Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model
Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model
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DOI：
10.1593/neo.05469
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Kippenberger, Stefan
中科院分区：
文献类型：
--
作者：
Hofmann, Matthias;Guschel, Maike;Kippenberger, Stefan
高肿瘤间质液体压(TIFP)是大多数实体肿瘤的特征。TIFP可能会阻碍肿瘤组织对大分子治疗药物的充分吸收。此外，TIFP还会产生影响肿瘤皮质的机械力，这可能会影响肿瘤细胞的生长参数。这似乎是可能的，因为在其他组织(即血管或皮肤)中，机械拉伸已知会引发增殖。因此，我们假设TIFP诱导的拉伸调节了与增殖相关的参数。实体上皮性肿瘤(A431和A549)在海军医学研究所裸鼠体内生长，产生约10 mm Hg(A431)或5 mm Hg(A549)的TIFP。肿瘤中央囊性区引流导致TIFP迅速下降，肿瘤皮质明显松弛。十二烷基硫酸钠聚丙烯酰胺凝胶电泳和Western印迹分析发现，降低TIFP可导致增殖相关的p44/42丝裂原活化蛋白激酶的磷酸化减少，并使肿瘤松弛。免疫组织化学染色证实，TIFP降低后肿瘤相关增殖标记物Ki-67表达下降。这些数据表明，TIFP诱导的机械拉伸是肿瘤增殖的正向调节因子。
High tumor interstitial fluid pressure (TIFP) is a characteristic of most solid tumors. TIFP may hamper adequate uptake of macromolecular therapeutics in tumor tissue. In addition, TIFP generates mechanical forces affecting the tumor cortex, which might influence the growth parameters of tumor cells. This seems likely as, in other tissues (namely, blood vessels or the skin), mechanical stretch is known to trigger proliferation. Therefore, we hypothesize that TIFP-induced stretch modulates proliferation-associated parameters. Solid epithelial tumors (A431 and A549) were grown in Naval Medical Research Institute nude mice, generating a TIFP of about 10 mm Hg (A431) or 5 mm Hg (A549). Tumor drainage of the central cystic area led to a rapid decline of TIFP, together with visible relaxation of the tumor cortex. It was found by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis that TIFP lowering yields a decreased phosphorylation of proliferation-associated p44/42 mitogen-activated protein kinase and tumor relaxation. In confirmation, immunohistochemical staining showed a decrease of tumor-associated proliferation marker Ki-67 after TIFP lowering. These data suggest that the mechanical stretch induced by TIFP is a positive modulator of tumor proliferation.