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Tumor Biology |
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [Y. B., R. K. J.], and Institute for Physiology, Physiological Chemistry and Animal Nutrition, Ludwig-Maximillians-University, Munich, Germany 80539 [M. Sto., M. Sta.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The equilibration of hydrostatic pressures between the interstitial and
microvascular spaces of tumors coupled with the leaky nature of tumor
vessels suggests that the oncotic pressure in both spaces should also
be similar (1
, 2
, 10)
. Despite its importance in drug
delivery, however, the oncotic pressure of tumor interstitial fluid has
not been measured to date. Estimates of oncotic pressure in tumors are
usually based on the protein content of interstitial fluid obtained
from tumors (1
, 2)
. Gullino et al.
(14)
sampled the interstitial fluid of tumors with a
micropore chamber and found the protein concentration to be 
60% of
the plasma concentration. Sylven and Bois (15)
obtained
interstitial fluid with micropipettes and found the protein
concentration to be higher (between 67 and 97% of plasma values). The
data of Sylven and Bois (15)
suggest that the proteins in
plasma and in the tumor interstitial fluid are close to equilibrium,
whereas the data of Gullino et al. (14)
would
suggest a significant gradient between the two spaces. The reasons for
these differences between these two studies are not clear.
Heterogeneity between tumor lines, and/or different techniques used to
collect the interstitial fluid could explain this discrepancy. For
example, the connective tissue layer formed around the chamber used by
Gullino et al. (14)
could potentially hinder
protein accumulation in the chamber. Similarly, the suction applied by
a micropipette could increase the filtration rate and dilute
interstitial proteins. Thus, a technique is needed to overcome these
potential artifacts.
The goals of the present study, therefore, are: (a) to develop a technique to measure directly the oncotic pressure in the interstitial space of tumors, and (b) to test the hypothesis that the oncotic pressures of the tumor interstitial fluid and plasma are similar. To collect interstitial fluid, multifilamentous wicks were implanted at the time of tumor inoculation (chronic wicks) or once the tumor had grown to a size of 8–10 mm (acute wicks). The oncotic pressure of the collected wick fluid was measured with a colloid osmometer. To understand differences in oncotic pressure values between normal and tumor tissues, total protein concentration and the molecular weight distributions of proteins in the wick fluid were characterized with a commercial kit and SDS-gel electrophoresis, respectively.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Colloid Osmometer.
A membrane colloid osmometer for measurements in samples as small as 5
µl was used (16)
. Amicon PM10 (Beverly, MA)
membrane with a molecular weight cutoff of
Mr 10,000 was inserted. The proteins
in the sample chamber create hypotension in the reference fluid
chamber, which is recorded via the pressure transducer (model P23XL,
Spectramed Inc., Oxnard, CA) and is equivalent to the oncotic pressure.
Plasma Oncotic Pressure.
To our knowledge, the oncotic pressure of mice plasma has never been
measured. Therefore, we characterized the plasma oncotic pressure
systematically and designed experiments to control for the influence of
anesthesia and repeated blood sampling. Three experimental groups were
compared. In group I (n = 5), four blood
samples were taken at t = 0, 0.5, 1, and
8 h from the venous sinus of the eye. From animals of group II
(n = 4), blood was taken at
t = 0 h, and mice were then anesthetized
with a mixture of ketamine (80 mg/kg body weight) and xylazine
(12 mg/kg body weight). Blood samples were obtained at
t = 0.5, 1, and 8 h. Mice were waking up
after 1 h and had completely recovered from anesthesia after
8 h. The animals of group III (n = 5)
were treated like those of group II with the only difference that there
was no blood sampling before anesthesia; the first blood sample was
obtained 30 min after anesthesia. Forty µl of blood were taken from
the venous sinus of the eye using heparinized glass capillary tubes and
transferred to 2 ml centrifuge tubes. After centrifugation for 5 min at
400 g, 5–10 µl of plasma were used for measurement of oncotic
pressure.
Interstitial Fluid Oncotic Pressure.
Oncotic pressure was determined in tumor interstitial fluid collected
with a wick technique (17)
. Interstitial fluid was sampled
with three-stranded nylon wicks (1 mm in diameter; Enkalon, Arnheim,
the Netherlands) prewashed in acetone, ethanol, and distilled water.
