CXCL12-CXCR4 Promotes Proliferation and Invasion of Pancreatic Cancer Cells

Objective: CXCL12 exerts a wide variety of chemotactic effects on cells. Evidence indicates that CXCL12,in conjunction with its receptor, CXCR4, promotes invasion and metastasis of tumor cells. Our objective was toexplore whether the CXCL12-CXCR4 biological axis might influence biological behavior of pancreatic cancercells. Methods: Miapaca-2 human pancreatic cancer cells were cultured under three different conditions:normal medium (control), medium + recombinant CXCL12 (CXCL12 group), or medium + CXCR4-inhibitorAMD3100 (AMD3100 group). RT-PCR was applied to detect mRNA expression levels of CXCL12, CXCR4, matrixmetalloproteinase 2 (MMP-2), MMP-9, and human urokinase plasminogen activator (uPA). Additionally, cellproliferation and invasion were performed using CCK-8 colorimetry and transwell invasion assays, respectively.Results: CXCL12 was not expressed in Miapaca-2 cells, but CXCR4 was detected, indicating that these cells arecapable of receiving signals from CXCL12. Expression of extracellular matrix-degrading enzymes MMP-2, MMP-9, and uPA was upregulated in cells exposed to exogenous CXCL12 (P<0.05). Additionally, both proliferationand invasion of pancreatic cancer cells were enhanced in the presence of exogenous CXCL12, but AMD3100intervention effectively inhibited these processes (P<0.05). Conclusions: The CXCL12-CXCR4 biological axisplays an important role in promoting proliferation and invasion of pancreatic cancer cells.     

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.     

CXCL12-CXCR4生物学轴与肿瘤转移

趋化因子CXCL12与其特异性受体CXCR4所构成的CXCL12-CXCR4生物学轴在肿瘤细胞选择性和非随意转移过程中发挥重要作用,对这一特殊生物学轴的研究可能为肿瘤转移防治找到新的突破口,现就其研究进展情况作一综述.     

CXCL12-CXCR4生物学轴在结直肠癌中的研究进展

结直肠癌是最常见的恶性肿瘤之一,远处转移是其预后不良的主要原因.近年来,趋化因子对肿瘤的趋化、定向转移方面的研究越来越被重视.趋化因子CXCL12与其特异性受体CXCR4通过信号转导机制在结直肠癌细胞选择性和非随意性转移中,发挥着重要作用.越来越多的研究表明通过多种方法阻断趋化因子受体CXCR4可以抑制肿瘤转移和侵袭.对这一信号通路的研究可望为结直肠癌转移的靶向治疗寻求新的突破.     

Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma

Neuroblastoma is the second most common pediatric malignancy. The clinical course of this disease ranges from spontaneous regression and good survival to highly malignant therapy-resistant tumors. There is a continuous need for genetic and biologic markers for the diverse clinical phenotypes observed in neuroblastoma patients. One of the known markers in neuroblastoma is expression of the CXCR4 chemokine receptor. CXCR4 expression correlates with high-stage disease, and the autocrine stimulation of CXCR4 by its ligand (CXCL12) was shown to be necessary for the survival of some neuroblastoma cells in vitro. However, the mechanisms responsible for activation of the CXCL12-CXCR4 autocrine pathway in neuroblastoma remain uncertain. Our previous findings suggest that Csk homologous kinase (CHK) is a physiological inhibitor of CXCR4 expression. Since CHK is highly expressed in neurons, we evaluated changes in CHK expression in human neuroblastoma. CHK protein expression was below detectable levels based on Western blot analyses in 13 out of 16 human neuroblastoma cell lines and in 6 out of 16 primary neuroblastoma tissues. When CHK expression was restored in IMR32 neuroblastoma cells by retrovirus-mediated cDNA transfer, diminished CXCR4 mRNA and protein levels were observed, as assessed by RT-PCR and flow cytometry analyses, respectively. Furthermore, exogenous expression of CHK markedly suppressed the mRNA levels and secretion of the CXCL12 chemokine from IMR32 cells as well as inhibited the growth rate of these cells. Taken together, our data strongly suggest that CHK is capable of inhibiting the CXCL12-CXCR4 pathway in neuroblastoma.     

CXCL12-CXCR4在消化道肿瘤转移中的研究进展

趋化因子CXCL12及其受体CXCR4不仅表达于免疫细胞,在某些肿瘤细胞中也呈高表达.最近研究表明,其与食管癌、胃癌、结直肠癌等的转移密切相关.展开其生物学特性、在消化道肿瘤中的表达及转移相关性研究,将为消化道肿瘤转移的防治提供新的思路.     

