Bevacizumab, a vascular endothelial growth factor (VEGF) specific antibody reduces interstitial fluid pressure (IFP) in human rectal cancer xenograft (HT29) by day 5: Is this evidence for rescheduling its timing relative to chemotherapy?

4043 Background: Interstitial fluid pressure (IFP) of most solid tumours is increased relative to normal tissues; this is thought to be associated with the development of structurally and functionally abnormal blood and lymphatic vessels and interstitial fibrosis. Such interstitial hypertension creates a barrier for tumour transvascular transport, consequently compromising the delivery and efficacy of chemotherapy. We investigated the effect of Bevacizumab on IFP of a human rectal cancer xenograft. Methods: SCID mice bearing subcutaneous HT29 tumours of =8.5 mm diameter received a single dose of 10 mg/kg Bevacizumab intraperitoneally; controls received saline. Tumour IFP was measured in sedated mice (Hypnorm) on days 1, 3 and 5 post injection, using the wick-in-needle technique. Experiments were conducted under Home Office licence and approved by the local ethical committee. Results: Groups of 8 treated and control tumours were examined on days 1, 3 and 5 (n = 48). IFP was significantly lower (p<0.0001) on day 5 in treated than control tumours (mean ± SD 15.1 ± 4.7 cf 36.9 ± 5.6 mm Hg). No significant differences (p>0.05) between treated and control groups were seen on day 1 (31.8 ± 3.5 cf 30.6 ± 3.1 mm Hg) or day 3 (33.4 ± 5.5 cf 31.5 ± 3.2 mm Hg). No data were acquired on day 7 as the tumours ulcerated. Conclusions: Our data show that Bevacizumab causes a significant reduction of tumour IFP, but not until 5 days after treatment. Reduced IFP could augment uptake of cytotoxic drugs into tumour cells, hence timing of Bevacizumab relative to the first dose of chemotherapy could be of critical importance. No significant financial relationships to disclose.

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Interstitial fluid pressure: A novel biomarker to monitor photo-induced drug uptake in tumor and normal tissues

Lasers in Surgery and Medicine ◽

10.1002/lsm.22687 ◽

2017 ◽

Vol 49 (8) ◽

pp. 773-780 ◽

Cited By ~ 5

Author(s):

Sabrina Cavin ◽

Xingyu Wang ◽

Matthieu Zellweger ◽

Michel Gonzalez ◽

Michaël Bensimon ◽

...

Keyword(s):

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Drug Uptake ◽

Normal Tissues

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The Solid Mechanics of Cancer and Strategies for Improved Therapy

Journal of Biomechanical Engineering ◽

10.1115/1.4034991 ◽

2017 ◽

Vol 139 (2) ◽

Cited By ~ 46

Author(s):

Triantafyllos Stylianopoulos

Keyword(s):

Tumor Progression ◽

Interstitial Fluid ◽

Solid Mechanics ◽

Fluid Pressure ◽

Lymphatic Vessels ◽

Chemotherapeutic Agents ◽

Interstitial Fluid Pressure ◽

Mathematical Framework ◽

Solid Stress ◽

Stress Levels

Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

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Interstitial fluid pressure, composition of interstitium, and interstitial exclusion of albumin in hypothyroid rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.5.h1627 ◽

2000 ◽

Vol 278 (5) ◽

pp. H1627-H1639 ◽

Cited By ~ 39

Author(s):

Helge Wiig ◽

Rolf K. Reed ◽

Olav Tenstad

Keyword(s):

Thyroid Hormones ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Albumin Concentration ◽

