CXCR7/CXCL12与乳腺癌淋巴结转移的关系

目的探讨CXCR7/CXCL12在乳腺癌淋巴结转移中的作用。方法应用Western blot法,检测乳腺癌组织中CXCR7/CXCL12的表达情况。结果乳腺癌组织中CXCR7/CXCL12表达水平明显高于正常乳腺组织(P<0.05);48例淋巴结转移癌组织中36例CXCR7/CXCL12蛋白表达水平高于原发癌组织;CXCR7/CXCL12表达水平与肿瘤淋巴结转移有关(P<0.05)。结论 CXCR7/CXCL12在乳腺癌及其淋巴结转移癌组织中均呈高表达,CXCR7/CXCL12可能在乳腺癌淋巴结转移过程中起重要作用。     

Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer.     

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。     

CXCR4/CXCL12轴与白血病复发

趋化因子受体CXCR4与其特异性配体CXCL12结合,启动下游信号通路形成CXCR4/CXCL12生物轴,在造血干细胞的归巢、再植以及维持正常造血和造血微环境的稳定过程中发挥重要作用.CXCR4/CXCL12轴同时也可促进白血病细胞存活、增殖、转移及耐药,与白血病髓内外复发关系密切.CXCR4的表达水平可作为判断白血病...     

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.     

CXCL12/CXCR4生物学轴诱导前列腺癌骨转移的作用机制研究进展

研究发现趋化因子CXCL12(Stromal-derived factor-1,SDF-1)和受体CXCR4[chemokine (C-X-C motif) receptor 4]广泛表达于组织和器官上,相关的研究发现其与前列腺癌细胞的黏附、侵袭、增殖和生存有关,并认为其在前列腺癌骨转移的发生中发挥重要作用.通过阐明CXCL12/CXCR4生物学轴和前列腺癌骨转移之间的关系,从而寻找有助于疾病治疗的新途径.     

CXCL12／CXCR4生物轴与消化系统恶性肿瘤

消化系统恶性肿瘤发病率及死亡率均远远高于其它系统恶性肿瘤，对消化系统恶性肿瘤的预防和治疗研究亟待进一步深入。细胞移位是相当多病理生理过程的基本步骤，包括恶性肿瘤细胞的生长及转移。越来越多地研究认为肿瘤细胞通过化学趋化因子及其相应受体介导的化学趋化机制调节其生长和转移，趋化因子在恶性肿瘤中具有多方面作用，归纳为：①诱导白细胞向肿瘤组织浸润，调节免疫功能，尤其是肿瘤相关的巨噬细胞、T细胞和树突状细胞；②引导肿瘤细胞迁移到特定部位；③调节血管生成；④直接活化肿瘤细胞，调控其恶性肿瘤相关的功能表现。近年研究发现，趋化因子CXCL12及其受体CXCR4构成的生物轴在包括乳腺癌在内的多种实体瘤的生长、转移中发挥重要作用。CXCL12／CXCR4生物轴与消化系统恶性肿瘤之间关系密切，CXCL12的刺激促进CXCR4的表达及消化系统恶性肿瘤的转移；CXCR4持续高表达预示肿瘤的复发及预后不良；在CXCL12作用下，肿瘤细胞黏附／迁移和增殖能力亦显著增强，这些效应被CXCR4的抗体所拮抗。未来研究寄希望通过拮抗影响肿瘤转移的CXCL12与CXCR4等趋化因子及其受体的作用来阻断消化系统恶性肿瘤转移，将可能会成为一种新的治疗消化系统恶性肿瘤的有效途径。     

