Interstitial fluid pressure in intracranial tumours in patients and in rodents

Abstract

Summary Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 ± 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.Keywords: interstitial fluid pressure; microvascular pressure; brain tumours in rodents; intracranial tumours in patients; antioedema therapy Studies from our group and other investigators have shown that the interstitial fluid pressure (IFP) of human tumours in situ is significantly elevated compared with normal tissues Roh et al, 1991;Gutmann et al, 1992;Less et al, 1992;Curti et al, 1993;Arbit et al, 1994;Nathanson and Nelson, 1994). In most normal tissues the IFP is around 0 mmHg while for the different carcinoma types measured to date the mean IFPs vary between 14 and 30 mmHg. In general, in human and experimental tumours the IFP increases with tumour size (Jain, 1987a;Boucher et al, 1990Boucher et al, , 1991Boucher et al, , 1995Gutmann et al, 1992;Lee et al, 1992;Nathanson and Nelson, 1994). However, in other studies, the IFP was found to be independent of the tumour volume (Less et al, 1992;Curti et al, 1993;Boucher et al, 1995;Tufto and Rofstad, 1995;Znati et al, 1996). Measurements in experimental tumours have demonstrated that (1) the IFP is uniform throughout the centre of tumours and drops steeply in the tumour periphery or in the normal tissue surrounding the tumour (Boucher et al, 1990;Boucher and Jain, 1992;DiResta et al, 1993) and (2) that the hydrostatic and oncotic pressures in the vascular and interstitial space are at or close to equilibrium Jain, 1989, Boucher andStohrer et al, 1995). The similarity in hydrostatic pressures between the microvascular and interstitial space is thought to be a major mechanism limiting the convective delivery of large therapeut...

Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor

“…The precise mechanism of this enlarged distribution after steroid use is not clear, however, dexamethasone may decrease the interstitial pressure and may provide better conditions for CED. Boucher et al (1997) demonstrated that the treatment with dexamethasone, mannitol, and fluosemide decreased the interstitial pressure in rodent intracranial tumor model. In this context, Yang et al (2014) demonstrated that pre-treatment with dexamethasone alone or in combination with mannitol and fluosemide increased the tumor carboplatin concentrations after intra-tumoral CED of carboplatin.…”

Molecular Mechanisms of Tumor Angiogenesis

“…20 The chaotic structure of the vasculature, poor smooth muscle cell/pericyte coverage, and the dysfunctional ability of the endothelium to transport fluid create a high intratumoral pressure that perpetuates difficulties in perfusion of the growing tumor. [23][24][25] Due to the hyperpermeability of tumor vessels and the focal leaks often seen in tumor vessels, blood flow rates are reduced as measured by red blood cell velocity. 20,26 Studies have shown that tumors often have increased interstitial pressure 23 and that they can affect the interstitial pressure of surrounding normal tissue.…”

“…20,26 Studies have shown that tumors often have increased interstitial pressure 23 and that they can affect the interstitial pressure of surrounding normal tissue. 25 Hydraulic conductivity studies using intratumoral injection of Evans blue dye into tumor centers have shown that tumors vary in their resistance to fluid flow. 24 This resistance could be relieved using hyaluronase to hydrolyze the ECM, demonstrating that tumoral ECM composition and density influence interstitial pressure.…”

Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism

“…Recently, Iliff and colleagues delineated mechanisms of fluid drainage from the brain indicating that fluid flow pathways in perivascular spaces act like a brain lymphatic system clearing the brain interstitium (14). When a brain tumor develops, the flow patterns are disrupted because of tumor fluid drainage, cyst development, and edema-associated heightened interstitial pressures in the tumor as compared with the surrounding brain leading to flow from the tumor bulk (15,16). Tumors originating further from white matter tracts (conduits for fluid flow) have a better prognosis (17).…”