胰腺癌CXCL12/CXCR4通路研究进展

目的:总结CXCL12/CXCR4生物学轴与胰腺癌侵袭和转移关系的研究现状.方法:应用PubMed及CNKI期刊全文数据库检索系统,以“CXCL12、CXCR4和胰腺癌”等为关键词,检索2005-2011年的相关文献,共检索到中文文献56条,英文文献152条.纳入标准:1)CXCL12-CXCR4生物学轴的生物学特性及功能;2)CXCL12/CXCR4生物学轴与肿瘤发生、发展的关系;3)CXCL12/CXCR4生物学轴信号转导通路的相关调控因子及其调节机制;4)CXCL12/CXCR4生物学轴在胰腺癌侵袭、转移中的作用及其机制;5)CXCL12/CXCR4生物学轴与胰腺癌的治疗及预后.根据纳入标准共采用中文文献3条,英文文献17条.结果:趋化因子受体CXCR4与其配体CXCL12结合组成的生物学轴具有高度特异性,在胰腺癌细胞的黏附、侵袭、转移、增殖和生存中发挥重要作用,与细胞外基质降解、胰腺癌血管、淋巴管生成及嗜神经侵袭密切相关,并受相关因子调控影响其信号转导通路.结论:CXCL12/CXCR4生物学轴在胰腺癌发生、发展中发挥着重要作用,有望成为胰腺癌靶向治疗的新靶点,但其具体作用的相关转导通路和调节机制还未完全明确,有待进一步研究.     

趋化因子受体CXCR7及其与肿瘤的关系

CXCR7是继CXCR4之后发现的趋化因子CXCL12的新受体.目前研究表明,CXCL12/CXCR7生物轴对多种肿瘤的发展有重要影响,与CXCL12/CXCR4生物轴的作用有一定相似性.CXCR7广泛表达于多种肿瘤组织及肿瘤细胞,在肿瘤细胞的生长增殖、黏附迁徙中起重要作用.抑制CXCR7表达或阻断其信号传导通路可能为肿瘤治疗提供新策略.     

结直肠癌CXCL12-CXCR4/CXCR7轴作用机制研究进展

目的 探讨趋化因子CXCL12及其受体与结直肠癌的关系,以总结最新研究进展。方法 应用PubMed、Web of Science数据库和中国期刊全文数据库(CNKI)检索系统,以“结直肠癌、CXCL12、CXCR4、CXCR7、靶向治疗和趋化因子等”为中文关键词,以“colorectal cancer、CXCL12、CXCR4、CXCR7、targeted therapy、chemokines”等为英文关键词,检索2010-01-01-2022-03-31的相关文献,共检索到中文文献76篇,英文文献256篇。纳入标准：(1)结直肠癌发生时CXCL12、CXCR4和CXCR7表达水平变化;(2)CXCL12-CXCR4/CXCR7轴对结直肠癌发生发展的影响及作用机制;(3)靶向干预CXCL12-CXCR4/CXCR7轴对结直肠癌的影响及相关临床研究。排除标准：结直肠癌与非CXCL12/CXCR4或CXCL12/CXCR7信号轴。最终共纳入分析文献56篇,中文16篇,英文40篇。结果 CXCL12及其受体在结直肠癌组织及常见转移部位表达显著升高,相关分子信号可通过CXCL12-CXCR4/...     

CXCR4和CXCR7在肿瘤中的研究进展

以往的研究认为趋化因子受体4(chemokine receptor 4,CXCR4)是趋化因子CXCL12的唯一受体,CXCL12/CXCR4生物轴在肿瘤发展过程中起重要作用,然而最近研究发现CXCL12尚存在CXCR7这一新的受体,并且CXCL12/CXCR7生物轴同样对肿瘤的发生发展起重要作用.本文就有关趋化因子受体CXCR4和CXCR7在肿瘤中的表达、促进肿瘤增殖和转移、促进血管新生以及肿瘤治疗等方面的研究作一综述.     

CXCL12-CXCR4生物学轴与肿瘤转移关系的研究

趋化因子CXCL12与其特异性受体CXCR4构成的CXCL12-CXCR4生物学轴在肿瘤细胞的选择性转移中起到重要的作用,并有可能参与了肿瘤的种植转移过程.对这一特殊生物学轴的研究可以为肿瘤的防治提供新的思路.     

