SDF-1/CXCR4轴与肿瘤

一、概述 趋化因子是一类小分子分泌型(8-14KDa)蛋白,是目前已知的最大的细胞因子家族,已发现超过50种.多数趋化因子氨基端(N端)有4个特征性的保守的半胱氨酸(Cys),相互形成二硫键.     

SDF-1／CXCR4与肿瘤研究进展

基质细胞衍生因子-1（SDF-1）及其受体CXCR4在促进肿瘤细胞增殖、定向迁移、黏附、降解细胞外基质、血管形成及诱导免疫耐受中发挥着重要作用。文章就SDF-1／CXCR4轴在肿瘤生物学行为中的作用进行简要综述。     

Can we incorporate geriatric assessment in the management of acute lymphoblastic leukemia in older adults?

Acute lymphoblastic leukemia (ALL) is an uncommon disease. Approximately 14% of new ALL cases occur in adults aged 60 and over, and the three-year overall survival in this population is poor at 12.8%. Older adults with ALL are heterogeneous in terms of their underlying health status, which can make treatment selection challenging given the disease rarity and limited inclusion of older patients in clinical trials. A comprehensive geriatric assessment (CGA) is a compilation of tools to assess multiple domains such as physical function and cognition, and may assist in guiding treatment selection and supportive care interventions. However, studies on the use of CGA are limited in older adults with ALL. In this review, we discuss the utility of CGA in patients with various hematologic malignancies. Using two patient cases of ALL, we also describe how CGA may be use to guide treatment and supportive care interventions.     

SDF-1/CXCR4与肝细胞肝癌淋巴结转移的关系

目的:探讨SDF-1/CXCR4与肝细胞肝癌淋巴结转移的关系及其可能的机制。方法:应用PubMed、CNKI、万方数据库、Medline数据库,以SDF-1、CX-CR4、VEGF、MMP、肝肿瘤和淋巴转移为关键词,检索2000-1010年相关文献,共检索到英文文献2 696篇,中文文献共105篇。纳入标准:1)SDF-1/CXCR4轴与肿瘤的关系;2)CXCR4参与了肿瘤淋巴结转移;3)肝细胞肝癌的淋巴结转移机制;4)CXCR4在肝细胞肝癌中的表达;5)VEGF与淋巴结转移的关系;6)MMP与淋巴结转移的关系。根据纳入标准符合分析的文献36篇。结果:SDF-1/CX-CR4在肝细胞肝癌的淋巴结转移过程中起重要作用,SDF-1/CXCR4有可能通过激活VEGF和MMP等细胞分子,通过多条信号途径来促进肝癌淋巴结的转移。结论:SDF-1/CXCR4可能通过激活VEGF和MMP等细胞因子来促进肝癌的淋巴转移,通过阻断SDF-1/CXCR4可以减少肝癌的淋巴转移。     

Reversing the multidrug resistance in acute leukemia: Until the leukemia initiating cell?

Reversal of drug resistance is of pivotal importance in order to improve the results of chemotherapy. Monitoring of such reversal is necessary in order to analyze the results of clinical trials. Nonetheless, the leukemia cell population to eradicate is the leukemia initiating cells characterized by a CD34+CD38- phenotype. The evaluation of novel drug resistance modulators should be performed both in the whole leukemic cell population and in the leukemia initiating cell compartment, that is responsible for "mature" leukemia cells replenishment.     

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.     

Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?

BACKGROUND:

Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m² daily for 5 days with mitoxantrone 80 mg/m² (the ALL‐2 regimen) as a novel induction regimen. Compared with historic controls, the ALL‐2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)‐positive ALL.

METHODS:

The authors conducted a multicenter, prospective, randomized trial of the ALL‐2 regimen compared with a standard 4‐drug induction (the L‐20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.

RESULTS:

The median follow‐up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL‐2 regimen versus the L‐20 regimen was 83% versus 71% (P = .06). More patients on the L‐20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL‐2) versus 7% (L‐20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL‐2 arm versus 27% on the L‐20.

CONCLUSIONS:

Despite superior results of induction therapy with the ALL‐2 regimen, this treatment did not improve long‐term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.     

SDF-1/CXCR4 promotes epithelial–mesenchymal transition and progression of colorectal cancer by activation of the Wnt/β-catenin signaling pathway

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in angiogenesis and are associated with tumor progression. This study aimed to investigate the role of SDF-1/CXCR4-mediated epithelial–mesenchymal transition (EMT) and the progression of colorectal cancer (CRC) as well as the underlying mechanisms. The data showed that expression of CXCR4 and β-catenin mRNA and protein was significantly higher in CRC tissues than in distant normal tissues. CXCR4 expression was associated with β-catenin expression in CRC tissues, whereas high CXCR4 expression was strongly associated with low E-cadherin, high N-cadherin, and high vimentin expression, suggesting a cross talk between the SDF-1/CXCR4 axis and Wnt/β-catenin signaling pathway in CRC. In vitro, SDF-1 induced CXCR4-positive colorectal cancer cell invasion and EMT by activation of the Wnt/β-catenin signaling pathway. In contrast, SDF-1/CXCR4 axis activation-induced colorectal cancer invasion and EMT was effectively inhibited by the Wnt signaling pathway inhibitor Dickkopf-1. In conclusion, CXCR4-promoted CRC progression and EMT were regulated by the Wnt/β-catenin signaling pathway. Thus, targeting of the SDF-1/CXCR4 axis could have clinical applications in suppressing CRC progression.     

