CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF‐1

Recent studies have shown that the chemokine stromal cell‐derived factor (SDF)‐1 and its receptor CXCR4 are involved in the metastatic process of colorectal cancer. The impact of SDF‐1 on the stimulated metastatic growth during hepatectomy‐associated liver regeneration is unknown. With the use of a heterotopic murine colon cancer model, we analyzed whether blockade of SDF‐1 inhibits angiogenesis and extrahepatic growth of colorectal cancer after liver resection. Functional neutralization of SDF‐1 by 1 mg/kg body weight anti‐SDF‐1 antibody only slightly delayed the initial tumor cell engraftment but also did not reduce the size of established extrahepatic tumors compared with controls. Tumor cell apoptosis was increased by anti‐SDF‐1 treatment only during the early 5–9‐day period of tumor cell engraftment, but was found significantly decreased during the late phase of tumor growth. The initial delay of tumor cell engraftment was associated with an increase of tumor capillary density and microvascular permeability. This was associated with an increased vascular endothelial growth factor (VEGF) expression and an enhanced tumor cell invasion of the neighboring tissue. In contrast to the neutralization of SDF‐1, blockade of the SDF‐1 receptors CXCR4 and CXCR7 significantly reduced tumor capillary density and tumor growth. Thus, our study indicates that neutralization of SDF‐1 after hepatectomy is not capable of inhibiting angiogenesis and growth of extrahepatic colorectal tumors, because it is counteracted by the compensatory actions through an alternative VEGF‐dependent pathway.     

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.     

C‐X‐C chemokine receptor 7

BACKGROUND:

C‐X‐C chemokine receptor 4 (CXCR4) and CXCR7 are 7‐transmembrane chemokine receptors of the stroma‐derived factor (SDF‐1). CXCR4, but not CXCR7, has been examined in bladder cancer (BCa). This study examined the functional and clinical significance of CXCR7 in BCa.

METHODS:

CXCR4 and CXCR7 levels were measured in BCa cell lines, tissues (normal = 25; BCa = 44), and urine specimens (n = 186) by quantitative polymerase chain reaction and/or immunohistochemistry. CXCR7 function in BCa cells were examined by transient transfections using a CXCR7 expression vector or small interfering RNA.

RESULTS:

In BCa cell lines, CXCR7 messenger RNA levels were 5‐ to 37‐fold higher than those for CXCR4. Transient overexpression of CXCR7 in BCa cell lines promoted growth and chemotactic motility. CXCR7 colocalized and formed a functional complex with epidermal growth factor receptor, phosphoinositide 3‐kinase/Akt, Erk, and src and induced their phosphorylation. CXCR7 also induced up‐regulation of cyclin‐D1 and bcl‐2. Suppression of CXCR7 expression reversed these effects and induced apoptosis. CXCR7 messenger RNA levels and CXCR7 staining scores were significantly (5‐ to 10‐fold) higher in BCa tissues than in normal tissues (P < .001). CXCR7 expression independently associated with metastasis (P = .019) and disease‐specific mortality (P = .03). CXCR7 was highly expressed in endothelial cells in high‐grade BCa tissues when compared to low‐grade BCa and normal bladder. CXCR7 levels were elevated in exfoliated urothelial cells from high‐grade BCa patients (P = .0001; 90% sensitivity; 75% specificity); CXCR4 levels were unaltered.

CONCLUSIONS:

CXCR7 promotes BCa cell proliferation and motility plausibly through epidermal growth factor receptor receptor and Akt signaling. CXCR7 expression is elevated in BCa tissues and exfoliated cells and is associated with high‐grade and metastasis. Cancer 2013. © 2012 American Cancer Society.     

Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor‐4

Rhabdomyosarcoma is the most common soft tissue sarcoma affecting children, and the overall cure rate of children with metastatic disease remains below 30%. The CXC chemokine receptor‐4 (CXCR4)/stromal cell‐derived factor‐1 (SDF1) axis has been implicated in the promotion of metastatic potential in several tumors. In this study, we developed a novel anti‐CXCR4 mAb, CF172, and investigated its antimetastatic activity against rhabdomyosarcoma cells in vitro and in vivo, to evaluate its potential as a therapeutic antibody to treat rhabdomyosarcoma. The CF172 molecule showed a specific binding reactivity against human CXCR4, as well as a specific neutralizing activity against CXCR4/SDF1 signal transduction. Using CF172, we determined that SJCRH30 rhabdomyosarcoma cells expressed high levels of CXCR4. In addition, CF172 was found to inhibit the SDF1‐induced migration activity of SJCRH30 cells in vitro. Using xenograft models of SJCRH30 cells, we carried out in vivo efficacy studies for peritoneal and lymph node metastasis, which were clinically observed in rhabdomyosarcoma. These studies indicated that CF172 significantly decreased both types of metastasis of SJCRH30. In conclusion, we found that a novel anti‐CXCR4 mAb, CF172, with specific reactivity against human CXCR4, prevented peritoneal metastasis and lymph node metastasis of rhabdomyosarcoma in animal models. These results suggest that CF172 is a potential antimetastasis therapeutic antibody for rhabdomyosarcoma treatment.     

Small interfering RNA‐mediated CXCR1 or CXCR2 knock‐down inhibits melanoma tumor growth and invasion

CXCR1 and CXCR2 are receptors for CXCL‐8 and are differentially expressed on melanoma and endothelial cells. In this study, we determined the functional role of these receptors in melanoma progression. We stably knock‐down the expression of CXCR1 and/or CXCR2 in A375‐SM (SM; high metastatic) human melanoma cells by short‐hairpin RNA transfection. Cell proliferation, migration, invasion, ERK phosphorlyation and cytoskeletal rearrangements were carried out in vitro. In vivo growth was evaluated using murine subcutaneous xenograft model. Our data demonstrate that knock‐down of CXCR1 and/or CXCR2 expression, inhibited melanoma cell proliferation, survival, migration and invasive potential in vitro. Moreover, we also observed inhibition of ERK phosphorylation and cytoskeltal rearrangement in SM‐shCXCR1, SM‐shCXCR2 and SM‐shCXCR1/2 cells. Furthermore, when SM‐shCXCR1 or SM‐shCXCR2 cells implanted in nude mice, tumor growth, proliferation and microvessel density was significantly inhibited as compared to SM‐control cells. In addition, we observed a significant increase in melanoma cell apoptosis in SM‐shCXCR1 and SM‐shCXCR2 tumors compared to SM‐control tumors. Together, these data demonstrate that CXCR1 and CXCR2 expression play a critical role in human melanoma tumor progression and, functional blockade of CXCR1 and CXCR2 could be potentially used for future therapeutic intervention in malignant melanoma.     

趋化因子CXC受体3在肝细胞癌中的表达及意义

背景与目的:最近研究揭示趋化因子及其受体网络在肿瘤侵袭转移中起重要作用。本研究旨在探讨趋化因子CXC受体3(CXCR3)在肝细胞癌(hepatocellularcarcinoma,HCC)中的表达,及其与HCC临床病理特征的关系。方法:选取7株人HCC细胞系、18例正常肝组织、64例HCC患者的癌组织和癌旁肝组织作为研究对象。采用RT-PCR和实时定量PCR方法,研究这些组织中CXCR3mRNA的表达情况。采用免疫组织化学方法,研究CXCR3蛋白的表达情况和HCC复发转移的关系。结果:在高转移细胞系MHCC97-H中,CXCR3与!2微球蛋白的mRNA拷贝均数之比为33.0×10-4,在低转移细胞系MHCC97-L中,该数值为8.7×10-4,在无转移能力的5株细胞系则未检出CXCR3的mRNA表达。在MHCC97-H和MHCC97-L中均见CXCR3蛋白强阳性染色,而在无转移能力的细胞系中只有HepG2见到微弱染色,其余4株均未见染色。CXCR3蛋白在HCC组织中的强阳性染色,与HCC的侵袭性正相关(P=0.003)。HCC组织中CXCR3蛋白强阳性的患者和CXCR3阴性或弱阳性的患者的1、2年无瘤生存率分别为66.7%、31.3%和75.0%、59.5%,差异有显著性(P=0.044)。结论:CXCR3的表达与HCC的侵袭和转移相关。     

Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy

Rhabdomyosarcomas (RMSs) are frequently characterized by bone marrow involvement. Recently, we reported that human RMS cells express the CXC chemokine receptor-4 (CXCR4) and postulated a role for the CXCR4 stromal-derived factor (SDF)-1 axis in the metastasis of RMS cells to bone marrow. Because RMS cells also express the tyrosine kinase receptor c-MET, the specific ligand hepatocyte growth factor (HGF) that is secreted in bone marrow and lymph node stroma, we hypothesized that the c-MET-HGF axis modulates the metastatic behavior of RMS cells as well. Supporting this concept is our observation that conditioned media harvested from expanded ex vivo human bone marrow fibroblasts chemoattracted RMS cells in an HGF- and SDF-1-dependent manner. Six human alveolar and three embryonal RMS cell lines were examined. We found that although HGF, similar to SDF-1, did not affect the proliferation of RMS cells, it induced in several of them: (a) locomotion; (b) stress fiber formation; (c) chemotaxis; (d) adhesion to human umbilical vein endothelial cells; (e) trans-Matrigel invasion and matrix metalloproteinase secretion; and (f) phosphorylation of mitogen-activated protein kinase p42/44 and AKT. Moreover HGF, but not SDF-1, increased the survival of RMS cells exposed to radio- and chemotherapy. We also found that the more aggressive alveolar RMS cells express higher levels of c-MET than embryonal RMS cell lines and "home/seed" better into bone marrow after i.v. injection into immunocompromised mice. Because we could not find any activating mutations in the kinase region of c-MET or any evidence for HGF autocrine stimulation, we suggest that the increased response of RMS cell lines depends on overexpression of functional c-MET. We conclude that HGF regulates the metastatic behavior of c-MET-positive RMS cells, directing them to the bone marrow and lymph nodes. Signaling from the c-MET receptor may also contribute to the resistance of RMS cells to conventional treatment modalities.     

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.     

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4‐mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3‐, CXCR4‐, and CXCR3/CXCR4 double‐knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3‐ and CXCR3/CXCR4 double‐knockdowns. In addition, CXCR3‐ and CXCR3/CXCR4 double‐knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.     

Regional Expression of CXCL12/CXCR4 in Liver and Hepatocellular Carcinoma and Cell-cycle Variation during in vitro Differentiation

The CXCL12/CXCR4 system may be important in carcinoma. Expression of the a‐chemokine SDF‐lα (stromal cell derived factor‐lα)/CXCL12 mRNA is reduced in many carcinomas, yet its tissue protein expression may guide metastasis. Here we first compare the mRNA and protein expression of CXCL12 and its receptor CXCR4 in human liver, hepatocellular carcinoma, and malignant cell lines, and then assess cell cycle variation in CXCR4 expression. CXCR4 mRNA was present in most normal human tissues and malignant cell lines; it was only marginally reduced in hepatomas, while CXCL12 was markedly reduced, P<0.0001. Immuno‐histochemical staining of adjacent non‐malignant liver showed regional CXCR4 cytoplasmic and cell‐surface staining, limited to those hepatocytes around the central vein, a distribution resembling that of CXCL12. CXCL12 protein was not present in hepatocellular carcinoma cells in vivo, nor was cytoplasmic CXCR4 staining; nuclear CXCR4 protein expression in some malignant hepatocytes and CXCR4 staining of capillary endothelial cells around tumor cells were noted. In some malignant cell lines that had no CXCL12 on northern blots CXCL12 was weakly detectable by RT‐PCR or protein staining in the cytoplasm of a few cells. With a view to future manipulation of CXCL12/CXCR4 expression and growth we noted that in HT‐29 cells CXCR4 protein expression was less on confluent than on non‐confluent cells and varied during the cell cycle. Higher expression was associated most closely with the percentage of cells in the S‐phase and inversely with the percentage of cells in the G1‐phase. Treatment of HT‐29 cells with butyrate reduced CXCR4 cell surface expression and reduced the percentage of cells in S‐phase. In summary, CXCL12 protein expression parallels its mRNA, being markedly reduced in malignant cell lines and hepatomas; in liver, the regional distributions of CXCL12 and cytoplasmic CXCR4 are similar; finally, in HT‐29, CXCR4 expression correlates with the S‐phase of the cell cycle and is reduced during butyrate‐induced differentiation.     