CXCR4阻断剂在转移性肿瘤治疗中的应用

肿瘤转移受到趋化因子受体和黏附分子的严密调控.肿瘤细胞表达的CXCR4是一种7次跨膜的G-蛋白耦联受体.肿瘤微环境中的间质细胞可以分泌CXCL12,是CXCR4的配体.CXCR4与CXCL12相互作用会诱导癌细胞迁移并粘附到间质细胞,促进癌细胞转移和耐药.CXCR4阻断剂,如AMD3100和T140类似物(TN14003/BKT140)可以抑制CXCR4介导的癌细胞与间质细胞的黏附,增加癌细胞对化疗药的敏感性,因此,阻断CXCR4/CXCL12轴是治疗肿瘤的一种新的有效方法.全文论述近年来CXCR4阻断剂在转移性肿瘤治疗中的应用.     

CXCL12/CXCR4轴与乳腺癌研究进展

趋化因子CXCL12与其受体CXCR4信号通路与乳腺癌细胞的定向播散和器官特异性转移密切相关,研究CXCL12/CXCR4轴在乳腺癌生长及转移中的重要作用,有望为乳腺癌靶向治疗提供新的策略。     

趋化因子CXCL12/CXCR4与肿瘤关系的研究进展

CXCL12及其受体CXCR4不仅在许多生命过程中发挥着重要的调控作用而且与肿瘤细胞的生长、增殖、侵袭、转移有密切的关系。本文将围绕CXCR4、CXCL12以及CXCL12/CXCR4轴在肿瘤增殖、侵袭、转移、肿瘤血管生成中的作用以及作用原理以及临床应用作一综述。     

趋化因子受体CXCR4及其配体CXCL12在胃癌组织中的表达及其意义

目的 探讨CXCR4/CXCL12在胃癌组织中表达及其在肝转移中的作用。方法 应用Western blot 检测40例胃癌患者标本中肿瘤组织、邻近正常黏膜以及肝转移组织中CXCR4/CXCL12通路成员的表达情况,免疫组织化学法检测CXCR4/CXCL12在细胞水平的分布。结果 胃癌组织中CXCR4/CXCL12表达水平明显增高（肿瘤组织vs正常黏膜,P<0.05）;10例肝转移组织中CXCR4/CXCL12表达增高（转移组织vs原发肿瘤,P<0.05）;CXCR4/CXCL12表达水平与TNM 分期晚（Ⅲ/Ⅳ）有关（P<0.05）。结论 CXCR4/CXCL12信号转导通路可能在胃癌肝转移过程中起一定作用,详细机制尚待进一步研究。     

趋化因子受体CXCR4/CXCL12信号转导通路与胃癌淋巴结转移关系的研究

目的：检测趋化因子受体CXCR4/CXCL12信号转导通路在胃癌组织、远癌正常粘膜以及转移淋巴结中的表达情况,分析CXCR4/CXCL12在胃癌淋巴结转移中的作用。方法：应用Westernblot检测胃癌组织中CXCR4/CXCL12通路成员表达。结果：胃癌组织中CXCR4/CXCL12表达水平明显高于正常胃粘膜（P〈0.05）;32例淋巴结转移癌组织中22例CXCR4/CXCL12蛋白表达高于原发癌;CXCR4/CXCL12表达水平与淋巴结转移有关（P（0.05）。结论：趋化因子受体CXCR4/CXCL12在原发胃癌及其淋巴结转移癌组织中均呈高表达,CXCR4信号转导通路可能在胃癌淋巴结转移过程中起重要作用。     

Effect of CXCL12 and Its Receptors on Unpredictable Renal Cell Carcinoma

Chemokines are chemotactic cytokines that participate in numerous cell functions during hematopoiesis, morphogenesis, inflammation, neovascularization, and autoimmune diseases and cancer. They achieve their functions on binding to their G protein-coupled receptors. CXCL12, or stromal cell-derived factor-1, is a homeostatic chemokine secreted by fibroblasts, macrophages, and endothelial cells. It binds to CXC receptor 4 (CXCR4), also known as fusin (CD184), and alternate CXC receptor 7 (CXCR7), also known as atypical chemokine receptor 3. The CXCL12/CXCR4 axis participates in homing of hematopoietic stem cells and the development and production of B and T lymphocytes, plasmacytoid dendritic cells, and natural killer cells. It has been examined in > 20 different malignancies. CXCL12 plays an important role in tumor metastasis because it mediates the migration of tumor cells through the endothelial vessel wall and extracellular matrix. Its expression has been highest in common metastatic sites such as the brain, bone marrow, lymph nodes, and liver. CXCR4 is expressed by tumor cells in prostate, breast, lung, and other malignancies. Numerous studies have shown its correlation with a poor prognosis, recurrence-free survival, and poor overall survival. The present review has addressed the structure and function of CXCL12 and its receptors and the effect CXCL12/CXCR4 axis has on the pathogenesis and clinical development of renal cell carcinoma, one of the most aggressive cancers in urology, with limited therapeutic options.     

Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer

Perineural invasion (PNI) is considered as an alternative route for the metastatic spread of pancreatic cancer cells; however, the molecular changes leading to PNI are still poorly understood. In this study, we show that the CXCL12/CXCR4 axis plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. Immunohistochemical staining results revealed that CXCR4 elevation correlated with PNI in 78 pancreatic cancer samples. Both in vitro and in vivo PNI models were applied to investigate the function of the CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of the CXCL12/CXCR4 axis significantly increased pancreatic cancer cells invasion and promoted the outgrowth of the dorsal root ganglia. CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4-positive cancer cells in a paracrine manner, eventually leading to PNI. In vivo analyses revealed that the abrogation of the activated signaling inhibited tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicate that the CXCL12/CXCR4 axis may be a novel therapeutic target to prevent the perineural dissemination of pancreatic cancer.     

Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer

CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.     

Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis

Cellular metastasis is the most detrimental step in carcinoma disease progression, yet the mechanisms that regulate this process are poorly understood. CXCL12 and its receptor CXCR4 are co-expressed in several tissues and cell types throughout the body and play essential roles in development. Disruption of either gene causes embryonic lethality due to similar defects. Post-natally, CXCL12 signaling has a wide range of effects on CXCR4-expressing cells, including the directed migration of leukocytes, lymphocytes and hematopoietic stem cells. Recently, this signaling axis has also been described as an important regulator of directed carcinoma cell metastasis. We show herein that while CXCR4 expression remains consistent, constitutive colonic epithelial expression of CXCL12 is silenced by DNA hypermethylation in primary colorectal carcinomas as well as colorectal carcinoma-derived cell lines. Inhibition of DNA methyltransferase (Dnmt) enzymes with 5-aza-2'-deoxycytidine or genetic ablation of both Dnmt1 and Dnmt3b prevented promoter methylation and restored CXCL12 expression. Re-expression of functional, endogenous CXCL12 in colorectal carcinoma cells dramatically reduced metastatic tumor formation in mice, as well as foci formation in soft agar. Decreased metastasis was correlated with increased caspase activity in cells re-expressing CXCL12. These data constitute the unique observation that silencing CXCL12 within colonic carcinoma cells greatly enhances their metastatic potential.     

The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis

Tumor cells are known to adapt to and utilize existing physiological mechanisms to promote survival and metastasis. The role of the microenvironment in the establishment of a metastatic lesion has become increasingly important as several factors secreted by stromal cells regulate metastatic pattern in a variety of tumor types. Tumor cells interact with osteoblasts, osteoclasts and bone matrix to form a vicious cycle that is essential for successful metastases. Here we review the current concepts regarding the role of an important chemokine/chemokine receptor (SDF-1 or CXCL12/CXCR4) pathway in tumor development and metastasis. CXCL12 secretion by stromal cells is known to attract cancer cells via stimulation of the CXCR4 receptor that is up regulated by tumor cells. CXCL12/CXCR4 activation regulates the pattern of metastatic spread with organs expressing high levels of CXCL12 developing secondary tumors (i.e., the bone marrow compartment). CXCL12 has a wide range of effects in regards to tumor development but the primary role of CXCL12 appears to be the mobilization of hematopoietic stem cells and the establishment of the cancer stem-like cell niche where high levels of CXCL12 recruit a highly tumorigenic population of tumor cells and promotes cell survival, proliferation, angiogenesis, and metastasis.     

趋化因子CXCL12及其受体与肿瘤转移的关系

趋化因子CXCL12(C-X-C chemokine ligand 12)及其受体CXCR4(c-x-c chemokine receptor4)在胚胎发育、干细胞的迁移和各种免疫反应中发挥重要作用,是许多生理和病理过程中指导细胞运动的中心因素.最近发现肿瘤细胞的转移机制和白细胞的迁移相类似,趋化因子CXCL12及其受体与肿瘤的生长、侵袭、转移和分泌密切相关,动物实验表明CXCR4可能成为抑制肿瘤生长、转移的重要靶目标.本文将对趋化因子CXCL12及其受体CXCR4在肿瘤转移、进展中的作用以及与此相关的信号转导、调节因子进行综述.     

CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells

Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT.