Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
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DOI：
10.1073/pnas.1213353109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Stylianopoulos, Triantafyllos;Martin, John D.;Jain, Rakesh K.
一段时间以来，人们一直怀疑肿瘤中存在生长诱导的固体应力，但这些应力主要是使用数学模型估计的。固体应力可使周围组织变形并压迫肿瘤内淋巴管和血管。淋巴管的压迫升高了间质液压力，而血管的压迫减少了血流量。减少的血流量，反过来，导致缺氧，这促进肿瘤进展，免疫抑制，炎症，侵袭和转移，并降低化疗，放疗和免疫治疗的疗效。因此，旨在缓解固体应激的策略有可能改善癌症治疗。然而，缺乏测量固体应激的方法阻碍了固体应激缓解药物的开发。在这里，我们提出了一种简单的技术来估计动物和人类肿瘤内积累的生长诱导的固体应力，我们表明，这种应力可以通过消耗癌细胞，成纤维细胞，胶原蛋白和/或透明质酸来减少，从而改善肿瘤灌注。此外，我们表明，治疗消耗癌相关的成纤维细胞与抑制剂的音刺猬途径减少固体应力，减压血管和淋巴管，并增加灌注。除了提供对肿瘤机制病理学的见解外，我们的方法还可以作为一种快速筛选减压和增强灌注药物的方法。
The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.