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识别侵润性癌症新的生物标记物

2018-07-17

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导读:据一项发表于Proceedings of National Academy of Sciences(PNAS)的研究报告称,研究人员发现一种能够使血液

据一项发表于Proceedings of National Academy of Sciences(PNAS)的研究报告称,研究人员发现一种能够使血液凝固的蛋白质——“选择性剪切组织因子(alternatively spliced Tissue Factor, asTF)”对某些转移性肿瘤的生长起关键作用。虽然身体的各个组织中都有asTF的存在,但该蛋白最主要还是存在与血管中。该研究是首个报道选择性剪切组织因子能够促进血管生成(angiogenesis)的研究报告。

肿瘤血管生成是在原有的血管基础上延伸扩展而形成的新生毛细血管,这些新生血管为不断侵润生长的原发肿瘤提供营养,同时这些肿瘤新生毛细血管也可延伸转移到其他组织中。研究人员发现asTF能够与内皮细胞表面的整合素(integrins)结合,并诱导信号级联引发血管生成。血管生成能够促进细胞粘连(cell adhesion),细胞迁移和新血管的生成,研究人员在人类宫颈癌中也发现asTF含量很高。

据研究人员Bogdanov介绍,该发现为科学家提供了一种全新的途径研究组织因子基因影响组织形成过程,如血管生成。由于在多种癌症中组织因子基因的表达量较高,因此研究人员希望可以利用该发现,针对各种特异性的组织因子找到一些能够终止癌细胞生长的方法。

PNAS October 29, 2009, doi: 10.1073/pnas.0905325106

Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Y. W. van den Berga, L. G. van den Hengela, H. R. Myersa, O. Ayachia, E. Jordanovab, W. Rufc, C. A. Spekd, P. H. Reitsmaa, V. Y. Bogdanove and H. H. Versteega,1

aThe Einthoven Laboratory for Experimental Vascular Medicine and

bDepartment of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands;

cDepartment of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;

dCenter for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; and

eDivision of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267

The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-αVβ3 integrin interaction induces endothelial cell migration, whereas asTF-dependent formation of capillaries in vitro is dependent on α6β1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to β1 and β3 integrin blockade and a TF-antibody that disrupts asTF-integrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.

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