Saline-soaked acute wicks were inserted in the tumor tissue. Chronic
wicks were implanted simultaneously with the tumors. At the end of the
implantation period, the wick ends along with any bloodstained portions
were cut off, and the remaining sections were transferred to 2-ml
centrifuge tubes provided with a funnel-shaped wick support
(18)
. The wicks were centrifuged in an Eppendorf table
centrifuge (model 5415 C, Eppendorf-Nethler-Hinz GmbH, Hamburg,
Germany) for 10 min at 16,000 g. The 5–10 µl of wick fluid obtained
were used for an oncotic pressure measurement in the above-described
colloid osmometer.
Electrophoresis of Plasma and Wick Fluid.
Total protein concentration was determined by a micro protein
determination kit (Sigma, St. Louis, MO). The molecular weight
distribution of proteins was characterized after separation of proteins
by SDS-gel electrophoresis. Gels were stained with Coomassie blue and
scanned on a Bio-Rad densitometer (model GS-670; Bio-Rad Laboratories
Inc., Richmond, CA).
Data Analysis.
All values are presented as mean ± SD. One-way ANOVA was
performed to test whether groups differed more than by chance. If the
ANOVA was significant (P < 0.05), Dunnett’s
multiple comparison test was applied to determine the groups that were
significantly different.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Fig. 1
) of awake mice was 20.9 ± 1.8 mm Hg (t = 0; n = 9; the data of groups I and II
at t = 0 were combined). In group I, oncotic
pressure of plasma decreased by 12%, 15%, and 14% after 30 min, 60
min, and 8 h, respectively. After anesthesia (group II), oncotic
pressure of plasma decreased further by 17%, 23%, and 13% after 30
min, 60 min, and 8 h, respectively. In the last group (group III),
there was a similar decrease of plasma oncotic pressure (24% after 30
min, 28% after 60 min, and 16% after 8 h). Thus, to minimize the
changes in oncotic pressure induced by anesthesia and blood collection,
the oncotic pressure data were obtained from only one puncture of the
venous sinus of the eye of nonanesthetized mice. Oncotic pressure in
blood plasma of mice without tumors was 20.9 ± 1.8 mm Hg
(n = 9); oncotic pressure in blood
plasma of tumor-bearing mice used for optimization of
interstitial fluid sampling was 20.3 ± 1.5 mm Hg
(n = 22); and oncotic pressure in blood
plasma of mice with the different tumor types was 19.9
± 1.7 mm Hg (n = 129). The mean
of all these data is 20.0 ± 1.6 mm Hg
(n = 160). Tumor-bearing animals had slightly
reduced plasma oncotic pressures compared with mice without tumors, but
the difference was not significant (two-tailed t test;
P < 0.07).
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). Oncotic pressures were high in tumor tissue of dead mice (21.6
± 1.5 mm Hg; n = 5; 60-min
sampling) and after short sampling times (after 10 min: 19.6
± 3.2 mm Hg, n = 6; after 30 min:
21.4 ± 2.3 mm Hg, n = 6; after 60
min: 21.0 ± 4.7 mm Hg, n = 6) and
decreased with longer sampling times (after 120 min: 17.9 ±
4.1 mm Hg, n = 5; after 24 h: 17.5
± 1.1 mm Hg, n = 4). The detected
differences were not significant, which is probably attributable to the
small sample size. The lowest values were measured with chronic wicks
[16.7 ± 3.0 mm Hg; n = 12;
significantly different from 30-min sampled acute wicks and
interstitial fluid collected from dead tumor tissue
(P < 0.05), respectively; Fig. 2
].
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. Oncotic pressures in subcutis (P < 0.001)
and LS174T (16.7 ± 3.0 mm Hg; n = 12; P < 0.05) were significantly
lower than the oncotic pressure of plasma. However, the oncotic
pressure of the three other tumor types and plasma were not
significantly different: RD: 24.2 ± 4.7 mm Hg,
n = 7; FADU: 19.9 ± 1.9 mm
Hg, n = 13; 54 A: 21.1 ± 2.8
mm Hg, n = 20. The oncotic pressure was
significantly lower in LS174T compared with RD (P < 0.001), FADU (P < 0.05), as well as
54 A (P < 0.001).
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Protein Fractions in Plasma and Interstitial Fluid of Tumor and
s.c. Tissue.
