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Tumor Biology |
Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 [P. A. N., D. A. B., M. A. S., R. K. J.], and Department of Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [A. J. G.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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In mature tissues, resistance to water and solute transport is generally attributed to the amount of so-called hydrophilic ground substance, predominately GAG (6, 7, 8, 9) . However, it is now appreciated that GAG content alone does not fully account for the high transport resistance presented by many soft tissues (10, 11, 12) . Tumor tissue may possess unique characteristics, attributable in part to an embryonic-like stage of development with extensive synthesis of ECM (13, 14, 15) , which leads to substantial differences in composition and assembly compared with the host tissue (16, 17, 18, 19) . These differences may have important functional consequences. This study explored whether resistance to macromolecule transport in a range of tumors is related to gross differences in tumor ECM composition.
We postulated that anomalous assembly of the collagen network component and its interaction with the proteoglycan component of the tumor ECM could greatly influence the physiological barrier to macromolecule motion posed by healthy tissue ECM. To test this hypothesis, we evaluated the interstitial transport of the proteins IgG and BSA in four different tumor lines and correlated the resistance with ECM structure and composition. As a corollary to this hypothesis, we also tested whether resistance to macromolecule penetration is correlated with the mechanical stiffness of tissue, a property that is also dependent on the fibrillar collagen network and its interaction with the proteoglycans.
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Materials and Methods |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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Mechanical and Fluid Transport Properties
The mechanical and fluid transport parameters of tumor
interstitium were determined by confined compression tests following
the same procedures adopted previously for cartilage (21
, 22)
. The diameter of s.c. tumors used for these measurements
ranged from 7 to 10 mm (15–20 days postimplantation). Slices of
freshly excised tissue, 6 mm in diameter and 0.8–1.6-mm thick, were
placed in a poly(methyl methacrylate) cylindrical confining chamber. A
fitted porous polyethylene platen was placed above to maintain chemical
equilibrium with the physiological saline and to allow interstitial
fluid to flow freely between the tissue and the saline reservoir during
the experiment. The chamber was mounted in an ultrasensitive
servo-controlled materials tester (Dynastat Mechanical Spectrometer;
IMASS, Hingham, MA) as described by Frank and Grodzinsky
(22)
. Each specimen was compressed 25 µm in ramps of
15 s and allowed to relax for 20 min. Ten successive measurements
were performed on each tissue slice. At each step of tissue
compression, the hydraulic conductivity K was estimated from
the transient stress relaxation rate by using a poroviscoelastic model
(see Appendix I) . Fig. 1
shows typical stress relaxation curves obtained for the four different
tumors analyzed. The solid lines are the data fitting obtained with the
model.
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40 µm diameter with an incident power of 30 mW. This pulse
of light creates a darkened photobleached region that subsequently
dissipates as nonfluorescent and fluorescent tracer molecules mix
because of diffusion. The rate of spot dissipation is quantified by
image analysis, and as described previously (23)
, is fit
to a two-component model that assumes a freely diffusing fraction of
fluorescent molecules and an immobile nonspecifically bound fraction. The diffusion coefficients were measured in tumors implanted in dorsal skinfold chambers, 15–17 days postimplantation, when each tumor had reached approximately 3–4 mm in diameter. The probe molecules (500 µg of BSA or 300 µg of IgG in 0.15 ml of sterile PBS) were administered systemically via tail vein. The IgG was a nonbinding monoclonal antibody, S1, of type IgG subclass 1. It was supplied as a gift from Hybritech (San Diego, CA) and prepared by filtration in a size exclusion chromatography column, eluted with isotonic PBS and filter-sterilized. The FRAP measurements for BSA and IgG were performed at 8 and 24 h after injection, respectively. In a different group of HSTS 26T and U87 tumors, diffusion coefficients were determined before and after collagenase treatment. Tumors were treated immediately after the initial determination of IgG mobility. Treatment consisted of a local injection of 0.3 ml of 10% collagenase (from Clostridium, obtained from United States Biochemical Corp., Cleveland, OH) in PBS or, for the control groups, 0.3 ml of saline alone. The diffusion coefficient was measured again 24 h after treatment, and statistical significance of the change was assessed by a two-tailed paired t test.