Selective upregulation of interleukin‐8 by human rhabdomyosarcomas in response to hypoxia: therapeutic implications

Rhabdomyosarcoma (RMS) is the most common soft‐tissue sarcoma of adolescence and childhood. Because RMS tumors are highly vascularized, we sought to determine which factors secreted by RMS cells are crucial in stimulating angiogenesis in response to hypoxia. To address this issue, we evaluated expression of several proangiogenic factors [interleukin (IL)‐8, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)‐2, stromal‐derived factor (SDF)‐1, hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF)] in 8 human RMS cell lines in both normal steady‐state and hypoxic conditions. We found by real‐time quantitative polymerase chain reaction (RQ‐PCR) and confirmed by enzyme‐linked immunosorbent assay (ELISA) that from all the factors evaluated, IL‐8, whose expression is very low in normoxia, had been very highly expressed and secreted by RMS cells lines during hypoxic conditions (∼40–170 times). Interestingly, this upregulation was not affected by knocking down hypoxia‐inducible factor (HIF)‐1α, but was inhibited by mitogen‐activated protein kinase (MAPK)p42/44 and phosphatidylinositaol 3‐kinase (PI3K)/AKT pathway inhibitors. This suggests that IL‐8 expression is regulated in an activating protein (AP)‐1‐ and nuclear factor (NF)‐κB‐dependent manner. Furthermore, we found that conditioned media (CM) harvested from RMS cells exposed to hypoxia activated and stimulated chemotactic responses in human umbilical vein endothelial cells (HUVECs) and that IL‐8 was responsible for hypoxia‐related effects. Finally, by employing shRNA, the expression of IL‐8 in human RH‐30 cells was downregulated. We noticed that such RMS cells, if injected into skeletal muscles of immunodeficient mice, have a reduced ability for tumor formation. We conclude that IL‐8 is a pivotal proangiogenic factor released by human RMS cells in hypoxic conditions and that the targeting of IL‐8 may prove to be a novel and efficient strategy for inhibiting RMS growth.     

CXCR4 peptide antagonist inhibits primary breast tumor growth,metastasis and enhances the efficacy of anti‐VEGF treatment or docetaxel in a transgenic mouse model

CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell‐derived factor (SDF)‐1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE‐9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE‐9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8–16 mice. We then combined CTCE‐9908 with docetaxel or DC101 (an anti‐VEGFR2 monoclonal antibody). We found that increasing doses of CTCE‐9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE‐9908 (p = 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE‐9908 (p = 0.01). In combination with docetaxel, CTCE‐9908 administration decreased tumor volume by 38% (p = 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE‐9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p = 0.01) and a 75% reduction in distant metastasis (p = 0.009). In combination with docetaxel or an anti‐angiogenic agent, the anti‐tumor and anti‐metastatic effects of CTCE‐9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF‐1/CXCR4 ligand/receptor pair.     

