科学家发现骨髓来源的内皮祖细胞有助于肝癌的预后判断

2006-10-10 00:00 来源:丁香园 作者:丁香园
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   肝细胞癌是肝癌中进展很快的一种,确诊时往往已经到了晚期,因此导致其预后极差。一项新的研究发现,骨髓来源的某种特定细胞有可能作为肝癌的早期诊断和预后判断标记物。该研究发现,没有手术指征的肝癌患者其前体内皮祖细胞(EPCs)水平比可手术者患者高。研究结果发表于2006年10月的《肝脏病杂志》上,该杂志是美国肝脏病研究协会(AASLD)的官方杂志。

    肝细胞癌其瘤体有广泛的新血管形成,因此需要大量的内皮细胞生长。最近的研究发现,可能肿瘤产生的某些蛋白激活了内皮祖细胞使其通过血流迁徙到肿瘤部位。尽管高水平的内皮祖细胞也与多种骨髓瘤的发生有关(骨髓来源的浆细胞瘤),但其与实体瘤的关系至今尚无人研究过。

    在香港大学Ronnie Poon教授的领导下,研究者们分析了80名肝细胞癌患者治疗前的血样,并与16名肝硬化患者的血样以及14名健康者的血样作了比较分析。由于内皮祖细胞难以分离和量化,所以他们尝试通过培养外周血内皮细胞并计算其形成的集落来计算内皮祖细胞的水平。这使得他们能够区分骨髓来源的内皮祖细胞和其他组织来源的内皮细胞。他们也分析了血管内皮生长因子和白介素-8的水平,这两种蛋白被认为参与了肿瘤新血管的形成。

    实验结果表明,肝细胞癌患者的集落数显著高于对照组,而非手术指征的肝细胞癌患者的集落数又显著高于可手术的患者。作者认为,“结果提示,肿瘤的高度进展性与内皮祖细胞循环高水平之间可能存在某种关联性”。

    在17名接受手术并被随访至少一年的患者中,一年内复发的患者其手术前的集落数得分明显更高一些。研究者们还分析了患者的甲胎蛋白水平(AFP)(肝细胞癌的特定生物标记),发现较高集落得分的患者其甲胎蛋白水平也较高。而血管内皮生长因子和白介素-8的水平与集落得分之间也有相似的关联性。作者说,“既然外周白介素-8和血管内皮生长因子的水平与血管发生(新血管的形成)和肝细胞癌的预后高度相关,那么我们的研究结果为内皮祖细胞在肿瘤血管发生可能作用提供了一个新的证据。”

    作者说,“综上所述,我们的研究表明内皮祖细胞可能在肝细胞癌的预后方面有重要意义”。他们认为有必要进一步扩大病人规模和延长随访时间的研究,以及进一步评估已知的预后因子和集落生成单位以及甲胎蛋白水平的价值。监测手术后的肝细胞癌患者的集落生成单位得分有助于确定肿瘤复发时起内皮祖细胞的水平是否升高。作者总结道,“我们的数据表明进一步的研究以确定肝细胞癌患者外周内皮细胞水平的预后价值,以及探讨针对骨髓内皮祖细胞的动员治疗肝细胞癌的策略是有意义的”。

Higher levels of cells originating in bone marrow may be useful in prognosis of liver cancer

A new study found that higher levels of specialized blood cells that originate in bone marrow may potentially be used as a prognostic marker in liver cancer. The study showed that elevated levels of endothelial progenitor cells (EPCs), the precursors to endothelial cells that are found in the lining of blood vessels, were found in patients with inoperable hepatocellular carcinoma (HCC) compared to those with tumors that could be treated surgically.

The results of this study appear in the October 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/hepatology.

HCC is a very aggressive form of cancer that is usually diagnosed when the disease is already at an advanced stage and therefore has a poor prognosis. HCC tumors have extensive new blood vessel formation, which requires the growth of endothelial cells. Recent studies have shown that proteins produced by the tumor may stimulate EPCs, which then travel to the tumor by way of the bloodstream. Although higher levels of EPCs have been associated with multiple myeloma (cancer of the plasma cells produced in bone marrow), their role in solid tumors has not been studied until now.

Led by Prof. Ronnie Poon of the Department of Surgery at the University of Hong Kong, researchers analyzed blood samples from 80 patients with HCC before they were treated and compared them with blood samples from 16 patients with cirrhosis and 14 patients who were healthy. Since EPCs are difficult to isolate and quantify, they measured EPC levels using a specific method that allowed them to culture blood cells and count the number of colonies (colony formation units or CFU) formed by endothelial cells. This enabled them to differentiate EPCs that originated in the bone marrow from endothelial cells that are found in normal tissues throughout the body. They also analyzed levels of vascular endothelial growth factor (VEGF) and interleukin-8 (IL8), two proteins that are thought to be involved in new blood vessel formation in tumors.

The results showed that the HCC patients had significantly higher CFU scores than the control patients, and that those with inoperable HCC had significantly higher CFU scores than those whose tumors could be treated surgically. "These findings could suggest a possible relationship between more aggressive tumor and higher circulating levels of EPCs," the authors state.

In addition, in the 17 patients who had surgery and were followed for at least one year, CFU scores prior to surgery were much higher in those who experienced recurrence within a year. Researchers also analyzed levels of alpha-fetoprotein (AFP), a specific biomarker of HCC, and found that patients with higher CFU scores had higher levels of AFP. Similarly, there was a correlation between both VEGF and IL8 levels and CFU scores. The authors note that "since both circulating levels of IL8 and VEGF have been reported to be highly associated with angiogenesis [new blood vessel formation] and prognosis of HCC, the finding in our study provides additional evidence for the possible role of EPCs in tumor angiogenesis."

"Taken together, our study suggests that EPCs may have a significant implication in HCC in terms of prognosis," the authors note. They suggest that further studies with more patients and longer follow-up times would be useful, as would further evaluations of known prognostic factors together with CFU and AFP levels. It would also be helpful to follow CFU scores over time in patients who undergo surgery for HCC to determine if EPC levels increase when and if tumors recur. The authors conclude: "Our data suggest that further studies are worthwhile to validate the prognostic value of circulating levels in HCC patients, and to explore possible therapeutic strategies against HCC by targeting bone marrow mobilization of EPCs."



编辑:蓝色幻想

编辑: 张靖

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