DuFort Christopher C, DelGiorno Kathleen E, Hingorani Sunil R
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
Gastroenterology. 2016 Jun;150(7):1545-1557.e2. doi: 10.1053/j.gastro.2016.03.040. Epub 2016 Apr 9.
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.
微环境影响实体瘤的发病机制，在某些实体瘤中发挥着巨大作用。我们对基质对癌症，尤其是胰腺导管腺癌的反应的理解，已从宿主防御转变为肿瘤攻击。我们知道，微环境中的大多数（尽管不是全部）因素和过程都支持肿瘤上皮细胞。对基质成分作用的这种重新评估也揭示了潜在的脆弱性和可利用的治疗机会。糖胺聚糖透明质酸在基质中的高浓度，以及它产生的大凝胶-流体相和压力，最近被确定为胰腺癌治疗耐药性的主要来源。虽然游离组织间液在肿瘤流体力学和灌注中的作用相对较小，这一点早已为人所知，但由于历史和技术原因，流动性较小的凝胶-流体相在很大程度上被忽视了。经典的流体压力测量方法无法捕捉凝胶-流体相，再加上对不能准确模拟肿瘤血管生物学的异种移植和同种异体移植系统的依赖，导致人们过度强调游离流体在阻碍灌注和药物递送中的作用，而几乎完全忽略了凝胶-流体相的主要作用。我们提出，富含透明质酸、相对不流动的凝胶-流体相诱导血管塌陷和灌注不足，是胰腺癌治疗耐药性的主要机制。类似的特性在其他实体瘤中可能也起作用，因此，有必要用现代技术重新审视和表征其他原发性癌症中的流体力学。
