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

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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Vascular Endothelial Growth Factor C-Induced Lymphangiogenesis Decreases Tumor Interstitial Fluid Pressure and Tumor

Translational Oncology ◽

10.1593/tlo.13274 ◽

2013 ◽

Vol 6 (4) ◽

pp. 398-404 ◽

Cited By ~ 9

Author(s):

Matthias Hofmann ◽

Ralph Pflanzer ◽

Nadja Nicole Zöller ◽

August Bernd ◽

Roland Kaufmann ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Vascular Endothelial ◽

Tumor Interstitial Fluid ◽

Factor C ◽

Endothelial Growth Factor

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High interstitial fluid pressure in rat tongue cancer is related to increased lymph vessel area, tumor size, invasiveness and decreased body weight

Journal of Oral Pathology and Medicine ◽

10.1111/j.1600-0714.2007.00602.x ◽

2007 ◽

Vol 37 (3) ◽

pp. 137-144 ◽

Cited By ~ 16

Author(s):

Bina Raju ◽

Sivakami Rethnam Haug ◽

Salah Osman Ibrahim ◽

Karin Johanne Heyeraas

Keyword(s):

Body Weight ◽

Tumor Size ◽

Interstitial Fluid ◽

Tongue Cancer ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Lymph Vessel ◽

Vessel Area ◽

Rat Tongue

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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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PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis

Blood ◽

10.1182/blood-2004-04-1485 ◽

2004 ◽

Vol 104 (10) ◽

pp. 3198-3204 ◽

Cited By ~ 100

Author(s):

Marko Uutela ◽

Maria Wirzenius ◽

Karri Paavonen ◽

Iiro Rajantie ◽

Yulong He ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Transgenic Mice ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Macrophage Recruitment ◽

Cell Coating ◽

Vessel Maturation

Abstract Platelet-derived growth factor-D (PDGF-D) is a recently characterized member of the PDGF family with unknown in vivo functions. We investigated the effects of PDGF-D in transgenic mice by expressing it in basal epidermal cells and then analyzed skin histology, interstitial fluid pressure, and wound healing. When compared with control mice, PDGF-D transgenic mice displayed increased numbers of macrophages and elevated interstitial fluid pressure in the dermis. Wound healing in the transgenic mice was characterized by increased cell density and enhanced recruitment of macrophages. Macrophage recruitment was also the characteristic response when PDGF-D was expressed in skeletal muscle or ear by an adeno-associated virus vector. Combined expression of PDGF-D with vascular endothelial growth factor-E (VEGF-E) led to increased pericyte/smooth muscle cell coating of the VEGF-E–induced vessels and inhibition of the vascular leakiness that accompanies VEGF-E–induced angiogenesis. These results show that full-length PDGF-D is activated in tissues and is capable of increasing interstitial fluid pressure and macrophage recruitment and the maturation of blood vessels in angiogenic processes.

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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?

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4043 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4043-4043

Author(s):

M. Dani ◽

B. Vojnovic ◽

R. Newman ◽

D. Honess ◽

I. Wilson ◽

...

Keyword(s):

Rectal Cancer ◽

Interstitial Fluid ◽

Interstitial Fibrosis ◽

Fluid Pressure ◽

Lymphatic Vessels ◽

Interstitial Fluid Pressure ◽

Home Office ◽

Normal Tissues ◽

Needle Technique ◽

And Control

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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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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