An Indirect Way to Tame Cancer
An Indirect Way to Tame Cancer
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DOI：
10.1038/scientificamerican0214-46
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发表时间：
2014-02-01
影响因子：
3
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Jain, Rakesh K.
例如，20多年前，我和当时在卡内基梅隆大学的同事们发现，肿瘤血管的结构异常会干扰大量恶性细胞的药物输送。这些血管往往过于扭曲和疏松，当血液进入肿块时，孔洞会导致血液中的液体和药物泄漏出来。然后，液体施加向外的压力，使它和药物分子从肿瘤渗出，进入周围的组织。我们后来发现，减少渗漏还可以降低这种所谓的间质液体压力，改善药物在肿瘤中的分布，从而增强对各种旨在攻击癌细胞的治疗的反应。最近，我们的研究表明，流体压力并不是唯一起作用的令人不安的物理力量。肿瘤是恶性细胞、非恶性细胞、血管和淋巴管的混合物，所有这些都嵌入了一种称为细胞外基质的纤维材料中。固体--基质和细胞--会挤压淋巴管和血管。这种被物理学家和工程师称为固体压力的压缩，可能会减少或阻止流向肿瘤许多部分的血液流动，这反过来可能会减少药物的输送，并建立促进癌症进展的条件。与此同时，这种基质--它在肿瘤中异常僵硬，在某些癌症中比在其他癌症中更丰富--可能直接阻碍抗癌药物在整个肿块中的传播。知道了肿瘤基质所扮演的所有令人担忧的角色后，我和我的同事们最近一直在寻找减少它的方法。我们现在找到了一种吸引我们的方法，部分原因是它依赖于一类已知安全的药物：某些广泛用于治疗高血压的药物。
More than two decades ago, for instance, my co-workers and I, then at Carnegie Mellon University, revealed that structural abnormalities in tumor blood vessels interfere with drug delivery to malignant cells in a mass. These vessels tend to be overly twisty and porous, and the porosity leads fluid and drugs in the blood to leak out as blood enters a mass. The fluid then exerts an outward pressure that causes it and the drug molecules to ooze out of the tumor into the surrounding tissue. We later showed that reducing the leakiness could also lower this so-called interstitial fluid pressure and improve drug distribution in the tumor, thereby enhancing responses to various treatments meant to attack cancer cells. More recently, our research has demonstrated that fluid pressure is not the only troubling physical force at work. Tumors are a mash-up of malignant cells, nonmalignant cells, and blood and lymph vessels, all embedded in a fibrous material known as the extracellular matrix. The solids—the matrix and cells—can squash the lymph and blood vessels. This compression, known to physicists and engineers as solid stress, may reduce or halt blood flow to many parts of the tumor, which can, in turn, reduce drug delivery and also set up conditions that foster cancer progression. Meanwhile the matrix—which is abnormally stiff in tumors and is more abundant in some cancers than in others—can directly impede the dissemination of anticancer drugs throughout a mass.Knowing all the worrisome roles played by the tumor matrix, my colleagues and I have lately been searching for ways to diminish it. We have now found an approach that appeals to us in part because it relies on a class of medicines already known to be safe: certain drugs prescribed widely for high blood pres-