CXCL12-CXCR4生物学轴与甲状腺乳头状癌淋巴结转移的相关性研究

探讨CXCL12-CXCR4生物学轴与甲状腺乳头状癌淋巴结转移的相关性。方法:采用半定量RT-PCR和免疫组织化学法分别检测72例新鲜甲状腺乳头状癌及淋巴结组织,52例甲状腺乳头状癌及淋巴结石蜡组织中CXCR4、CXCL12 mRNA及蛋白的表达。结果:甲状腺乳头状癌组织及转移灶组织中CXCR4 mRNA及蛋白高表达,淋巴结转移组的表达显著高于非转移组,差异有统计学意义（P<0.05）;颈部淋巴结组织中CXCL12 mRNA及蛋白均高表达,转移淋巴结及非转移淋巴结差异无统计学意义（P>0.05）。结论:CXCR4、CXCL12的表达与甲状腺乳头状癌淋巴结转移密切相关,推测CXCL12-CXCR4生物学轴在甲状腺乳头状癌转移的过程中发挥重要作用,CXCR4可作为抑制甲状腺乳头状癌转移的有效靶点。      

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis

CXCR4 and its ligand CXCL12 can promote the proliferation, survival, and invasion of cancer cells. They have been shown to play an important role in regulating metastasis of breast cancer to specific organs. High CXCR4 expression was also correlated to poor clinical outcome. Previous study also showed that tumor cells express a high level of CXCR4 and that tumor metastasis target tissues (lung, liver, and bone) express high levels of the ligand CXCL12, allowing tumor cells to directionally migrate to target organs via a CXCL12-CXCR4 chemotactic gradient. However, the exact mechanisms of how CXCR4 and CXCL12 enhance metastasis and/or tumor growth and their full implications on breast cancer progression are unknown. Yet it is likely that chemokine receptor signaling may provide more than just a migrational advantage by also helping the metastasized cells establish and survive in secondary environments. In this study, we investigated CXCR4 and CXCL12 expression in breast cancer and analyzed its association with clinicopathological factors by immunohistochemistry first. Then, we detected the mRNA and protein expression of CXCR4 and CXCL12 in breast cancer cell lines by Western blot and RT-PCR. The MDA-MB-231 has CXCR4 expression and very weak CXCL12 expression. So, we constructed the functional CXCL12 expression in MDA-MB-231 using a gene transfection technique. Further experiments were conducted to evaluate the effect of CXCL12 transfection on the biological behaviors of MDA-MB-231. The cell proliferation of MDA-MB-231–CXCL12 was accessed by MTT assay; the apoptosis was analyzed by an AnnexinV-FITC/propidium iodide double staining of flow cytometry method; and the cell invasive ability was examined by Matrigel invasion assay. Immunohistochemical analysis showed the co-expression of CXCR4 and CXCL12 correlated with lymph node metastasis and TNM stage (p?CXCL12 and its sole ligand CXCR4 play important role in the malignance of breast cancer. To gain a deeper insight into it, we picked CXCR4-expressing cells MDA-MB-231 to be transfected with CXCL12 stably. The decreased cellular proliferation, increased apoptosis, and invasive ability were found in MDA-MB-231 with successful CXCL12 transfection (p?CXCL12-CXCR4 axis correlated tightly with breast cancer metastasis. CXCL12-CXCR4 axis can increase the invasion and apoptosis of MDA-MB-231 simultaneously. These data strongly support the hypothesis that CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Our findings could have significant implications in terms of breast cancer aggressiveness and the effectiveness of targeting the receptors and downstream signaling pathways for the treatment of breast cancer.     

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

CXCL12-CXCR4生物学轴在胰腺癌中的表达及其与血管生成的相关性

肿瘤转移是一个复杂的、非随机的多步骤过程,肿瘤细胞的运动迁移、黏附、生长、新血管生成、特异性转移器官的归巢和逃避免疫等关键步骤.近年来的研究显示,趋化因子CXCL12与其特异性受体CXCR4所构成的CXCL12-CXCR4生物学轴,在多种肿瘤的播散和器官特异性转移中发挥重要作用.     

CXCL12-CXCR4生物学轴在肿瘤侵袭与转移中的研究进展

研究发现多种肿瘤细胞表达趋化因子CXCL12及其受体CXCR4,并与肿瘤细胞的迁徙和转移密切相关;CXCL12-CXCR4生物学轴在多种肿瘤的播散和器官特异性转移中发挥重要作用.     

