Morris V L, Schmidt E E, Koop S, MacDonald I C, Grattan M, Khokha R, McLane M A, Niewiarowski S, Chambers A F, Groom A C
Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
Exp Cell Res. 1995 Aug;219(2):571-8. doi: 10.1006/excr.1995.1266.
Adhesion molecules, including integrins, are important for interactions of cancer cells with vessel walls, a step leading to cancer metastasis. Disintegrins block the action of integrins by binding to them. We tested the hypothesis that the disintegrin eristostatin would block metastasis by interfering with cancer cell adhesion to vessel walls, thus preventing extravasation. Experimental metastasis assays, in which B16F1 melanoma cells (controls vs eristostatin-treated, 25 micrograms/ml) were injected via mesenteric veins of anesthetized C57BL/6 mice, showed that eristostatin reduced (P < 0.05) the mean number of liver metastases from 14.4 to 0.6 at 11 days postinjection (p.i.). We examined three different steps in metastasis at which eristostatin could have exerted its effect, namely, cell arrest, extravasation, and migration. Control and eristostatin-treated B16F1 cells were fluorescently labeled and examined by videomicroscopy in liver microcirculation in vivo at various times up to 14 days p.i. Measurements of vessel size in which cell arrest occurred and length/width ratio of arrested cells showed only small differences between control and eristostatin-treated cells. Eristostatin treatment did not prevent extravasation, and the timing and process of extravasation were similar for both treated and control cells; by 3-4 days p.i. more than 90% of the cells had extravasated or were in the process. Eristostatin also did not affect the ability of extravasated cells to migrate through the extracellular matrix to the subcapsular region where tumors later form. Therefore, we conclude that eristostatin exerted its primary effect by regulating the number of individual cancer cells that grow after extravasation.
包括整合素在内的黏附分子对于癌细胞与血管壁的相互作用至关重要，而这是导致癌症转移的一个步骤。去整合素通过与整合素结合来阻断其作用。我们检验了这样一个假说，即去整合素埃里斯托他汀（eristostatin）会通过干扰癌细胞与血管壁的黏附来阻断转移，从而防止癌细胞外渗。在实验性转移分析中，将B16F1黑色素瘤细胞（对照组与用25微克/毫升埃里斯托他汀处理的组）经麻醉的C57BL/6小鼠的肠系膜静脉注射，结果显示，在注射后11天，埃里斯托他汀使肝转移的平均数量从14.4减少到了0.6（P < 0.05）。我们研究了转移过程中埃里斯托他汀可能发挥作用的三个不同步骤，即细胞滞留、外渗和迁移。对对照组和经埃里斯托他汀处理的B16F1细胞进行荧光标记，并在注射后长达14天的不同时间通过体内肝脏微循环的视频显微镜检查。对发生细胞滞留的血管大小以及滞留细胞的长宽比的测量显示，对照组和经埃里斯托他汀处理的细胞之间只有微小差异。埃里斯托他汀处理并未防止外渗，且处理组和对照组细胞的外渗时间和过程相似；注射后3 - 4天，超过90%的细胞已经外渗或正在外渗过程中。埃里斯托他汀也不影响外渗细胞穿过细胞外基质迁移到后来形成肿瘤的被膜下区域的能力。因此，我们得出结论，埃里斯托他汀主要是通过调节外渗后生长的单个癌细胞数量来发挥其作用的。
