非小细胞肺癌化疗中循环内皮祖细胞的检测

背景与目的:循环内皮祖细胞(circulating endothelial progenitor cells,cEPCs)在血管新生和肿瘤生长中具有重要作用.本研究旨在了解化疗对非小细胞肺癌(non-small cell lung cancer,NSCLC)患者cEPCs的影响.方法:35例晚期NSCLC紫杉醇联合顺铂化疗过程中,分别于化疗前1天、化疗开始后第7天、第15天和第42天用流式细胞仪检测外周血cEPCs数量.cEPCs的分子标志物定义为CD34+/CD133+/VEGFR-2+.结果:化疗周期的不同时间点外周血cEPCs数量存在差异.化疗后第15天cEPCs最多(F=4.36,P=0.006),化疗获益者化疗后cEPCs减少(t=4.35,P＜0.001),疾病进展者cEPCs增加(t'=5.35,P=0.001),cEPCs数量变化与化疗疗效相关(t=0.641,P＜0.001).化疗获益者治疗前的cEPCs数量低于化疗无效者(t=4.46,P＜0.001).结论:NSCLC的化疗疗效与cEPCs数量密切相关.     

Circulating endothelial progenitor cells

Angiogenesis research investigates the formation of new blood vessels in wound healing, tumour growth and embryonic development. Circulating, bone marrow-derived endothelial progenitor cells (EPCs) were first described 8 years ago, yet the exact nature of these endothelial precursor cells remains unclear. The contributions of circulating EPCs to angiogenesis in tumours, ischaemic injury and other diseases as well as their usefulness in the repair of wounded hearts and limbs remain under intense investigation.     

Increase in circulating endothelial progenitor cells predicts response in patients with advanced non-small-cell lung cancer

Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets.     

循环内皮祖细胞与肿瘤血管生成

恶性肿瘤细胞可产生多种细胞因子,可使骨髓中的内皮祖细胞(EPC)动员至外周血,并将这些细胞募集到肿瘤组织的血管床,参与肿瘤的血管生成.EPC有望成为抗肿瘤血管生成的靶点或肿瘤基因治疗的载体.     

Circulating numbers of endothelial progenitor cells in patients with gastric and breast cancer

Angiogenic factors like VEGF or G-CSF were reported to mobilize endothelial progenitor cells (EPCs) from the bone marrow. These EPCs were shown to be incorporated in the neovessels of developing tumors. Although the concentrations of angiogenic factors in the peripheral blood were reported to be elevated in cancer patients, the number of circulating EPCs has not been previously investigated. In this study, the number of EPCs circulating in the blood in 16 healthy controls and 71 newly diagnosed cancer patients was examined by a culture assay of peripheral blood mononuclear cells. The number of circulating EPCs was not found to be increased in cancer patients, although the plasma levels of VEGF were elevated. It is suggested that VEGF, at concentrations typical of those observed in the blood of cancer patients, does not mobilize EPCs into the peripheral blood.     

Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer

Tumor growth and metastasis is dependent on the formation and assembly of new blood vessels, a process known as neo-angiogenesis. Both pre-existing and circulating vascular cells have been shown to contribute to the assembly of tumor neo-vessels in specific tumors. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow constitutes a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be increased in certain malignant states. However, the role of circulating EPCs in breast cancer is largely unknown. We recruited twenty-five patients with biopsy-proven invasive breast cancer at Weill Cornell Breast Center to participate in a pilot study investigating the correlation of circulating EPCs to extent of disease and initiation of chemotherapy. For each patient, a baseline sample was drawn before systemic treatment, and for seventeen of those patients, a second sample was taken after the first round of chemotherapy. Levels of peripheral blood EPCs, as defined by co-expression of CD133 and VEGFR2, were quantified by flow cytometry. Breast cancer patients with stage III & IV disease had statistically higher levels of circulating EPCs than did patients with stage I & II disease (median = 165,000 EPCs/5 × 10⁶MNCs vs. median = 6,920 EPCs/5 × 10⁶MNCs, respectively, P < 0.0001). In addition, in late-stage patients, levels of EPCs demonstrated a statistically significant drop after initiation of chemotherapy (median = 162,500 EPCs/5 × 10⁶MNCs [pre] vs. median = 117,500 EPCs/5 × 10⁶MNCs [post], P = 0.01). These results suggest that circulating EPCs may serve as a potential tumor biomarker in breast cancer and that EPCs may represent a plausible target for future therapeutic intervention.     

Circulating endothelial cells and tumor blood volume as predictors in lung cancer

The current criteria for evaluating antiangiogenic efficacy is insufficient as tumor shrinkage occurs after blood perfusion decreases. Tumor blood volume (BV) in computed tomography perfusion imaging and circulating endothelial cells (CEC) might predict the status of angiogenesis. The present study aimed to validate their representation as feasible predictors in non‐small‐cell lung carcinoma (NSCLC). A total of 74 patients was categorized randomly into two arms undergoing regimens of vinorelbine and cisplatin (Navelbine and platinum [NP]) with rh‐endostatin or single NP. The response rate, perfusion imaging indexes and activated CEC (aCEC) during treatment were recorded. Progression‐free survival (PFS) was determined through follow up. Correlations among the above indicators, response and PFS were analyzed: aCEC increased significantly in cases of progressive disease after single NP chemotherapy (P = 0.024). Tumor BV decreased significantly in cases with a clinical benefit in the combined arm (P = 0.026), whereas inverse correlations existed between ?aCEC (post‐therapeutic value minus the pre‐therapeutic value) and PFS (P = 0.005) and between ?BV and PFS (P = 0.044); a positive correlation existed between ?aCEC and ?BV. Therefore, both aCEC and tumor BV can serve as predictors, and detection of both indicators can help evaluate the chemo‐antiangiogenic efficacy in NSCLC more accurately.     

