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High interstitial fluid pressure — an obstacle in cancer therapy

Key Points

  • Transcapillary flow, which is important for tissue homeostasis, is influenced by the hydrostatic and colloid osmotic pressures of capillaries and interstitium.

  • The interstitial fluid pressure (IFP) of normal tissues is actively regulated through interactions between stromal cells and the extracellular-matrix molecules.

  • Most solid tumours have increased IFP.

  • The reasons for increased tumour IFP include blood-vessel leakiness, lymph-vessel abnormalities, interstitial fibrosis and a contraction of the interstitial matrix mediated by stromal fibroblasts.

  • Increased tumour IFP causes inefficient uptake of therapeutic agents.

  • Lowering of tumour IFP — for example, by certain cytokine antagonists — can improve drug uptake and thereby improve treatment efficiency.

Abstract

Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

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Figure 1: Forces that regulate transcapillary transport in tissues.
Figure 2: Structural differences between normal and tumour tissues that affect interstitial fluid pressure.

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Acknowledgements

The authors thank I. Schiller for skilful help in the preparation of this manuscript. Work in the authors laboratories were, in part, supported by funds from the Swedish Cancer Society. The authors also thank editors and anonymous reviewers for valuable suggestions.

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Correspondence to Carl-Henrik Heldin.

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DATABASES

Cancer.gov

breast cancer

cervical cancer

colorectal cancer

head and neck cancer

melanoma

Entrez Gene

ANG1

PDGF

PDGFRβ

TGFβ

TNFα

VEGF

FURTHER INFORMATION

Ludwig Institute for Cancer Research Uppsala Branch

Glossary

COLLOID OSMOTIC PRESSURE

A pressure built up by the tendency of water to diffuse through a semipermeable membrane into a compartment with higher concentration of high-molecular-weight molecules, like proteins, that are unable to pass through the membrane.

HYDRAULIC CONDUCTIVITY

A measure of the permeability of the vessel wall for water.

PROTEIN REFLEXION COEFFICIENT

A measure of the impermeability of the capillary vessel wall for proteins.

STARLING'S FORCES

Starling's hypothesis describes the transcapillary fluid flux, Jv, as Jv = Lp × S × ΔP, where Lp is the hydraulic conductivity of the capillary membrane and S is the surface area for exchange. ΔP is the net pressure difference determined by ΔP = (PCAP − PIF) − σ(COPCAP − COPIF), where PCAP and PIF are the hydrostatic pressures in capillaries and interstitium, respectively; COPCAP and COPIF are the colloid osmotic pressures of capillaries and interstitium, respectively; and σ is the plasmaprotein reflexion coefficient for proteins.

INTEGRINS

Transmembrane receptors, consisting of different combinations of α- and β-subunits. Many bind different extracellular-matrix proteins, such as collagen, fibronectin and laminin.

HYALURONAN

A large linear polysaccharide of repeating disaccharide units. It crosslinks proteoglycans and so contributes to the elasticity of tissues.

PERICYTES

Mural cells present in capillaries and venules that are embedded in the basal lamina and also form close contact with endothelial cells. Pericytes are recruited to blood vessels by PDGF-BB produced by endothelial cells.

ANGIOTENSIN II

A short peptide that, after cleavage from its precursor, binds to a G-protein-coupled receptor present on vascular smooth muscle cells and increases the blood pressure.

DNA APTAMER

A DNA molecule of 20–40 nucleotides, obtained by a repeated selection procedure, which specifically binds other molecules with high affinity.

HYDROXYPROLINE

A post-translationally modified amino acid, hydroxylated proline, often detected in collagen.

51Cr-EDTA

A low-molecular-weight compound that is widely used as a tracer for extracellular fluid. It is not taken up by cells and distributes freely between blood and interstitial fluids.

MICRODIALYSIS

A method to determine transport of low-molecular-weight compounds from blood to tissues. A small dialysis probe, usually about 0.3 × 5 mm is inserted in the tissue and connected to a pump. The concentration of the low-molecular-weight compound in the dialysate is determined and related to the concentration in blood.

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Heldin, CH., Rubin, K., Pietras, K. et al. High interstitial fluid pressure — an obstacle in cancer therapy. Nat Rev Cancer 4, 806–813 (2004). https://doi.org/10.1038/nrc1456

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