According to their electrophoretic mobility, the proteins
(concentration in g/100 ml) were categorized in four different
molecular weight intervals (Table 2
; Fig. 4
). The larger proteins (>Mr
75,000) are present in the highest concentration in blood plasma. As a
consequence of their reduced penetration across the vascular wall and
because of their high osmotic reflection coefficient at the
microvascular wall, they are significantly lower in the subcutis. The
gradient between plasma and tumor is smaller because of the high
vascular permeability of tumor blood vessels. The same pattern is found
in the next two fractions (Mr
75,000–50,000 and 50,000–25,000), with a significant gradient for
subcutis. With further reduction in protein size, the pattern is
opposite; the concentration of small proteins is highest in tumor
interstitial fluid.
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). The albumin-containing fraction
(Mr 75,000–50,000) of LS174T is lower
than 54A (P < 0.01) and RD
(P < 0.05). The small protein fraction
(<Mr 25,000), however, is similar
between tumor types. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Effect of Anesthesia and Repeated Bleeding on Oncotic Pressure.
We measured the plasma oncotic pressure (Fig. 1
) in awake mice without
tumors to be 20.9 ± 1.8 mm Hg. In awake mice, plasma
oncotic pressure decreased with repeated blood sampling (Fig. 1
). After
anesthesia, plasma oncotic pressure decreased further (Table 1
; Fig. 1
). The effect of anesthesia and blood volume withdrawal can be
explained by a reduction in mean arterial blood pressure leading to an
increase in fluid reabsorption across the microvascular wall.
Therefore, repeated blood sampling and anesthesia should be avoided for
the measurement of plasma oncotic pressure of mice using blood sampled
from the venous sinus of the eye. As a result, plasma oncotic pressure
was measured as a control parameter, in all tumor experiments, without
anesthesia and with a single puncture of the venous sinus of the eye:
19.9 ± 1.7 mm Hg, n = 129
(Fig. 1
). This value is similar to the plasma oncotic pressure of most
species, which is typically around 20 mm Hg (23
, 24)
.
Effect of Sampling the Interstitial Fluid.
The published results on interstitial fluid composition are
controversial because of methodological problems as well as the
heterogeneity of tumors (1
, 2)
. Three methods have been
used to collect fluid from the interstitial space: direct sampling
using needle or micropipettes; implanted wicks; and a chronically
implanted micropore chamber. Each method has its own limitations. The
puncturing of tissue with the direct sampling method causes cellular
and vascular damage; as a result, the collected fluid may be a mixture
of vascular, cellular, and pericellular fluids. Furthermore, the
applied suction may increase net capillary filtration and lower the
concentration of interstitial proteins. The micropore chamber may
influence the structure of the surrounding tissue; the chamber fluid
may not represent interstitial fluid because of hindered transport
across the micropore membrane or the surrounding connective tissue
layer. Consequently, we decided to use the wick technique to collect
fluid from the tumor interstitium. One problem of this method is that
artificially high protein concentrations in the wick fluid can be
caused by the wick insertion provoking bleeding or local inflammation,
and thus increasing microvascular permeability to proteins. On the
other hand, hyperemia with increased capillary pressure and without
change of microvascular permeability increases filtration rate and
produces lower interstitial protein concentrations than normal.
The influence of bleeding can be easily excluded by cutting the blood-stained parts of the wicks. Two approaches were chosen to control for increased protein concentrations resulting from local inflammation: (a) comparison with dead tumor tissue, and (b) comparison of different sampling times. Oncotic pressures were elevated in dead tissue and after short sampling times. This could be attributable to the loss of cell membrane integrity with release of intracellular proteins in dead tissue and the occurrence of temporary inflammation after short sampling times. This problem is probably less significant or absent with longer sampling times or chronic wicks. The oncotic pressure in chronic wicks of 16.7 mm Hg for LS174T is 82% of the blood oncotic pressure, which is higher than the interstitial oncotic pressure of s.c. tissue, which is 41% of the plasma value.
The approach used here has two limitations: Protein distribution in the interstitium is heterogeneous, and, thus, may lead to microscopic heterogeneities in the oncotic pressure. Furthermore, the oncotic pressure of systemic blood may not be equal to that in tumor microvessels. A more microscopic technique is needed to address these two issues.
Protein Distribution in the Tumor Interstitial Fluid.
Sylven and Bois (15)
and Gullino et al.