CXCL12及受体CXCR4在卵巢上皮性癌中的表达及其临床意义

目的:探讨趋化因子CXCL12及其受体CXCR4在卵巢上皮性癌组织中的表达及与临床病理特征和预后的关系。方法:采用免疫组织化学SP法检测6例正常卵巢表面上皮、44例卵巢上皮性癌原发灶和30例相应大网膜转移灶组织中的CXCL12和CXCR4蛋白表达。结果:正常卵巢表面上皮无CXCL12和CXCR4蛋白表达;卵巢上皮性癌原发灶的CXCL12和CXCR4表达阳性率分别为91%和59%。CXCL12表达强度与术中腹水量有显著相关性(P=0.014)。难治复发组的CXCR4阳性率(81%)显著高于无复发组(28%,P<0.001)。单因素分析显示:CXCR4阳性表达的患者中位数肿瘤无进展生存时间和总生存时间(15个月、27个月)明显短于CXCR4阴性表达者(>21个月、>32个月,分别为P<0.001和P=0.017)。多因素分析显示:CXCR4表达和残余灶大小是影响卵巢上皮性癌患者的肿瘤无进展生存时间和总生存时间的独立预后因素。结论:CXCR4在卵巢上皮性癌中的表达阳性率较高,是影响其预后的独立指标之一。     

The biological role of the CXCL12/CXCR4 axis in esophageal squamous cell carcinoma

Esophageal cancer is the eighth most common malignant tumor and the sixth leading cause of cancer-related death worldwide. Esophageal squamous cell carcinoma (ESCC) is the main histological type of esophageal cancer, and accounts for 90% of all cancer cases. Despite the progress made in surgery, chemotherapy, and radiotherapy, the mortality rate from esophageal cancer remains high, and the overall 5-year survival rate is less than 20%, even in developed countries. The C-X-C motif chemokine ligand 12 (CXCL12) is a member of the CXC chemokine subgroup, which is widely expressed in a variety of tissues and cells. CXCL12 participates in the regulation of many physiological and pathological processes by binding to its specific receptor, C-X-C motif chemokine receptor type 4 (CXCR4), where it causes embryonic development, immune response, and angiogenesis. In addition, increasing evidence indicates that the CXCL12/CXCR4 axis plays an important role in the biological processes of tumor cells. Studies have shown that CXCL12 and its receptor, CXCR4, are highly expressed in ESCC. This abnormal expression contributes to tumor proliferation, lymph node and distant metastases, and worsening prognosis. At present, antagonists and imaging agents against CXCL12 or CXCR4 have been developed to interfere with the malignant process and monitor metastasis of tumors. This article summarizes the structure, function, and regulatory mechanism of CXCL12/CXCR4 and its role in the malignancy of ESCC. Current results from preclinical research targeting CXCL12/CXCR4 are also summarized to provide a reference for the clinical diagnosis and treatment of ESCC.     

Oncogenic roles and drug target of CXCR4/CXCL12 axis in lung cancer and cancer stem cell

Although the great progress has been made in diagnosis and therapeutic in lung cancer, it induces the most cancer death worldwide in both males and females. Chemokines, which have chemotactic abilities, contain up to 50 family members. By binding to G protein-coupled receptors (GPCR), holding seven-transmembrane domain, they function in immune cell trafficking and regulation of cell proliferation, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. In addition to human tissues of the bone marrow, liver, adrenal glands, and brain, the CXC chemokine SDF-1 or CXCL12 is also highly expressed in lung cancer tissues and is associated with lung metastasis. Lung cancer cells have the capabilities to utilize and manipulate the CXCL12/CXCR system to benefit growth and distant spread. CXCL12/CXCR4 axis is a major culprit for lung cancer and has a crucial role in lung cancer initiation and progression by activating cancer stem cell. This review provides an evaluation of CXCL12/CXCR4 as the potential therapeutic target for lung cancers; it also focuses on the synergistic effects of inhibition of CXCL12/CXCR4 axis and immunotherapy as well as chemotherapy. Together, CXCL12/CXCR4 axis can be a potential therapeutic target for lung cancers and has additive effects with immunotherapy.     

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.     

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.     

CXCL12／CXCR4生物学轴诱导前列腺癌骨转移的作用机制研究进展

研究发现趋化因子CXCL12（Stromal—derived factor-1,SDF-1）和受体CXCR4[chemokine（C—X—Cmotif）receptor4]广泛表达于组织和器官上,相关的研究发现其与前列腺癌细胞的黏附、侵袭、增殖和生存有关,并认为其在前列腺癌骨转移的发生中发挥重要作用。通过阐明CXCL12／CXCR4生物学轴和前列腺癌骨转移之间的关系,从而寻找有助于疾病治疗的新途径。     

CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer

The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.     

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph‐node‐positive lung cancer patients

The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site‐specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph‐node‐positive non‐small‐cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1‐2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1‐2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08‐3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs 25%, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph‐node‐positive NSCLC patients.     

Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma

Chemokines and its receptors have significant impact on physiological and pathological processes and studies concerning their association with tumor biology are subject of great interest in scientific community. CXCL12/CXCR4 axis has been widely studied due to its significant role in tumor microenvironment, but it is also important to development and maintenance of tissues and organs, for example, in the brain and cerebellum. Studies have demonstrated that CXCL12 and CXCR4 are required for normal cerebellar development and that dysfunction in this pathway may be involved with medulloblastoma pathogenesis. In this context, a new molecular subgroup has been suggested based on the importance of the association between CXCR4 overexpression and sonic hedgehog subgroup. Treatment using CXCR4 antagonists showed significant results, evidencing the important role and possible therapeutic capacity of CXCR4 in MB. This review summarizes studies on MB cell biology, focusing on a chemokine‐receptor axis, CXCL12/CXCR4, that may have implications for treatment strategies once it can improve life expectancy and reduce neurocognitive sequelae of patients with this neoplasia.     

CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms

Our previous studies demonstrate that CXCL6/CXCR6 chemokine axis induces prostate cancer progression by the AKT/mTOR signaling pathway; however, its role and mechanisms underlying invasiveness and metastasis of breast cancer are yet to be elucidated. In this investigation, CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 shows a higher epithelial staining in breast cancer nest site and metastatic lymph node than the normal breast tissue, suggesting that CXCR6 may be involved in breast cancer (BC) development. In vitro and in vivo experiments indicate that overexpression of CXCR6 in BC cells has a marked effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by shRNAs in these cells greatly reduce its invasion and metastasis ability. Mechanistic analyses show that CXCL16/CXCR6 chemokine axis is capable of modulating activation of RhoA through activating ERK1/2 signaling pathway, which then inhibits the activity of cofilin, thereby enhancing the stability of F-actin, responsible for invasiveness and metastasis of BC.Taken together, our data shows for the first time that the CXCR6 / ERK1/2/ RhoA / cofilin /F-actin pathway plays a central role in the development of BC. Targeting the signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for BC.     

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.     

CXCL12- CXCR4在乳腺浸润性导管癌中的表达及临床意义

目的：研究乳腺浸润性导管癌中趋化因子 CXCL12及其对应的特异趋化因子受体 CXCR4的表达,分析其与浸润性导管癌临床病理学特征的关系。方法：用免疫组化法研究200例乳腺浸润性导管癌中 CX-CL12、CXCR4的表达情况,并探讨二者单一表达或共表达与临床病理因素的相关性。结果：CXCL12在40%（80/200）浸润性乳腺癌中阳性表达,其与 TNM 分期和肿瘤大小相关（P <0.05）;CXCR4在48%（96/200）浸润性乳腺癌中阳性表达,其表达与浸润性乳腺癌的 TNM 分期相关（P <0.05）。CXCL12与 CXCR4共表达于29%（58/200）的浸润性乳腺癌,二者的共表达与 TNM 分期和淋巴结转移情况相关（ P <0.01）。结论：CX-CL12与 CXCR4共表达很可能是协同乳腺浸润性导管癌进展及淋巴结转移的重要因素,检测 CXCL12与 CX-CR4共表达比检测 CXCL12或 CXCR4单一分子标记更有意义。