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies

Dose-dense adjuvant breast cancer chemotherapy is a new treatment strategy that aims to improve tumour control by using more frequent cytotoxic dosing together with continuous granulocyte colony-stimulating factor (G-CSF) to minimize neutropaenia. In addition to stimulating neutrophil proliferation, G-CSF mobilizes neutrophils from the bone marrow through proteolytic disruption of the chemokine receptor CXCR4 and its chemotactic ligand CXCL12. As breast cancers also express CXCR4 and oestrogen induces CXCL12, the success of dose-dense treatment could partly reflect inhibition of CXCR4-dependent micrometastatic homing and/or paracrine survival, and suggests a benefit of adjuvant oestrogen suppression for patients with oestrogen-receptor-negative, CXCR4-positive disease.     

CXCL12-CXCR4轴、CCL21-CCR7轴在非霍奇金淋巴瘤中的研究进展

非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL）是由免疫系统中成熟和未成熟细胞的恶性转化所致,涉及B淋巴细胞(B细胞,约占所有NHL的86%)、较小比例的T细胞和自然杀伤(NK)细胞(在发展中地区约占14%)。近年来相关研究表明,趋化因子受体4（CXCR4）、趋化因子受体7（CCR7）在淋巴细胞归巢中发挥重要作用,且已被证实在多种实体及血液恶性肿瘤中高表达,通过与其相应的配体结合显示出促肿瘤发生、发展的多向性效应。针对CXCR4、CCR7靶向治疗应用的研究,尤其是CXCR4定向成像和放射性核素治疗领域的研究非常活跃,预计在未来几年内,转化医学方面将有新的发展。然而现就CXCR4、CCR7在NHL中作用的相关报道甚少。本文就CXCL12-CXCR4轴、CCL21-CCR7轴在NHL中的作用机制、预后意义及治疗应用等方面的研究进展作一综述。     

Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway

Angiogenesis is one of the key features of glioblastoma (GBM). Our objective was to explore the potential changes of angiogenic factors in GBM between initial diagnosis and recurrence after radiotherapy-temozolomide (RT/TMZ). Paired frozen tumors from both initial and recurrent surgery were available for 29 patients. Screening of genes expressions related to angiogenesis was performed using RT- PCR arrays on 10 first patients. Next, RNA expressions of the selected genes were analyzed on all samples. Protein expression was examined by immunohistochemistry. The anti-tumor effect of AMD3100 (anti-CXCR4) was tested in GBM explants. In the screening step, the initial-recurrence expression changes contributed to a selection of seven genes (VEGFA, VEGFR2, VEGFR1, CXCL12, CXCR4, uPA HIF1α). By quantitative RT-PCR, RNA expressions of CXCR4 (p = 0.029) and CXCL12 (p = 0.107) were increased while expressions of HIF1α (p = 0.009) and VEGFR2 (p = 0.081) were decreased at recurrence. Similarly, CXCL12 protein expression tended to increase (p = 0.096) while VEGFR2 staining was decreased (p = 0.004) at recurrence. An increase of anti-tumoral effect was observed with the combination of AMD3100 and RT/TMZ versus RT/TMZ alone in GB explants. Recurrence of GB after chemo-radiation could be associated with a switch of angiogenic pattern from VEGFR2-HIF1α to CXCL12-CXCR4 pathway, leading to new perspectives in angiogenic treatment     

Targeting DNA Repair in Ovarian Cancer Treatment Resistance

Most patients with advanced high-grade serous ovarian cancer (HGSOC) develop recurrent disease within 3 years and succumb to the disease within 5 years. Standard treatment for HGSOC is cytoreductive surgery followed by a combination of platinum (carboplatin or cisplatin) and taxol (paclitaxel) chemotherapies. Although initial recurrences are usually platinum-sensitive, patients eventually develop resistance to platinum-based chemotherapy. Accordingly, one of the major problems in the treatment of HGSOC and disease recurrence is the development of chemotherapy resistance. One of the causes of chemoresistance may be redundancies in the repair pathways involved in the response to DNA damage caused by chemotherapy. These pathways may be acting in parallel, where if the repair pathway that is responsible for triggering cell death after platinum chemotherapy therapy is deficient, an alternative repair pathway compensates and drives cancer cells to repair the damage, leading to chemotherapy resistance. In addition, if the repair pathways are epigenetically inactivated by DNA methylation, cell death may not be triggered, resulting in accumulation of mutations and DNA damage. There are novel and existing therapies that can drive DNA repair pathways towards sensitivity to platinum chemotherapy or targeted therapy, thus enabling treatment-resistant ovarian cancer to overcome chemotherapy resistance.