(14)
found a significantly increased protein concentration
in tumor interstitial fluid compared with normal tissue. The data of
Sylven and Bois (Ref. 15
; 4.9 g/100 ml in
Ehrlich-Landschütz carcinoma and 5.5 g/100 ml in a mammary
carcinoma) are closer to the present study (5.3 g/100 ml) than the data
of Gullino et al. (Ref. 14
; 3.2 g/100 ml, mean of four
tumor types). However, in the data of Gullino et al. (14)
,
the albumin concentrations in the fibrosarcoma 4956 and the Novikoff
hepatoma were 1.55 and 1.65 g/100 ml, respectively, which are similar
to our value of 1.54 g/100 ml in the LS174T tumor. The total protein
content of the three tumors included in our study was similar to
plasma. For the LS174T tumors, the total protein content was 12% lower
and for RD, 20% higher than in plasma. This higher total protein
content could result from difference in small proteins with
<Mr 25,000, which were found to be
2- to 4-fold higher in the interstitial fluid of tumors than in
plasma (Fig. 4A
).
Mechanisms of High Oncotic Pressure in Tumors.
The larger proteins (>Mr 75,000) are
found in the highest concentration in blood plasma. As a consequence of
their reduced penetration across the vascular wall, they are
significantly lower in the subcutis. The gradient between plasma and
tumor is smaller because of the high vascular permeability of tumor
blood vessels and the absence of functional lymphatic vessels in
tumors. The same pattern is found in the next two protein fractions
(Mr 75,000–50,000 and
Mr 50,000–25,000), with a significant
gradient for the subcutis. In contrast, for the smaller molecular
weight fraction, a higher concentration of protein was found in tumor
interstitial fluid than in plasma. The smaller proteins could be
breakdown products from necrotic areas or other tumor cell-derived
proteins. Recent studies have shown that the presence of a tumor can
induce antiangiogenic molecules, which are proteolytic fragments of
larger proteins. The molecular size of known antiangiogenic molecules
resulting from enzymatic fragmentation, like vasculostatin, prolactin,
and endostatin, varies between Mr
13,000 and Mr 20,000
(25)
. Some of the matrix-degrading enzymes released by
tumor cells are also <Mr 25,000.
Cellular enzymes can be released into tumor interstitial fluid
(15)
. Because the identity and molecular weight of
different proteins in the tumor interstitium are not known, calculating
oncotic pressure from the total protein concentration using empirical
equations becomes difficult. Therefore, we chose to measure the oncotic
pressure in tumor directly.
The difference between the measured oncotic pressure and the physiologically relevant oncotic pressure difference across the vascular wall must also be considered. Using the oncometer with a molecular cutoff size of Mr 10,000, all proteins with a molecular weight >Mr 10,000 contribute to the measured oncotic pressure independently of their individual size. But the physiologically relevant oncotic pressure difference across vascular wall is dependent on the molecular weight of each protein. Because small macromolecules can permeate the vascular wall more easily and quickly, their contribution to the effective oncotic pressure is less as compared with larger macromolecules (1) . Interestingly, the difference in oncotic pressure between plasma and interstitial fluid in LS174T is in agreement with the significant hydrostatic pressure difference (2.0 mm Hg) between the microvascular and interstitial space in that tumor (11) . In two other tumor types, the microvascular and IFPs were similar (10 , 11) . Thus, it is likely that the oncotic pressure measured in LS174T is close to the effective oncotic pressure.
Conclusion.
This is the first study describing a method of direct measurement of
oncotic pressures in tumor interstitium. The results indicate that long
sampling times are required for acute wicks; when chronic wicks are
used, the risk of artifacts attributable to cellular damage or
bleeding during wick introduction is avoided. The high oncotic pressure
is consistent with the elevated vascular permeability and IFP in
tumors. This equilibration of oncotic and hydrostatic pressures across
tumor vessels may reduce the convective delivery of macromolecules in
large regions of solid tumors (12)
.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Outstanding Investigator Grant
R35-CA-56591 from the National Cancer Institute (to R. K. J.). 
2 To whom requests for reprints should be
addressed, at Massachusetts General Hospital, Department of Radiation
Oncology, Cox-7, Boston, MA 02114. Phone: (617) 726-4083; Fax: (617)
726-4172; E-mail: jain{at}steele.mgh.harvard.edu
3 The abbreviation used is: IFP, interstitial
fluid pressure.
Received 1/27/00. Accepted 5/30/00.
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REFERENCES |
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