Elevated Physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma
Elevated Physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma
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DOI：
10.1158/1078-0432.ccr-04-2048
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发表时间：
2005-03-15
影响因子：
11.5
通讯作者：
Healey, JH
中科院分区：
文献类型：
--
作者：
Nathan, SS;DiResta, GR;Healey, JH
目的：探讨组织间液压力升高对骨肉瘤生理及化疗敏感性的影响。实验设计：我们对诊断为高级别骨肉瘤的患者在切开活检时进行了血压和血流量评估，并将其与生存和化疗相关的肿瘤坏死相关联。然后在复制的高压环境中评估骨肉瘤细胞系的增殖和治疗指标。结果：16例体内骨肉瘤均表现为间质液压力升高（平均35.2 +/- SD, 18.6 mmHg）。通过多普勒探头在单个部位测量，这与血流明显受阻无关（P < 0.12）。然而，高间质液压力的肿瘤有更大的化疗相关坏死和更长的生存期（P < 0.05）。在体外，细胞在压力下发生显著的生理变化。骨肉瘤细胞系生长在一个新的流体静压系统具有可变的细胞系特异性生长成比例的压力水平。细胞周期分析显示，加压48h后，S期细胞增多（P < 0.01）。细胞周期相关转录因子E2F-1 （P < 0.03）和E2F-4 （P < 0.002）显著升高。这些变化与化学敏感性增加有关。在压力下测试的细胞显示对顺铂（P < 0.00006）和阿霉素（P < 0.03）的敏感性增加，这与临床研究中在间质液压力较高的肿瘤中观察到的化疗相关坏死增加有关。结论：本研究结果表明，体内加压环境中的细胞比传统细胞培养系统中的细胞处于更高的再生活性状态。肿瘤间质液压力的变化有可能改变化疗效果。
Purpose: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity. Experimental Design: We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment.Results: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 +/- SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P < 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P < 0.05).In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line-specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P < 0.01). There was a significant elevation in the cell cycle-related transcription factors E2F-1 (P < 0.03) and E2F-4 (P < 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P < 0.00006) and doxorubicin (P < 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study.Conclusions: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.