Determination of the Composition and Structure of Tumor
Interstitial Matrix.
The biochemical analysis for GAG, HA, and collagen content was
performed on s.c. tumors of 7–8 mm diameter. Tumor tissues were
surgically excised from the s.c. tissue of the hind limb, cut in three
pieces, rapidly frozen in liquid nitrogen, and stored at -70°C. Each
piece (40–50 mg) was then used for one of the three analyses. GAG
content was determined by the method described previously
(24)
. Tissues were finely dispersed with a homogenizer
(Polytron; Brinkmann Instrument, Westbury, NY), solubilized in 1 ml of
digest buffer (125 µg/ml papain in 0.1 M sodium
phosphate, 5 mM Na2 EDTA, and 5
mM cysteine-HCl, pH 6.0), and incubated for 18 h at
60°C. Sulfated GAG content was determined with the Blyscan
Proteoglycan and Glycosaminoglycan assay (Biocolor Ltd., Belfast,
Ireland). The total amount of GAG was determined by acids-carbazole
reaction (25)
. The results of both measurements were
expressed as equivalent mass of hexuronic acid. The amount of HA was
estimated as the difference between the total and sulfated GAG
measurements.
To measure total collagen content, 100 ml of papain digest were hydrolyzed in 6 N HCl at 110°C for 18 h. The hydroxyproline content of the hydrolysate was then assessed by colorimetry (26) . Results are expressed as mg of collagen by reference to a standard solution of purified collagen type I (Vitrogen 100; Collagen Corp., Palo Alto, CA) in which a hydroxyproline:collagen ratio of 6.8 was measured.
Three tumors of each group were processed for histological staining. The tissue was embedded in paraffin, and 5-µm sections were cut from the fixed tissue and stained with Masson’s trichrome for collagen or PAS for proteoglycans. The stained sections were observed by transmitted light microscopy with a x40 objective, and images were recorded on color photographic film and subsequently digitized on a flatbed color scanner. The collagen stain images shown here were produced by subtracting the red from the blue channel of the digitized image (Adobe Photoshop software) so that the regions of greatest collagen staining (red absorbance) appear blue.
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RESULTS |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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shows composite equilibrium stress-strain curves for the four different
tumor lines. The elastic moduli shown in Table 1
are calculated from the stress-strain curve at strains <10%
(inset of Fig. 2
). The sarcoma (HSTS 26T) and glioblastoma
(U87) display sequential increases of stress with strain, as is typical
of normal soft tissues (21
, 22)
. The two carcinomas, in
contrast, exhibit viscous behavior typical of a macromolecular solution
rather than a well-structured solid matrix. This is also evident by the
data of Fig. 1
. After each successive compression, the stress measured
in the two carcinomas relaxed down to the initial value, whereas for
the sarcoma and glioblastoma, the stress decayed to a plateau value
higher than the initial value. Fig. 2
indicates that at strains <5%,
the two carcinomas show a virtually infinite compliance (zero slope of
the stress-strain curve), indicating an absence of structural integrity
(Fig. 1
, inset). The hydraulic conductivity of the tumor
tissues was evaluated by fitting the data for stress relaxation after
confined compression (Fig. 1)
. Fig. 3
shows the tissue hydraulic conductivity for the four tumors as a
function of tissue deformation (i.e., hydration). As
expected, the hydraulic conductivity is a strong function of tissue
hydration, according to data reported for other soft tissues
(27)
. The dependence of K on tissue hydration
is well described by an exponential law, in agreement to that suggested
in the literature for soft tissues (28)
and hydrogels
(29)
. To compare our results with those published for
normal tissues, we obtained the hydraulic conductivity of tumor tissues
by extrapolating the data of Fig. 3
to zero deformation. This value
represents the hydraulic conductivity of unstrained tissue. By
comparing our values with a compilation of published values for normal
tissue (27)
, we found that the resistance to water flow in
all but one of the tumors was lower than that of normal tissues of
comparable GAG content.