SDF-1/CXCR7轴与肿瘤的研究进展

基质细胞衍生因子-1（SDF-1）及其受体CXCR4所构成的SDF-1/CXCR4生物轴在肿瘤发生、发展及肿瘤血管新生中发挥重要作用。最近研究发现CXCR7也是SDF-1的受体,且与肿瘤密切相关。全文就SDF-1新受体CXCR7的生物学特征,SDF-1/CXCR7轴在肿瘤细胞中的表达,SDF-1/CXCR7轴与肿瘤细胞增殖和存活、肿瘤侵袭和转移以及肿瘤血管新生的关系作一综述。     

SDF-1/CXCR4及CCL19/21-CCR7与肿瘤的关系

趋化因子(Chemokine)是一类可诱导的,由多种细胞产生,有激活和趋化白细胞作用,分子量为7KDa～10KDa的促炎细胞因子,它们在抗感染和免疫中有至关重要的作用.根据其前两个半胱氨酸残基的相对位置不同,将它们分为了四大类:CXC趋化因子,CC趋化因子,C趋化因子和CX3C趋化因子.相应的趋化因子受体则分为CXC趋化因子受体(CXCR),CC趋化因子受体(CCR),C趋化因子受体(CR)和CX3C趋化因子受体(CX3CR),但它们都为GPCR家族成员(一类介导趋化因子使功能性GTP-蛋白耦连的七次跨膜受体).     

Retrovirus-Mediated CXCR4-siRNA Can Inhibit the Invasion of Prostate Carcinoma In Vitro

Objective： CXCR4 is a potential target for cancer gene therapy. In this study, an RNA interference retrovirus vector targeting CXCR4 gene was constructed, and its influence on the invasion of prostate cancer cells by depressing CXCR4 gene expression was analyzed. Methods： the CXCR4-specific siRNA gene was cloned by PCR and inserted into the Pgensil-1 plasmid eonstaining U6 promoter and EGFP, and then the recombinant fragment was sub-cloned into PLXSN and tested by restriction enzyme and sequencing. The virus obtained from transfected PA317 cells was transfected into prostate cancer cells. The expression of CXCR4 mRNA was detected by RT-PCR. The ability of invasion of prostate cancer cells in vitro was estimated by Transwell experiment. Results： it was showed that with the recombinant PLXSN transfection, the expression of CXCR4 mRNA in prostate cancer cells PC-3m and LNCaP was reduced at rates of （84.26±10.20）% and （88.17±11.23）%, respectively. The results of Transwell experiment also showed that the number of cells under micro-membrane were 14.7±3.1 and 18.9±4.2 in the treated group of PC-3m and LNCaP, respectively, compared with 46.9±5.3 and 66.7±6.0 in the control group （P〈0.05）. Conclusion： PLXSN/EGFP-U6-siCXCR4 can significantly depress the expression f CXCR4, by which the invasiveness of prostate cancer cells in vitro was inhibited as well. This recombinant fragment would be helpful in the treatment of prostate cancer.     

Comparison of the intracellular pharmacokinetics of doxorubicin and 4′-epi-doxorubicin in patients with acute leukemia

Summary A direct comparison of the intracellular pharmacokinetics of 4-epi-doxorubicin and doxorubicin was carried out in five patients with leukemia who were given weekly low doses of a combination of these drugs at 20 mg each in an i.v. injection. Blood samples were collected for 48 h after administration and the drug concentrations in leukemic cells were determined by high-performance liquid chromatography (HPLC). The intracellular peak concentrations of 4-epi-doxorubicin were higher than those of doxorubicin in all patients. The AUC for the intracellular drug concentration vs time curve was significantly higher for 4-epi-doxorubicin. The intracellular uptake and retention were also studied in vitro after incubation of isolated leukemic blast cells with the two drugs; they showed the same pattern observed in vivo. We conclude that 4-epi-doxorubicin and doxorubicin exhibit different pharmacokinetics in malignant cells. The therapeutic significance of this finding requires further evaluation.     

Prognostic impact of δ-like ligand 4 and Notch1 in acute myeloid leukemia

Notch signaling plays a critical role in embryonic vascular development and tumor angiogenesis. The present study was conducted to investigate the prognostic role of the angiogenesis-related Notch ligand and the receptor in acute myeloid leukemia (AML) and assess whether their expression correlates with that of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2. Bone marrow mononuclear cells from 60 untreated AML patients and 40 healthy controls were obtained. Real-time RT-PCR was performed to evaluate the mRNA expression of δ-like ligand 4 (Dll4), Notch1, VEGF, VEGF receptor (VEGFR)-1, VEGFR-2, Ang-1, Ang-2 and Tie2. Western blot analysis was used to determine the protein levels of Dll4 and Notch1. The results demonstrated that Dll4, Notch1, VEGF, VEGFR-2 and Ang-2 expression were significantly higher in untreated AML patients than in the controls. Univariate analysis of factors associated with the overall survival showed a significantly shorter survival in patients with the unfavorable karyotype, higher Dll4 expression, higher Notch1 expression, higher VEGF expression or higher Ang-2 expression. Furthermore, multivariate analysis revealed that the karyotype and expression levels of Notch1, Dll4, VEGF and Ang-2 were independent prognostic factors for overall survival. Additionally, the prognostic value of Dll4 expression (but not Notch1) was more significant in the subgroup consisting of patients with intermediate-risk cytogenetics. Subgroup analysis showed that Notch1 and Dll4 expression levels had a prognostic impact on patients with high VEGF or Ang-2 levels. Taken together, our data provide evidence that the activation of the Notch pathway may indicate an unfavorable prognosis in AML. In particular, Dll4 may be a relevant prognostic marker in intermediate-risk AML.