Rat Serum ◽

Interstitial Fluid Volume ◽

Hindlimb Muscle ◽

The Difference ◽

And Control

Lack of thyroid hormones may affect the composition and structure of the interstitium. Hypothyrosis was induced in rats by thyroidectomy 4–12 wk before the experiments. In hypothyroid rats ( n = 16), interstitial fluid pressure measured with micropipettes in hindlimb skin and muscle averaged +0.1 ± 0.2 and +0.5 ± 0.2 mmHg, respectively, with corresponding pressures in control rats ( n = 16) of −1.5 ± 0.1 ( P < 0.001) and −0.8 ± 0.1 mmHg ( P < 0.001). Interstitial fluid volume, measured as the difference between the distribution volumes of 51Cr-EDTA and125I-labeled BSA, was similar or lower in skin and higher in hypothyroid muscle. Total protein and albumin concentration in plasma and interstitial fluid (isolated from implanted wicks) was lower in hypothyroid compared with control rats. Hyaluronan content ( n = 9) in rat hindlimb skin was 2.05 ± 0.15 and 1.92 ± 0.09 mg/g dry wt ( P > 0.05) in hypothyroid and control rats, respectively, with corresponding content in hindlimb skeletal muscle of 0.35 ± 0.07 and 0.23 ± 0.01 mg/g dry wt ( P < 0.01). Interstitial exclusion of albumin in skin and muscle was measured after 125I-labeled rat serum albumin infusion for 120–168 h with an implanted osmotic pump. Relative excluded volume for albumin (Ve/Vi) was calculated as 1 − Va/Vi, and averaged 28 and 28% in hindlimb muscle ( P > 0.05), 44 and 45% in hindlimb skin ( P > 0.05), and 19 and 32% in back skin ( P < 0.05) in hypothyroid and control rats, respectively. Albumin mass was higher in back skin in spite of a lower interstitial fluid albumin concentration, a finding explained by a reduced Ve/Vi in back skin in hypothyroid rats. These experiments suggest that lack of thyroid hormones in rats changes the interstitial matrix again leading to reduced interstitial compliance and changes in the transcapillary fluid balance.

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Integrins and Control of Interstitial Fluid Pressure

Physiology ◽

10.1152/physiologyonline.1997.12.1.42 ◽

1997 ◽

Vol 12 (1) ◽

pp. 42-49 ◽

Cited By ~ 5

Author(s):

RK Reed ◽

K Woie ◽

K Rubin

Keyword(s):

Molecular Biology ◽

Connective Tissue ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Connective Tissues ◽

Adhesion Receptors ◽

Recent Information ◽

Interstitial Volume ◽

And Control

The present review summarizes recent information on the physiology of connective tissues, in particular, control of interstitial fluid pressure (Pif) and, thereby, interstitial volume. A combination of classic physiological techniques and techniques from cellular and molecular biology have provided new insights into control of Pif by connective tissue cells and the adhesion receptors anchoring them to structural connective tissue components.

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Lymphangiogenesis Facilitates Initial Lymph Formation and Enhances the Dendritic Cell Mobilizing Chemokine CCL21 Without Affecting Migration

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.117.309883 ◽

2017 ◽

Vol 37 (11) ◽

pp. 2128-2135 ◽

Cited By ~ 8

Author(s):

Tine V. Karlsen ◽

Tore Reikvam ◽

Anne Tofteberg ◽

Elham Nikpey ◽

Trude Skogstrand ◽

...

Keyword(s):

Transgenic Mice ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Lymphatic Vessels ◽

Interstitial Fluid Pressure ◽

Lymph Vessel ◽

Vessel Area ◽

Lymphatic Network ◽

Factor C ◽

Endothelial Growth Factor

Objective— Lymphatic vessels play an important role in body fluid, as well as immune system homeostasis. Although the role of malfunctioning or missing lymphatics has been studied extensively, less is known on the functional consequences of a chronically expanded lymphatic network or lymphangiogenesis. Approach and Results— To this end, we used K14-VEGF-C (keratin-14 vascular endothelial growth factor-C) transgenic mice overexpressing the vascular endothelial growth factor C in skin and investigated the responses to inflammatory and fluid volume challenges. We also recorded interstitial fluid pressure, a major determinant of lymph flow. Transgenic mice had a strongly enhanced lymph vessel area in skin. Acute inflammation induced by lipopolysaccharide and chronic inflammation by delayed-type hypersensitivity both resulted in increased interstitial fluid pressure and reduced lymph flow, both to the same extent in wild-type and transgenic mice. Hyperplastic lymphatic vessels, however, demonstrated enhanced transport capacity after local fluid overload not induced by inflammation. In this situation, interstitial fluid pressure was increased to a similar extent in the 2 strains, thus, suggesting that the enhanced lymph vessel area facilitated initial lymph formation. The increased lymph vessel area resulted in an enhanced production of the chemoattractant CCL21 that, however, did not result in augmented dendritic cell migration after induction of local skin inflammation by fluorescein isothiocyanate. Conclusions— An expanded lymphatic network is capable of enhanced chemoattractant production, and lymphangiogenesis will facilitate initial lymph formation favoring increased clearance of fluid in situations of augmented fluid filtration.

