Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: A computational model

Mohammadi, Mahya; Chen, P.

doi:10.1016/j.mvr.2015.06.001

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…Previous studies have demonstrated the significant correlation between high microvascular densities, elevated IFP, and metastasis in cancers (35). Our results have provided direct evidence that TIF is the driving force for lung cancer cells to survive under conditions of nutrient scarcity.…”

Section: Discussionsupporting

confidence: 69%

Tumor Interstitial Fluid Promotes Malignant Phenotypes of Lung Cancer Independently of Angiogenesis

Li¹,

Li²,

Liu³

et al. 2015

Cancer Prevention Research

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Angiogenesis is necessary for cancer progression, but antiangiogenic therapy actually promotes tumor recurrence, progression, and metastasis. This study focused on the contribution of the tumor interstitial fluid (TIF) to lung cancer progression. TIF was isolated and quantified for 10 mg protein/mL. Malignant driver characteristics of TIF were examined by tumor-initiating cells (TIC), self-renewal, epithelial-mesenchymal transition (EMT), autophagy, and apoptosis in vitro. In vivo tumor model was used to investigate the mechanistic roles of TIF in lung cancer progression. In vitro, TIF exhibited distinct malignant driver characteristics, which led to increased numbers of TICs, increased selfrenewal and EMT, as well as to decreased autophagy and apoptosis under cell starvation conditions. In vivo, the contribution of TIF was similar, as judged by increased TICs indicated by the cancer stem cell marker Nanog, the proliferation marker proliferating cell nuclear antigen, and the EMT marker N-cadherin; TIF also increased the formation of pulmonary tumors. Interestingly, the blockers of inflammation, Na-K-ATPase, and aldosterone receptor decreased TIF-induced tumor progression but increased angiogenesis. Further, we found that the water content of the tissue was positively correlated with the levels of plasma 5-hydroxyindoleacetic acid or tissue aquaporin-1 but not with CD31. However, vadimezan reduced angiogenesis but promoted TIF-induced tumor progression. Our results suggested that TIF could provide better nutrition to the tumor than angiogenesis and that it could promote the development of malignant phenotypes of lung cancer independently of angiogenesis.

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Section: Discussionsupporting

confidence: 69%

Tumor Interstitial Fluid Promotes Malignant Phenotypes of Lung Cancer Independently of Angiogenesis

Li¹,

Li²,

Liu³

et al. 2015

Cancer Prevention Research

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“…The blood flow estimation model by Fry et al [39] has been thoroughly tested using 202 mesenteric networks [50] in which blood flow measurements were taken in individual 203 vessels and used to inform parameter estimation [39,42,48,51]. Darcy's law has been effectively used to describe the passage of fluids [3,14,[30][31][32][33]52] or 206 solutes [40,45] through tissues. In this study, we use Darcy's law to describe the 207 relationship between the volume-averaged IFP, p, and interstitial fluid velocity (IFV), u, 208 within the porous interstitial domain:…”

mentioning

confidence: 99%

Modelling the transport of fluid through heterogeneous, whole tumours in silico

Sweeney

d’Esposito

Walker‐Samuel

et al. 2019

Preprint

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It is critically important to understand and predict fluid transport within both physiological and pathological tissues in order to develop effective treatment strategies.Recent advances in high-resolution optical imaging allow the acquisition of whole tumour vascular networks which can be used to parameterise computational models to predict the fluid dynamics at all length scales across the tissue. This enables hypothesis testing around the role of the tumour microenvironment in determining transport characteristics, which would otherwise be unavailable using traditional experiments.In this study, we present a novel computational framework for the efficient simulation of vascular blood flow and interstitial fluid transport based on complete three-dimensional, whole tumour vasculature obtained using high-resolution optical imaging. This framework comprises a Poiseuille flow model which simulates vascular blood flow within the vessel network, coupled via point sources of flux to a porous medium model describing interstitial fluid transport. We develop a computational algorithm for prescription of network boundary conditions and validation of tissue-scale fluid transport against measured in vivo perfusion data acquired using biomedical imaging tools. We present simulations of the model on orthoptic murine glioma and December 24, 2018 1/36 human colorectal carcinoma xenograft data (GL261 and LS147T, respectively), and perform sensitivity analysis on key unknown parameters relating to the tissue microenvironment, to understand their impact in predicting vascular and interstitial flow. Finally, we simulate radially varying vascular normalisation in a LS147T tumour and hypothesise that uniform normalisation is required to lower tumour interstitial fluid pressure.Our computational framework permits predictions of whole tumour fluid dynamics which incorporate the inherent architectural heterogeneities appearing at the micron-scale, and outputs three-dimensional spatial maps detailing these flow properties from micro to macro length scales. This provides vital information on the tumour microenvironment which could enable the design and delivery of future anti-cancer therapies. Author summaryThe structure of tumours varies widely, with dense and chaotically-formed networks of blood vessels that differ between each individual tumour and even between different regions of the same tumour. This atypical environment can inhibit the delivery of anti-cancer therapies. Computational tools are urgently required which incorporate micron-scale tumour biomechanics to predict tissue-scale fluid dynamics, and consequently the efficacy of cancer therapies.We have developed a computational framework which integrates the complex tumour vascular architecture to predict fluid transport across all lengths scales in whole tumours. This enables computationally efficient hypothesis testing of cancer therapies which manipulate the tumour microenvironment in order to improve drug delivery to tumours. Introduction 1 Architectural heterogeneities in...

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“…Tumor size is not the only reason affecting IFP; dense stroma (ECM deposition), microvascular density, and abnormal angiogenesis work in a comprehensive way. 18,62,63 CAFs have been proved to promote ECM production to increase interstitial and mechanical pressure to elevate IFP. 9,64,65 Disruption of active CAFs ( Figure 5E and F) may account for IFP reduction via ECM reduction.…”

Section: Discussionmentioning

confidence: 99%

“…More than that, abnormal neo-vasculature related to imbalanced angiogenic signals secreted by CAFs serves a bad role to block drug delivery. [16][17][18] Because of these obstacles in the TME, passive targeting nanoparticles may fail to achieve good penetration into the inner part of tumors. Therefore, the targeting at CAFs may help to overcome TME barriers, leading to enhanced nanoparticle delivery efficiency in tumors.…”

Section: Introductionmentioning

confidence: 99%

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

Pang¹,

Li²,

Sun³

et al. 2018

IJN

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BackgroundAbnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression.MethodTo surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells.ResultsDiverse experiments demonstrated that tranilast enhanced DTX-Ms’ antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent.ConclusionOur proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency.

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Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: A computational model

Cited by 26 publications

References 33 publications

Tumor Interstitial Fluid Promotes Malignant Phenotypes of Lung Cancer Independently of Angiogenesis

Tumor Interstitial Fluid Promotes Malignant Phenotypes of Lung Cancer Independently of Angiogenesis

Modelling the transport of fluid through heterogeneous, whole tumours in silico

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

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