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100 s; this fraction was attributed to nonspecific binding.
Comparison among the tumor groups revealed no significant difference in
the nonspecific binding. The diffusion rate of the remaining unbound
fraction was observed to depend on the molecule and tumor type. Fig. 4
shows the mean diffusivity of macromolecules in the four different
tumor tissues. The diffusion coefficients in buffered saline solution
alone (+) were also determined. The lines shown in the plot indicate
the power law dependence of diffusion coefficient on macromolecule
radius (DR-n) over a limited range:
the free-solution data fit the Stokes-Einstein hydrodynamic model of
mobility (n = 1); the glioblastoma/sarcoma
group exhibits a much stronger dependence (n = 3) than the carcinoma group (n = 1.5).
Consistent with previous studies, BSA diffused at a modestly hindered
rate that did not differ significantly among tumor types. Although the
mean BSA mobility in the MCaIV and LS174T groups are 10% greater
than in the U87 and HSTS 26T groups, the difference is not significant
given the variance in the data (ANOVA test). However, as indicated in
Table 1
, the diffusion coefficient of the larger IgG molecule is
significantly greater in the two carcinomas (MCaIV and LS174T) compared
with the glioblastoma (U87) and sarcoma (HSTS 26T). The statistical
comparison between tumor types (two-tailed unpaired t test)
is as follows: no significant difference between LS174T
versus MCaIV (P = 0.88) or between
HSTS 26T versus U87 (P = 0.76);
significant differences between LS174T versus HSTS 26T
(P = 0.0027), MCaIV versus HSTS
26T (P = 0.0023), LS174T versus
U87 (P = 0.00044), and MCaIV
versus U87 (P = 0.0002). These
results indicate a correlation between mechanical stiffness and
resistance to movement of macromolecules of tumor tissues.
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shows the total GAG, sulfated GAG, and HA contents of each
tumor. We detected no significant differences in sulfated GAG content
among the tumors. However, HSTS 26T and MCaIV had a higher content of
total GAG and, by inference, HA compared with both U87 and LS174T. When
HA content is calculated as the difference between total and sulfated
GAG, the 2-fold greater value measured for MCaIV and HSTS 26T
compared with LS174T and U87 is statistically significant
(P < 0.05). The significant differences in
HA content, however, are not consistent with the differences seen in
the functional parameters. Altogether, there is poor correlation
between functional properties (resistance to transport or compression;
Table 1
) and GAG or HA content. On the other hand, the total collagen
content of each tissue (Fig. 5B)
does appear to mirror the
measurements of elasticity and IgG mobility. The "rigid" U87 and
HSTS tumors have significantly higher collagen levels compared with the
"soft" carcinoma group.
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shows typical cross-sections of each tumor type stained for collagen.
The U87 and HSTS 26T tumors show more intense staining for collagen
compared with the two carcinomas, consistent with the biochemical data
from Fig. 5
. In addition, it is remarkable to note the apparent absence
of any collagen organization in the two carcinomas, whereas the sarcoma
and glioblastoma instead show apparently well-organized collagen
lattices. A relatively collagen-rich area was evident at the border
between the carcinomas and the host tissue; this "capsule" probably
constitutes the major portion of collagen detected by chemical assay
(Fig. 5B)
in the carcinomas.
