Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer.
Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer.
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胶原蛋白复杂性在空间上定义了胰腺癌总组织压力的微区域。
DOI：
10.1038/s41598-017-10671-w
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发表时间：
2017-08-30
影响因子：
4.6
通讯作者：
Pogue BW
中科院分区：
文献类型：
--
作者：
Nieskoski MD;Marra K;Gunn JR;Hoopes PJ;Doyley MM;Hasan T;Trembly BS;Pogue BW
胰腺导管腺癌（PDAC）中全身性癌症治疗的不良疗效部分归因于胶原蛋白和透明质酸的沉积，导致间质性高血压使血管和淋巴管塌陷，限制药物递送。本文研究了透明质酸（HA）、胶原蛋白和封闭血管的机械应力的空间来源之间的内在微区域相互作用。多个局部压力测量值与HA、胶原和血管灌注的空间匹配组织化学图像进行分析。已知HA会溶胀，拟合线性弹性模型，总组织压（TTP）直接随胶原蛋白含量增加而增加至高于间质液压（IFP）。然而，局部TTP似乎起源于胶原面积分数，以及增加其熵和分形维数，并在形态学上似乎是最大化时，HA区域被胶原包裹。TTP与血管通畅性和维替泊芬摄取呈负相关，表明间质性高血压导致血管压缩和PDAC中分子递送减少。胶原酶注射导致总组织压急性降低和药物灌注增加。PDAC内胶原分布的大的微观变化导致在数百微米距离尺度上变化的微区域TPP值，导致分子灌注的微观异质性限制，并缩小了全身递送治疗剂的可行治疗方案。
The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics.
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影响因子：
8.8
作者：
Provenzano, P. P.;Hingorani, S. R.
通讯作者：
Hingorani, S. R.
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
1.9
作者：
Davis, Scott C.;Pogue, Brian W.;Paulsen, Keith D.
通讯作者：
Paulsen, Keith D.
影响因子：
3.1
作者：
Ozerdem, Ugur
通讯作者：
Ozerdem, Ugur
DOI：
10.1146/annurev-bioeng-071813-105259
发表时间：
2014-07-11
影响因子：
9.7
作者：
Jain RK;Martin JD;Stylianopoulos T
通讯作者：
Stylianopoulos T