CXC‐chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer

Angiogenesis is essential for tumor growth and metastasis. Although ELR⁺‐CXC‐chemokines and their corresponding receptor, CXC‐receptor 2 (CXCR2), are known mediators of angiogenesis, little is known about their role in pancreatic cancer (PaCa). The aim of our study was to determine the role of ELR⁺‐CXC‐chemokine/CXCR2 biological axis in promoting PaCa angiogenesis. We prospectively collected secretin‐stimulated exocrine pancreatic secretions (SSEPS) from normal individuals (NP) and PaCa patients. We showed that summed concentrations of ELR⁺‐CXC‐chemokines in SSEPS from PaCa patients were significantly higher than in those from NP (p = 0.002). We measured ELR⁺‐CXC‐chemokine levels in supernatants from multiple PaCa cell lines and confirmed that BxPC‐3, Colo‐357 and Panc‐28 had significantly higher expression compared with an immortalized human pancreatic ductal epithelial (HPDE) cell line. After confirming lack of autocrine effects of ELR⁺‐CXC‐chemokines on PaCa cells (due to absence of CXCR2 expression), we investigated paracrine effects of these chemokines on human umbilical vein endothelial cells (HUVEC). Both recombinant ELR⁺‐CXC‐chemokines and co‐culturing with BxPC‐3 significantly enhanced proliferation, invasion, and tube formation of HUVEC (p < 0.05). These biological effects were significantly inhibited by treatment with a neutralizing antibody against CXCR2 (anti‐CXCR2 Ab) (p < 0.05). Finally, anti‐CXCR2 Ab significantly reduced tumor volume (p < 0.05), Ki‐67 proliferation index (p = 0.043) and Factor VIII⁺ microvessel density (p = 0.004) in an orthotopic nude mouse PaCa model. Our results show that ELR⁺‐CXC‐chemokines promote PaCa tumor‐associated angiogenesis through CXCR2, suggesting that CXCR2 is an anti‐angiogenic target in PaCa. © 2009 UICC     

RNAi阻断CXCR4基因对胰腺癌AsPC-1细胞肺转移能力的影响

目的:观察针对CXCR4基因的RNAi(RNA interference)转染AsPC-1细胞后肿瘤细胞增殖、迁移、侵袭的情况及在裸鼠肺内血行转移的情况,探讨SDF-1/CXCR4在胰腺癌转移中的作用.方法:利用小发夹结构RNA作为载体设计针对人CXCR4基因的RNA干扰,利用慢病毒成功转染人胰腺癌细胞系AsPC-1细胞,然后分为转染组(LV-siCXCR4-1)、阴性对照组(AsPC-1-LV-con)和空白对照组(AsPC-1细胞),三组加入SDF-1α后采用MTT法检测细胞增殖,Transwell小室检测细胞迁移,体外侵袭实验检测细胞的体外侵袭能力,并将三组细胞注入已建立急性血行转移模型的裸鼠尾静脉,45天后观察裸鼠肺部转移结节和肺脏组织,计数肿瘤转移结节的数目并进行HE染色.结果:SDF-1α可促进阴性对照组和空白对照组细胞增殖、迁移和体外侵袭.空白对照组和阴性对照组裸鼠可见大量肺转移结节,而转染组裸鼠未见明显肺转移结节.结论:CXCR4基因RNAi可显著抑制AsPC-1细胞增殖、体外迁移和侵袭及肺血行转移.CXCR4/SDF-1受体配体系统参与了胰腺癌的转移,通过RNAi干扰技术可抑制胰腺癌细胞的转移.     

Potential of CXCR4 antagonists for the treatment of metastatic lung cancer

Despite advances in surgery, chemotherapy and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed, and targeting CXCR4 constitutes such a novel, attractive strategy. Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokine receptors and adhesion molecules. Lung cancer cells express CXCR4 (CD184), a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the tumor microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces lung cancer cell migration and adhesion to stromal cells, which in turn provides growth- and drug-resistance signals to the tumor cells. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogues (TN14003/BKT140), can disrupt CXCR4-mediated tumor cell adhesion to stromal cells and sensitize lung cancer cells to cytotoxic drugs. Therefore, targeting the CXCR4–CXCL12 axis is a novel, attractive therapeutic approach in small-cell lung cancer and non-small-cell lung cancer. In this article, we summarize data about the cellular and molecular microenvironment in small-cell lung cancer and non-small-cell lung cancer, as well as the role of CXCR4 in tumor–stroma crosstalk. In addition, we review the current status of the preclinical and clinical development of CXCR4 antagonists.     

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。     

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.