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2-fold (Fig. 7)
to the same level observed in the two (untreated) carcinomas (values
shown in Table 1
). Collagenase treatment induced increases in the IgG
interstitial diffusion coefficient by 100% in HSTS 26T
(P < 0.0001) and 80% in U87
(P < 0.05), whereas the control saline
treatment had no significant effect. This observation supports the
hypothesis that an intact collagen network is required for tissue to
effectively resist penetration by macromolecules.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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Tissue collagen composition alone is unlikely to completely control the resistance to transport of macromolecules. It has been reported that collagen gels in vitro exhibit resistances to transport of fluid (34) and macromolecules (35) , which are significantly less than that shown by tissues having the same collagen composition. Our results suggest that the organization of the collagen and the combination of collagen and proteoglycans contribute significantly to the interstitial transport resistance. This hypothesis is also supported by in vitro data showing that composite gels of collagen and hyaluronic acid have a higher resistance to macromolecular transport than gels of collagen or hyaluronic acid alone (36) .
The transport barrier posed by the ECM is particularly important in
tumor because it may prevent the penetration of therapeutic agents. To
assess the role of ECM composition and organization on the penetration
of high molecular weight therapeutic agents, we evaluated the diffusion
hindrance of probe macromolecules (BSA and nonspecific IgG) within the
tumor interstitium in vivo. The data show that resistance to
IgG penetration is related to tumor rigidity and to collagen
organization, as suggested by histology (Fig. 6)
and tested by
collagenase treatment (Fig. 7)
. In contrast, total tissue content of
proteoglycans did not vary substantially among the four tumor types,
and modest differences in HA and total GAG did not correspond to the
observed differences in the tissue functional properties. This result
is supported by published observations of direct intratumoral infusion
of macromolecular solutions in the two of the same tumor types used for
the present study. Boucher et. al (37)
reported
that when a solution of Evans-blue-stained albumin was infused into the
center of LS174T tumors at flow rates of 0.1 µl/min for 90 min, the
dye flowed radially outward from the needle tip into a spherical volume
of 2.5–4.0 mm diameter. In contrast, using the same infusion protocol
in HSTS 26T tumors, they observed a greater resistance to flow,
indicated by a nonuniform distribution of the dye and significant
accumulation in a narrow region around the infusion needle. These data
show that tumors with a well-defined collagen network are more
resistant to penetration by macromolecular drugs compared with tumors
that exhibit a loose collagen network. We propose that macromolecule
access to tumor tissue is dominated by deficiencies in collagen
assembly and relatively insensitive to variations in GAG content.
Degeneration of the collagen network and a resulting compromised
physiological function may be general features of tumors. Proteolytic
remodeling of the ECM may be a requirement for tumor angiogenesis,
growth, invasion, and metastasis (38)
. Moreover, molecular
defects in the assembly process may be associated with the loss of
normal cellular growth regulation mechanisms. For example,
ß1 integrin fibronectin receptor expression
such as 
5ß1 affects
ECM organization and is altered in neoplastic cells
(39, 40, 41, 42)
. Regardless of the reason, ECM organization is
often abnormal in tumors (16
, 17
, 19)
.
The results identify measurable tumor characteristics that could be useful in predicting penetration by therapeutic macromolecules. We suggest that simple histological staining of tumor tissue biopsies can be used to assess the feasibility of therapeutic approaches requiring macromolecule penetration. Delivery of high molecular weight agents should be facilitated in tumors with poorly organized and loosely interconnected collagen networks. In this study, both types of carcinoma exhibit deficient collagen assembly, but in general this trait is probably determined by the interaction of both neoplastic and host cells. Particularly in tumors of epithelial origin, host stromal cells are involved in the production and organization of matrix molecules (43) . Hence, the transport properties of the tumor interstitial matrix likely depend on the site of tumor growth as well as the tumor type.
If "molecular medicine" is to have an impact on cancer treatment, it will be necessary to confront and overcome the delivery problems affecting these novel agents. Modification of the tumor ECM is one strategy that could promote better delivery. Hyaluronidase treatment reportedly enhances chemotherapy of some tumors. However, this approach may not be applicable in systemic treatments, and it is possible that the chemosensitizing effect occurs by mechanisms other than enhanced permeability of the ECM (44) . This study points to collagen as a likely target for modification. A tumor with a well-developed collagen network could be considered "physiologically resistant" to macromolecule-based therapies, but this resistance could be reduced by treatments that reverse or inhibit collagen production and assembly.
