Here, in this study, we aim to explore whether the blockade of CXCL12–CXCR4 axis with AMD3100 (a selective CXCR4 antagonist) has effects on the progression of OC. On the basis of the gene expression omnibus database of OC gene expression chips, the OC differentially expressed genes were screened by microarray analysis. OC (nonmetastatic and metastatic) and normal ovarian tissues were collected to determine the expressions of CXCL12 and CXCR4. A series of AMD3100, shRNA against CXCR4, and pCNS-CXCR4 were introduced to treat CAOV3 cells with the highest CXCR4 was assessed. Cell viability, apoptosis, migration, and invasion were all evaluated. The microarray analysis screened out the differential expression of CXCL12–CXCR4 in OC. CXCL12 and CXCR4 expressions were increased in OC tissues, particularly in the metastatic OC tissues. Downregulation of CXCR4 by AMD3100 or shRNA was observed to have a critical role in inhibiting cell proliferation, migration, and invasion of the CAOV3 OC cell line while promoting cell apoptosis. Overexpressed CXCR4 brought significantly promoting effects on the proliferation and invasiveness of OC cells. These results reinforce that the blockade of CXCL12–CXCR4 axis with AMD3100 inhibits the growth of OC cells. The antitumor role of the inhibition of CXCL12–CXCR4 axis offers a preclinical validation of CXCL12–CXCR4 axis as a therapeutic target in OC.     

LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells

Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide, and over 50% of patients will develop hepatic metastasis during the course of their disease. CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α)/chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we have shown that lipopolysaccharides (LPS) promoted the migratory capacity of colon cancer cells in vivo and in vitro, which correlated with the activation of SDF-1α/CXCR4 axis and epithelial-mesenchymal transition (EMT) occurrence. Additionally, we found that LPS-induced CXCR4 expression and EMT through NF-κB signaling pathway activation. And inhibition of NF-κB pathway, which recovered the epithelial phenotype and attenuated CXCR4 expression, inhibited cell migratory capacity. Clinically, high levels of CXCR4 always correlated with metastasis and poor prognosis of CRC patients. In conclusion, LPS participate in the whole process of hepatic metastasis of CRC, not only causing liver damage resulting in the production of SDF-1α, but also enhancing the invasive potential of CRC cells by promoting CXCR4 expression and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.     

Involvement of the CXCR7/CXCR4/CXCL12 Axis in the Malignant Progression of Human Neuroblastoma

Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.     

Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12

Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12–CXCR4 axis have emerged as additional or alternative agents for neo-adjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of “selective blockade” of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.     

The N-terminal polypeptide derived from vMIP-II exerts its antitumor activity in human breast cancer through CXCR4/miR-7-5p/Skp2 pathway

Breast cancer is a malignant tumor with the highest incidence in women of the world. CXCR4 and Skp2 are highly expressed in breast cancer cells and CXCR4 was positively correlated with Skp2 by interference or overexpression. The microRNA array was used to detect the differentially expressed spectrum of micro RNAs in breast cancer cells the changes of miR-7-5p after CXCR4 inhibitor (NT21MP) treatment to block the CXCR4/SDF-1 pathway was founded. MiR-7-5p has been found to be correlated with Skp2 in various tumors in the literature, and Skp2 expression can be regulated by transfection with miR-7-5p mimics or inhibitors. The expression level of miR-7-5p was upregulated or downregulated after CXCR4 interference or overexpression. Combined with the correlation between CXCR4 and miR-7-5p in the chip results, CXCR4 may regulate Skp2 through miR-7-5p. Epithelial cells have the morphological characteristics of mesenchymal cells for some reason called epithelial–mesenchymal transformation (EMT). Transfection of miR-7-5p mimics into drug-resistant cells reduced Skp2 levels, decreased the expression of Vimentin, Snail, and slug, and increased the expression of E-cadherin. CXCR4 inhibitor (NT21MP) can reverse the EMT changes caused by miR-7-5p inhibitor. Similarly, in vivo results suggesting that CXCR4 inhibitors can reverse the EMT phenotype of drug-resistant breast cancer cells through the CXCR4/miR-7-5p/Skp2 pathway. In summary, the CXCR4/miR-7-5p/Skp2 signaling pathway plays an important role in the progression of breast cancer. This study provides a theoretical basis for the treatment of breast cancer by targeting the CXCR4 pathway.