Circulating endothelial progenitor cells (EPC) for tumor vasculogenesis in gastric cancer patients

It has been suggested that vasculogenesis by endothelial progenitor cells (EPC) as well as angiogenesis play an important role in the production of blood vessels in neoplasm. The present study was designed to isolate and characterize the EPC in gastric cancer patients as a tumor specific angiogenesis marker. The cells derived from CD34 positive PBMC presented with a cobblestone appearance at 28 days, revealing differentiation into endothelial cells. They were also positive to the LDL-uptake reaction, showing that they have biological endothelial cell functions. These cells demonstrated tube formation, showing their ability to participate in neovascularization. The cells derived from CD34 positive PBMC expressed CD133 and demonstrated telomerase activity, showing the stem cell character. In xenograft model, EPC derived from CD34 positive PBMC mobilized mainly into tumor area after being injected through tail vein. With isolation, ex vivo amplification and characterization of EPC from gastric cancer patients receiving chemotherapy, endothelial progenitor cells may be used as a candidate prognostic and predictive biomarker for cancer.     

循环肿瘤细胞与肺癌

循环肿瘤细胞(CTC)与肿瘤转移有明显的相关性,CTC检测有助于指导肿瘤治疗,为判断预后、预测疗效提供可靠依据.CTC与非小细胞肺癌的分期及远处转移相关.CTC数量变化与非小细胞肺癌患者化放疗疗效及预后有关.小细胞肺癌中CTC检出率和数量均明显高于其他肿瘤,与其分期及化疗疗效有关.CTC有望用于指导肺癌个体化治疗.初步研究结果提示可用CTC来动态了解肺癌患者分子靶向药物治疗过程中耐药肿瘤细胞的出现.     

血管内皮祖细胞在肿瘤中的研究进展

来源于骨髓的血管内皮祖细胞具有高度的扩增潜能。各种恶性肿瘤患者外周血中血管内皮祖细胞均有不同程度的增多,血管内皮祖细胞可能成为抗血管生成治疗的监测标记和可能的治疗靶点。     

Wnt signaling in stem cells and non-small-cell lung cancer

Evidence suggests that stem cells may be the source of mutant cells that cause cancers to develop and proliferate. Wnt signaling has been shown to promote self-renewal in gut epithelial and hematopoietic stem cells and to trigger critical pathways in carcinogenesis. In this review, we highlight the progress in understanding how the Wnt pathway contributes to stem cell maintenance and its role in lung carcinogenesis. Although the function of stem cells in solid tumor development is unclear, the Wnt pathway's role in determining the fate and self-renewal potential of cancer stem cells suggests a critical role in carcinogenesis and that developing drugs to inhibit this pathway may be of therapeutic interest.     

Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P < 0.02) and microvessel density (P < 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC.     

Circulating deoxyribonucleic Acid as prognostic marker in non-small-cell lung cancer patients undergoing chemotherapy.

PURPOSE: Circulating cell-free DNA is present in increased amounts in the blood of cancer patients, but the clinical relevance of this phenomenon remains unclear. We conducted a clinical study to assess the value of circulating DNA as a prognostic marker in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A standard protocol for the quantification of circulating DNA by real-time polymerase chain reaction was set up and validated at two oncology units. One hundred eighty-five informed patients with NSCLC and 46 healthy controls were included in the study. DNA concentrations were determined in paired plasma and serum samples and analyzed for a relationship with leukocyte counts and lactate dehydrogenase (LDH) levels. DNA concentrations in healthy controls and in patients were compared, and cutoff levels for plasma and serum DNA were determined. Patient survival was analyzed relative to baseline DNA concentrations, and the relationship between tumor responses and changes in DNA concentrations was assessed in patients receiving chemotherapy. RESULTS: We found a significant correlation between increased plasma DNA concentrations and elevated LDH levels (P = .009), advanced tumor stage (P < .003), and poor survival (P < .001). Tumor progression after chemotherapy was significantly (P = .006) associated with increasing plasma DNA concentrations. Serum DNA concentrations strongly correlated (P < .001) with leukocyte counts. CONCLUSION: Our data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.     

Follow-up in non-small-cell lung cancer

The major impetus for structured follow-up after primary treatment of localized non-small-cell lung cancer is both early detection and re-treatment of recurrent disease with a curative intent, and early detection and treatment of a secondary primary tumor. In patients with lung cancer, the significance of intensive follow-up is still under debate.     

Cetuximab in non-small-cell lung cancer

Cetuximab is a chimeric human-mouse anti-EGF receptor monoclonal antibody. In Phase I studies, no dose-limiting toxicities were observed with cetuximab as a single agent or combined with chemotherapy; pharmacokinetic and pharmacodynamic analyses supported 250 mg/m(2) weekly administration. Skin toxicity, diarrhea and fatigue were the most common toxicities. The positive results obtained in Phase II trials in patients with advanced non-small-cell lung cancer prompted two randomized Phase III trials evaluating cetuximab in addition to first-line chemotherapy. Both trials showed a small benefit in overall survival for the experimental treatment, which was considered insufficient by the EMA for marketing approval. However, a subgroup analysis of the FLEX Phase III trial recently demonstrated a larger survival benefit from the experimental treatment in patients with high immunohistochemical EGF receptor expression. This finding, if confirmed prospectively, could represent a new opportunity for positioning cetuximab into the standard treatment of advanced non-small-cell lung carcinoma.