Tumors interstitial fluid

Diffusion in the interstitial space is closely related to the volume fraction of space that is available to fluid and solute transport in tissues. The volume fraction of tumor interstitial fluid space varies from 15% in human gliomas up to 60% in a rat fibrosarcoma 4956 (Jain, 1987). The available volume fraction (KAV) of solutes is a measure of the steady state ratio of drag concentrations between tissues and the plasma (Krol et al., 1999). Thus, drug and gene delivery can be significantly improved through increasing KAV. In ex vivo experiments, KAV determines the ratio of concentrations between tissues and external solutions at the equilibrium state. KAV has been studied extensively in normal tissues but poorly in tumor tissues (Table 20.1) (Krol el al., 1999). KAV depends on the size of solutes and the dependence is determined by both the size and the connectedness of pores (Yuan et al., 2001). 

Another feature of tumors that can have a major impact on the distribution of targeted radiotherapeutics is tumor interstitial fluid pressure. Interstitial fluid pressure results in a pressure gradient that can inhibit the delivery of molecules from the plasma to the extracellular fluid in central regions of a tumor. Tliis pressure gradient is not present in normal tissues because they have a lymphatic system however, tumors do not, creating an additional barrier that must be overcome. Experimental evidence of an elevated interstitial pressure in murine tumor models has been reported by Boucher et al. (1990). As expected, the effect was most apparent at the tumor periphery. Using a mathematical model, the magnitude of this outward convection fluid flow was predicted to be 0.1-0.2 pm/s (Jain and Baxter 1988). 

Celis, J.E., et al. (2004) Proteomic characterization of the interstitial fluid perfusing the breast tumor microenvironment a novel resource for biomarker and therapeutic target discovery. Mol Cell Proteomics. 3, 327 4. 

The velocity of interstitial fluid in solid tumors is often lower than the resolution of experimental techniques, which is 0. lpm/sec, except in some special tumor models. For example, Chary and Jain (1989) have examined interstitial fluid velocity in granulation tissues and VX2 mammary carcinoma grown in rabbit ear chambers, using the fluorescence recovery after photobleaching (FRAP) technique. The average velocities in both tissues are about 0.6 pm/sec. 

The physical factors include mechanical stresses and temperature. As discussed above, IFP is uniformly elevated in solid tumors. It is likely that solid stresses are also increased due to rapid proliferation of tumor cells (Griffon-Etienne et al., 1999 Helmlinger et al., 1997 Yuan, 1997). The increase in IFP reduces convective transport, which is critical for delivery of macromolecules. The temperature effects on the interstitial transport of therapeutic agents are mediated by the viscosity of interstitial fluid, which directly affects the diffusion coefficient of solutes and the hydraulic conductivity of tumor tissues. The temperature in tumor tissues is stable and close to the body temperature under normal conditions, but it can be manipulated through either hypo- or hyper-thermia treatments, which are routine procedures in the clinic for cancer treatment. 

Griffon-Etienne, G., Boucher, Y., Brekken, C., Suit, H.D. and Jain, R.K. (1999) Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors clinical implications. Cancer Res., 59, 3776-3782. 

Soluble Serum, interstitial fluid, urine, CSF, other body fluids Cytokines, chemokines, complement factors, shed tumor antigens Little to unknown... 

Fig. 2 Continued, (c) These macromolecules move toward the center by the slow process of diffusion (=>). In addition, interstitial fluid oozing from tumor carries macromolecules with it by convection (- ) into the normal tissue. Note that the interstitial movement may be further retarded by binding. Products of metabolism may be cleared rapidly by blood. (Reproduced with permission from Jain, 1989.) These transport processes have been mathematically modeled by Jain and Baxter (1988) and Baxter and Jain (1989, 1990, 1991a, b).

Fig. 6. (a) Interstitial pressure gradients in the mammary adenocarcinoma R3230AC as a function of radial position. The circles ( ) represent data points (Boucher et al., 1990), and the solid line represents the theoretical profile based on our previously developed mathematical model (Jain and Baxter, 1988 Baxter and Jain, 1989). Note that the pressure is nearly uniform in most of the tumor, but drops precipitously to normal tissue values in the periphery. Elevated pressure in the central region retards the extravasation of fluid and macromolecules. In addition, the pressure drop from the center to the periphery leads to an experimentally verifiable, radially outward fluid flow. (Reproduced from Boucher et al., 1990, with permission.) (b) Microvascular pressure (MVP) in the peripheral vessels of the mammary adenocarcinoma R3230AC is comparable to the central interstitial fluid pressure (IFP) (adapted from Boucher and Jain, 1992). These results suggest that osmotic pressure difference across vessel walls is small in this tumor. 

Interstitial fluid pressures in normal tissues are approximately atmospheric or slightly sub-atmospheric, but pressures in tumors can exceed atmospheric by 10 to 30mmHg, increasing as the tumor grows. For 1-cm radius tumors, elevated interstitial pressures create an outward fluid flow of 0.1 fim/s [11]. Tumors experience high interstitial pressures because (i) they lack functional lymphatics, so that normal mechanisms for removal of interstitial fluid are not available, (ii) tumor vessels have increased permeability, and (iii) tumor cell proliferation within a confined volume leads to vascular collapse [12]. In both tissue-isolated and subcutaneous tumors, the interstitial pressure is nearly uniform in the center of the tumor and drops sharply at the tumor periphery [13]. Experimental data agree with mathematical models of pressure distribution within tumors, and indicate that two parameters are important determinants for interstitial pressure the effective vascular pressure, (defined in Section 6.2.1), and the hydraulic conductivity ratio, (also defined in Section 6.2.1) [14]. The pressure at the center of the tumor also increases with increasing tumor mass. 

Sylven. B. Lysosomal enzyme activity in the interstitial fluid of solid mouse tumor transplants. Eur. J. Cancer. 4 463-474.1968. Szent-Gydrgyi. A. Observations of the functions of peroxidase systems and the chemistry of the adrenal cortex. Biochem. J.. 22 1387-1409, 1928. 

Interstitial Fluid Pressure and Convective Currents into the Interstitial Space of Tumors 57... 

Increased vascular permeability has been demonstrated, with extravasation of blood plasma expanding the interstitial fluid space and— because of the lack of functional lymphatics— drastically increasing the hydrostatic pressure in the tumor interstitium. 

The tumor interstitial space is three to five times larger than in most normal tissues and contains a relatively large quantity of mobile (i.e., freely moving) fluid. 

Inadequate lymphatic drainage in the tumor center Interstitial fluid flow Interstitial hypertension... 

Fig. 4.4. Mean relative volumes of the intracellular fluid, the vascular compartment, and the interstitial fluid space in malignant tumors (rightpanel) and in normal tissue (leftpanel, adapted from Vaupel 1994a)...

After seeping copiously out of the highly permeable tumor microvessels—an equilibrium is reached when the hydrostatic and oncotic pressures within the microvessels and the respective interstitial pressures become equal—fluid accumulates in the tumor extracellular matrix and a high interstitial fluid pressure (IFP) builds up in sohd tumors (Young et al. 1950 Gutmann et al. 1992 Less et al. 1992 Milosevic et al. 2001,2004). 

Table 43. Interstitial fluid pressure in normal tissues and in human tumors ...

Fig. 4.5. Interstitial fluid flow (IFF) as a function of blood flow (TBF) in xenografted human ovarian cancers (lowerpart). Schematic representation of convective fluid currents in normal and tumor tissues (upper part adapted from Vaupel 2004b)...

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