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Appendix 1 |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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 |
 | (A1) |
 |
is the drag coefficient;
u
is the displacement of the solid phase;
vf and
u/t
are the local velocities of the fluid
and solid phase, respectively. This equation can also be written as:
 | (A2) |
is the tissue volume fraction and K (=
2/) is the tissue hydraulic conductivity (a
measure of the resistance to water flow). Eq. A2 represents a
generalized Darcy’s law, where the hydrostatic pressure gradient acts
on the relative velocity between the solid and liquid phases, and it
expresses the basic concept of the biphasic theory, i.e.,
the coupling between stress and fluid movement. Indeed, if the
divergence of the solid stress tensor
(
· 
s) is not zero, then a
hydrostatic pressure gradient arises, leading to a relative motion
between the solid and fluid phase.
The mass balance equations for the fluid and solid phase,
respectively, are:
 | (A3) |
 | (A4) |
) is
irrotational (46), it can be described as a perfect fluid,
i.e.:
 |
 | (A5) |
is the deformation tensor,
e is the dilatation of the tissue
), µ
and 
are the Lamé constant, m(t) is the
memory function of the material, and c is a material
constant. The first term is the Laplacian multipliers to take into
account the effect of hydrostatic pressure on the solid matrix; the
second and third terms represent the elastic components of the
mechanical response of the material; and the fourth term takes into
account the effects of viscoelasticity of the matrix. The memory
function can be expressed in terms of the spectrum of relaxation times
of the material [H]:
 |
 | (A6) |
- 
and + are the
shortest and the longest relaxation times, respectively. The parameter
is a measure of the range of the relaxation times. Similar forms of
the relaxation spectrum have been used to describe the viscoelasticity
of soft tissues such as ligaments and skin (48)
.
Combining equations A1
–A4 with the constitutive equations of
the fluid and solid phases, the governing equation in the Laplace space
for a uniaxial geometry results:
 | (A7) |
 | (A8) |
 | (A9) |
is compression displacement at each step (25
µm), t0 is the time required for the
compression step (15 s), and h is the thickness of the
specimen.
Eq. A8
with the boundary conditions (A9) is integrated in the Laplace
space and then numerically converted in the time domain to fit the
experimental data and estimate the parameters K, H, c, and
.
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Appendix 2 |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Outstanding Investigator Grant
R35-CA56591 from the National Cancer Institute (to R. K. J.). 
2 Present address: Department of Material and
Production Engineering, University of Naples ‘Federico II,’ Piazzale
Tecchio, 80, 80125 Napoli, Italy.
3 Present address: School of Pharmacy and
Pharmaceutical Sciences, University of Manchester, Oxford Road,
Manchester M13 9PL, United Kingdom.
4 Present address: Department of Chemical
Engineering, Northwestern University, Evanston, IL 60208.
5 To whom requests for reprints should be
addressed. Phone: (617) 726-4083; Fax: (617) 726-4172; E-mail: jain{at}steele.mgh.harvard.edu
6 The abbreviations used are: ECM, extracellular
matrix; GAG, glycosamingoglycan; FRAP, fluorescence recovery after
photobleaching; HA, hyaluronan; PAS, periodic acid Schiff.
Received 8/26/99. Accepted 3/ 1/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMaterials and MethodsRESULTSDISCUSSIONAppendix 1Appendix 2REFERENCES |
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5ß1 integrin receptor in malignancy. Invasion Metastasis, 14: 87-97, 1994.[Medline]
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) tissues are stiffer than the LS174T (
) and MCaIV
(
) carcinomas. At low strain, the two carcinoma tissues showed
virtually no increase of stress between two successive compressions
(inset), behaving as a macromolecular solution rather
that a mature well-assembled soft tissue. Bars, SE of
all measurements at each compression step.
