Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15101-8. doi: 10.1073/pnas.1213353109. Epub 2012 Aug 29.
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.
肿瘤中生长诱导的固有力已被怀疑存在一段时间，但这些力主要是使用数学模型来估计的。固有力会使周围组织变形，并压缩肿瘤内的淋巴管和血管。淋巴管的压缩会增加间质液压力，而血管的压缩会减少血流量。血流量的减少反过来又会导致缺氧，从而促进肿瘤的进展、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，旨在减轻固有力的策略有可能改善癌症治疗效果。然而，缺乏测量固有力的方法阻碍了减轻固有力药物的开发。在这里，我们提出了一种简单的技术来估计动物和人体肿瘤内积累的生长诱导的固有力，我们发现通过消耗癌细胞、成纤维细胞、胶原和/或透明质酸，可以减轻这种力，从而改善肿瘤灌注。此外，我们还表明，用 sonic hedgehog 通路抑制剂治疗性消耗癌相关成纤维细胞可以减轻固有力、解压血管和淋巴管，并增加灌注。除了为肿瘤的机械病理学提供深入了解外，我们的方法还可以作为一种快速筛选减轻固有力和增强灌注的药物的方法。