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Subcutaneous interstitial fluid pressure during external loading

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1981.240.5.r327 ◽

1981 ◽

Vol 240 (5) ◽

pp. R327-R329 ◽

Cited By ~ 3

Author(s):

N. P. Reddy ◽

V. Palmieri ◽

G. V. Cochran

Keyword(s):

Interstitial Fluid ◽

Cuff Pressure ◽

Applied Pressure ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

External Loading ◽

Decubitus Ulcers ◽

Normal Tissues ◽

Fibrous Network ◽

Yorkshire Pigs

Interstitial fluid pressure (IFP) distribution generated as a result of externally applied pressure (EAP) may play an important role in the etiology of decubitus ulcers. In the forelimbs of 10 thiopental sodium-anesthetized Yorkshire pigs, weighing 16-20 kg, we placed wick catheters 2-5 mm below the skin. After equilibration, we applied a pediatric cuff and added EAP. With zero EAP, the IFP was -3.9 +/- 1.4 (SD) mmHg. In each case of EAP, IFP as measured with the wick catheter increased and reached a plateau within 10-15 min. In normal tissues, IFP reached approximately 65-75% of EAP. When we created an edematous condition by preinfusing with excess saline, IFP was found to reach 100% of EAP. The total normal stress in the tissue, generated as a result of external cuff pressure, can be considered as a sum of interstitial fluid pressure and extranormal stress. Integrity of the fibrous network and pore fraction may be important in transmitting pressure to the fluid.

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Micropuncture measurement of interstitial fluid pressure in rat subcutis and skeletal muscle: Comparison to wick-in-needle technique

Microvascular Research ◽

10.1016/0026-2862(81)90014-5 ◽

1981 ◽

Vol 21 (3) ◽

pp. 308-319 ◽

Cited By ~ 83

Author(s):

H. Wiig ◽

R.K. Reed ◽

K. Aukland

Keyword(s):

Skeletal Muscle ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Needle Technique

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Control of interstitial fluid pressure: Role of [beta ]-integrins

Seminars in Nephrology ◽

10.1053/snep.2001.21646 ◽

2001 ◽

Vol 21 (3) ◽

pp. 222-230 ◽

Cited By ~ 42

Author(s):

Rolf K. Reed ◽

Ansgar Berg ◽

Eli-Anne B. Gjerde ◽

Kristofer Rubin

Keyword(s):

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure

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Dynamics of Interstitial Fluid Pressure in Extracellular Matrix Hydrogels in Microfluidic Devices

Journal of Biomechanical Engineering ◽

10.1115/1.4031020 ◽

2015 ◽

Vol 137 (9) ◽

Cited By ~ 5

Author(s):

Joe Tien ◽

Le Li ◽

Ozgur Ozsun ◽

Kamil L. Ekinci

Keyword(s):

Extracellular Matrix ◽

Pressure Distribution ◽

Interstitial Fluid ◽

Scaling Laws ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

External Loading ◽

Interstitial Pressure ◽

Time Resolved ◽

Long Time

In order to understand how interstitial fluid pressure and flow affect cell behavior, many studies use microfluidic approaches to apply externally controlled pressures to the boundary of a cell-containing gel. It is generally assumed that the resulting interstitial pressure distribution quickly reaches a steady-state, but this assumption has not been rigorously tested. Here, we demonstrate experimentally and computationally that the interstitial fluid pressure within an extracellular matrix gel in a microfluidic device can, in some cases, react with a long time delay to external loading. Remarkably, the source of this delay is the slight (∼100 nm in the cases examined here) distension of the walls of the device under pressure. Finite-element models show that the dynamics of interstitial pressure can be described as an instantaneous jump, followed by axial and transverse diffusion, until the steady pressure distribution is reached. The dynamics follow scaling laws that enable estimation of a gel's poroelastic constants from time-resolved measurements of interstitial fluid pressure.

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