Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma.
Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1053/j.gastro.2016.03.040
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发表时间：
2016-06
期刊：
影响因子：
29.4
通讯作者：
Hingorani SR
中科院分区：
文献类型：
--
作者：
DuFort CC;DelGiorno KE;Hingorani SR
微环境影响实体瘤的发病机制，并在某些实体瘤中发挥着巨大的作用。我们对癌症（特别是胰腺导管腺癌）基质反应的理解已经从宿主防御发展到肿瘤进攻。我们知道，微环境中的大多数（尽管不是全部）因素和过程支持肿瘤上皮细胞。对基质成分作用的重新评估也揭示了潜在的脆弱性和可利用的治疗机会。基质中糖胺聚糖透明质酸的高浓度，连同其产生的大凝胶流体相和压力，最近被确定为胰腺癌治疗抵抗的主要来源。尽管长期以来人们一直认识到游离间质液在肿瘤的流体力学和灌注中相对较小的作用，但由于历史和技术原因，流动性较差的凝胶流体相在很大程度上被忽视。经典的流体压力测量方法无法捕获凝胶-流体相，再加上对异种移植和同种异体移植系统的依赖，不能准确地模拟肿瘤血管生物学，导致过分强调游离流体在阻碍灌注和药物输送方面的作用，并且几乎完全忽视了凝胶-流体相的主要作用。我们提出，富含透明质酸、相对固定的凝胶流体相诱导血管塌陷和低灌注，作为胰腺癌治疗抵抗的主要机制。类似的特性也可能在其他实体瘤中发挥作用，因此可能有必要利用现代技术在其他本土癌症中重新审视和表征流体力学。
The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted.