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Tumor Biology |
Cell Biology Laboratory, Department of Gynecology and Obstetrics [A. E., S. K., V. G., H. G. A.] and Department of Pathology [B. H.], University of Göttingen Medical School, 37075 Göttingen, Germany, and Department of Neuropathology, Erlangen-Nürnberg University Medical School, 91054 Erlangen, Germany [K. H. P.]
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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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Despite the enormous efforts aimed at elucidating the molecular determinants of angiogenesis (8, 9, 10) and the intense search for natural and synthetic angiogenesis inhibitors (4 , 6) , surprisingly little is known about the nature of the vascular bed in human tumors. Almost all of the studies that have assessed endothelial cell turnover in tumors were performed in experimental animal models with rapidly growing tumors whose growth kinetics are vastly different from the growth kinetics of human tumors (11 , 12) . In fact, the few endothelial cell turnover studies that have been performed in human tumors do suggest that endothelial cell proliferation in these tumors is detectable, albeit at a relatively low rate (13, 14, 15, 16) . Average tumor endothelial cell proliferation indices of 0.15% have been reported for prostatic carcinomas (13) . The endothelial cell labeling index in mammary carcinoma varies between 2.2% (14) and 2.7% (15) , and a value as high as 9.9% has been reported for colorectal adenocarcinomas (16) .
As early as 1972, Brem et al. (17) proposed a microscopic angiogenesis grading system to assess the angiogenic status of the tumor vasculature. Based on the analysis of the vascular density, the number of endothelial cell nuclei, and the cytological properties of tumor-associated endothelial cells, an angiogenesis score was determined and used to establish an angiogenic rank order of different human brain tumors (17) . In recent years, the vascular bed of human tumors has been characterized extensively by performing MVD4 counting studies (18 , 19) . These studies have revealed that high MVD counts within vascular hot spots of tumors correspond with a poor prognosis for the patient. MVD studies using panendothelial cell markers reflect the vascular status of a tissue, i.e., the presence of blood vessels. However, they do not give an indication of the angiogenic status of a tissue vascular bed, i.e., the rate of ongoing angiogenesis and the functional status of tumor neovasculature. To more realistically assess the angiogenic status of the vasculature within human tumors, the present study was aimed at functionally analyzing the properties of the tumor vascular bed. Based on the analysis of tumor endothelial cell proliferation and pericyte recruitment, angiogenesis and the functional status of the tumor microvascular bed were quantitated in six different types of malignant human tumors. These findings were compared with the angiogenesis kinetics in the cyclic ovarian corpus luteum, one of the few organ sites in the adult with significant physiological angiogenesis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Staining of Proliferating Endothelial Cells.
A double-labeling immunohistochemical technique was used to
simultaneously stain nuclei of proliferating cells and endothelial
cells. Deparaffinized and rehydrated sections (4 µm) were microwaved,
endogenous peroxidase was blocked, and sections were incubated with an
antibody to PCNA (clone PC10; 1:100 dilution; final concentration, 3.9
µg/ml; Dako, Hamburg, Germany; 60 min, room temperature) or Ki67
(clone MIB1; 1:10 dilution; final concentration, 20 µg/ml; Dianova,
Hamburg, Germany; 60 min, room temperature). A biotinylated secondary
antibody, streptavidin alkaline phosphatase complex, and nitroblue
tetrazolium as a substrate (Zymed, South San Francisco, CA) were used
to visualize binding of the first antibody. Single-color-stained tissue
sections were incubated with double-staining enhancer (Zymed) for 30
min, and then endothelial cells were stained for CD34 expression (human
tissues; clone QBEnd/10; 1:25 dilution; Novocastra, Newcastle, United
Kingdom; 2 h, room temperature; secondary antibody; Zymed) or
binding of the lectin BS-I (bovine tissues; biotinylated BS-I;
10 µg/ml; Sigma, Deisenhofen, Germany; 37°C, 2 h) using
streptavidin-peroxidase as enzyme and AEC as chromogenic
substrate (Zymed).
Staining of Mural Cells.
To quantitatively assess the pericyte coverage of microvessels, a
double-labeling immunohistochemical technique was used to
simultaneously stain endothelial cells (CD34 or vWF) and mural cells
(
-SMA). Of the analyzed tumors, 25% of archive-retrieved specimens
were not suitable for the CD34/-SMA double-staining technique.
Deparaffinized and rehydrated tissue sections were peroxidase-blocked,
trypsinized, incubated with blocking serum, and then double-stained for
-SMA expression to detect pericytes and smooth muscle cells,
followed by CD34 staining (human tumors) or vWF staining (bovine
ovaries) to label endothelial cells. For -SMA staining, sections
were incubated with a monoclonal mouse antihuman -SMA antibody
(clone 1A4; 1:400 dilution; final concentration, 20 µg/ml; Sigma) for
2 h at room temperature. A biotinylated secondary antibody,
streptavidin alkaline phosphatase complex, and nitroblue tetrazolium as
substrate (Zymed) were used to visualize binding of the -SMA
antibody. Subsequent staining of endothelial cells was essentially
performed as described above using an antibody to CD34 to stain
endothelial cells in human tumors and a polyclonal antiserum to vWF
(polyclonal rabbit antihuman vWF antiserum; 1:200 dilution; final
concentration, 28.5 µg/ml; DAKO).
Quantitation of MVDs, PCI, and MPI.
Sections were assessed for uniformity of staining at low power
(x100), and individual microvessel counts were then performed in on a
x400 field. To express MVD counts microscope-independent,
counts were transformed and expressed as the number of
microvessels/mm2 (1 HPF = 0.0681
mm2). Density counts of CD34-, BS-I-, or
vWF-stained microvessels were performed independently by three
investigators, as described previously (18
, 20)
. At least
five independent microscopic fields per tissue section were analyzed by
two independent investigators to count PCNA-positive tumor cells and
endothelial cells. Tumor cell proliferation and endothelial cell
proliferation were quantitated in vascular hot spots that were
identified by screening for the areas with highest vessel density at
low magnification. A PCI was determined by calculating the ratio of the
number of microvessels with proliferating endothelial cells:the total
number of microvessels. A MPI was correspondingly established by
quantitating the percentage of microvessels that colocalized
endothelial cell staining (CD34 or BS-I) and pericyte staining
(-SMA). For MPI quantitation, at least five independent microscopic
fields per section were independently analyzed by two investigators.
Statistical Analysis.
Results were analyzed for statistical significance by an ANOVA and the
Mann-Whitney U test. Two-sided statistical calculations were
performed using the Statistica 5.1 program (StatSoft, Tulsa, OK) on an
IBM-compatible personal computer.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. To quantitate angiogenesis in these tumors, we used a double-labeling
immunohistochemical technique, simultaneously staining endothelial
cells for the expression of CD34 and detecting proliferating cells by
using the proliferation markers PCNA and Ki67. This approach
facilitated the detection of the relatively few proliferating
endothelial cells among the numerous tumor cells (Fig. 1)
. Counting the CD34-positive microvessels in tumor vascular hot spots
revealed relatively uniformly high MVDs in the different tumor types,
with glioblastomas and renal cell carcinomas having the highest average
MVDs (Fig. 2)
. Nevertheless, it is noteworthy that MVD counts in all tumors except
for prostate carcinomas were lower than the MVD counts for the
corresponding normal tissues (brain tissue versus
glioblastomas, 128%; kidney tissue versus renal cell
carcinomas, 141%; colon tissue versus colon carcinomas,
103%; mammary tissue versus mammary carcinomas, 135%; lung
tissue versus lung carcinomas, 348%; prostate tissue
versus prostate carcinomas, 68%).
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. Glioblastomas (mean ± SD,
9.6 ± 6.1%; median, 8.6%) and renal cell carcinomas
(mean ± SD, 9.4 ± 5.2%; median, 8.3%)
had significantly higher PCIs than mammary carcinomas
(mean ± SD, 5.0 ± 4.8%; median,
3.4%), lung carcinomas (mean ± SD, 2.6 ± 2.5%; median, 2.3%), and prostate carcinomas (mean ± SD, 2.0 ± 1.4%; median, 1.9%;
P < 0.005). Colon carcinomas had
intermediate PCI values of 7.8 ± 5.2% (mean ± SD; median, 6.6%). In contrast, PCI values of all
corresponding normal tissues were at the detection limit, with only an
occasional PCNA-labeled endothelial cell being detectable (median of
all tissues, 0%). The organs of the female reproductive system
represent the only organ system with significant physiological
angiogenesis (20
, 24) . We consequently determined PCI
values in the cyclic ovarian corpus luteum. The highest PCI values were
determined in the growing corpus rubrum (mean ± SD,
40.6 ± 11.2%; median, 37.8%; Fig. 2B
). PCI
values during corpus luteum angiogenesis were significantly higher than
the PCI values of all analyzed tumor groups (P < 0.005).
When comparing PCI values of individual tumors, a large degree of
variation was seen (Fig. 3A)
. PCI values in glioblastomas, renal cell carcinomas, and
colon carcinomas varied over a wide range. Some tumors were found to
have extremely high PCI values (>20%), whereas others had PCI values
that were not higher than those of the groups with low PCI values
(mammary, lung, and prostate carcinomas). With few exceptions, PCI
values in these tumors were consistently low.
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).
Glioblastomas and renal cell carcinomas had PTE indices around 10,
colon and mammary carcinomas had PTE indices between 20 and 30, and
lung and prostate carcinomas had PTE indices between 40 and 70.
Pericyte Coverage of the Neovasculature in Human Tumors.
To quantitatively assess the functional status of the tumor
neovasculature, we applied a double-labeling immunohistochemical
technique to simultaneously stain endothelial cells for CD34 expression
and mural cells (pericytes/smooth muscle cells) with an antibody to
-SMA (21)
. Association of -SMA with capillary
endothelial CD34 expression was interpreted to reflect pericyte
staining, whereas -SMA association with CD34 expression in arteries
and veins was interpreted to reflect smooth muscle cell staining (Fig. 4)
. A MPI was quantitated that reflects the percentage of capillaries
associated with -SMA-positive pericytes. MPIs were determined for
all tumor types. Glioblastomas and renal cell carcinomas were
identified as the tumor types with the lowest MPI values
(glioblastomas, mean ± SD = 12.7 ± 7.9% and median = 9.7%; renal
cell carcinomas, mean ± SD = 17.9 ± 7.8% and median = 17.6%; Figs. 2D
and 3B
). Mammary carcinomas had the highest
MPI values (mean ± SD, 67.3 ± 14.2%;
median, 70.4%). Similarly, colon carcinomas also had relatively high
MPI values (mean ± SD, 65.4 ± 10.5%;
median, 67.7%). Lastly, lung and prostate carcinomas had intermediate
MPI values of 40.8 ± 14.5% (mean ± SD;
median, 40.6%) and 29.6 ± 9.5% (mean ± SD; median, 29.3%), respectively.
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and 4G
). The MPI of the mature midstage
corpus luteum (62.4%) characterizes an overall immature neovasculature
that rapidly undergoes regression at the onset of luteolysis. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Essentially all of the antiangiogenic animal studies have used
experimental models with a very high intensity of angiogenesis. These
include rapidly growing tumor models such as the Lewis lung carcinoma
(7
, 25) , the rabbit cornea assay with an implanted
angiogenic factor (26)
, or the naturally occurring
angiogenic processes in the female reproductive system
(27)
. Contrasting these experimental models with a high
intensity of angiogenesis, little is known about the degree of active
angiogenesis and the functional status of the vasculature within human
tumors. Vessel density counting studies have used panendothelial cell
markers that facilitate the quantitation of the number of blood vessels
within tumors (17
, 18)
. These studies have demonstrated
that high vessel densities in tumors correspond with poor prognosis.
However, the use of panendothelial cell markers, such as CD31 or CD34,
facilitates the assessment of the vascular status of a tumor but does
not give an indication of the tumor’s angiogenic status. In fact,
recent histomorphological studies indicate that some tumors may be
vascularized without significant angiogenesis, probably by using the
preexistent organ vasculature (28)
or even by forming
vascular channels on their own through a nonendothelial cell process
designated as vascular mimicry (29)
. Recent studies have
tried to circumvent this problem by using marker molecules that are
up-regulated during angiogenesis, such as CD105 (30)
and
the integrin vß3
(31)
.
In this study, we have quantitatively assessed the rate of
angiogenesis (based on the proliferation of endothelial cells) as well
as the functional status of the neovasculature (based on the
recruitment of -SMA-positive pericytes) in six different types of
malignant human tumors. The results indicate that there is active
angiogenesis in human tumors, albeit at a much lower rate compared with
the physiological cyclic angiogenic processes in the ovarian corpus
luteum. Furthermore, the varying degrees of pericyte recruitment
indicate differences in the functional status of the tumor vasculature
in different tumors that may reflect varying degrees of maturation of
the tumor vascular bed.
Studies performed as early as 1972 have attempted to establish a procedure for the assessment of the angiogenesis status of tumors (17) . To date, however, no standardized scheme is available to reliably assess the angiogenesis status of a given tissue or a tumor. Despite the increasingly recognized distinct phenotypic properties of angiogenic endothelial cells (4 , 32) , proliferation of endothelial cells may still be considered as the single most reliable parameter to quantitate angiogenesis. Few endothelial cell proliferation studies in human tumors have been reported (13, 14, 15, 16) . These studies describe tumor endothelial cell proliferation indices between 0.15% (13) and 9.9% (16) . Much of the variation in the literature data may be attributed to differences in methodology. Thus, one of the goals of the present study was to standardize one technique and to comparatively apply this technique to different tumors. When assessing angiogenesis based on endothelial cell proliferation in different types of human tumors, we identified significant differences in the degree of active angiogenesis between different types of tumors as well as within one tumor type. Glioblastomas, renal cell carcinomas, and colon carcinomas were identified as the most angiogenic types of tumors. There was a high degree of variation among the individual tumors, indicative of a low rate of active angiogenesis in a subgroup of these tumors. In contrast to the intense angiogenesis in some types of tumors, lung carcinomas, prostate carcinomas, and most of the mammary carcinomas had relatively low endothelial cell proliferation indices. Nevertheless, these low PCI values (around 2%) are still indicative of active angiogenesis in these tumors. Endothelial cell turnover in the corresponding normal tissues was below the detection limit, with only single PCNA- or Ki67-positive endothelial cells being detectable. A very careful analysis of endothelial cell turnover in normal tissue has identified around 0.1% proliferating endothelial cells in normal tissues (12) , which is still lower than the PCI values for prostate and lung carcinomas by a factor of 20. When comparing tumor PCI values to angiogenesis in the cyclic ovary, it became apparent that angiogenesis in human tumors is operative, albeit at a much lower rate than in the corpus luteum. Angiogenesis in the growing corpus luteum in the first few days after ovulation was found to be fourfold to twentyfold more intense than the angiogenesis in the different malignant human tumors (PCI > 40%), corresponding to previous reports on the high intensity of angiogenesis in the female reproductive system (33 , 34) .
In addition to assessing tumor endothelial cell proliferation, we quantitated the recruitment of mural cells (pericytes, smooth muscle cells) to the tumor neovasculature. The identification of the angiopoietins (35, 36, 37) and the phenotype of platelet-derived growth factor-ß-deficient mice (inability to recruit pericytes) (38 , 39) has focused attention on the molecular mechanisms of blood vessel maturation mediated by the recruitment of pericytes. The mature phenotype of the quiescent organ vasculature in most organs is characterized by an extensive coverage with pericytes that appear to play a role in controlling the quiescent endothelial cell phenotype. Correspondingly, it has long been speculated that the tumor vasculature is characterized by a distinct maturation defect that is at least partially responsible for the irregular, tortuous, and leaky blood vessels found within tumors (40 , 41) . It was recently shown that androgen ablation therapy of prostate tumors leads to a down-regulation of vascular endothelial growth factor within the tumor, leading selectively to the regression of immature tumor microvessels that were not covered by pericytes (42) . In line with these findings, we determined in the present study that only one-third of the vasculature within prostate carcinomas is covered by pericytes, despite the fact that prostate tumors were identified as not very angiogenic tumors based on the assessment of endothelial cell proliferation.
The degree of pericyte recruitment to the neovasculature in the different tumor types varied significantly. The neovasculature in mammary and colon carcinomas had the highest rate of pericyte coverage, with as many as 70% of all microvessels being in contact with mural cells. In contrast, glioblastomas and renal cell carcinomas had pericyte coverage indices between 10% and 20%, indicating that most microvessels did not establish mural cell contact. These quantitative differences in mural cell recruitment could reflect varying degrees of vessel maturation of the tumor vascular bed. There is good evidence to suggest that pericyte coverage is a correct functional reflection of the degree of microvessel maturation (38 , 39 , 42 , 43) . However, it should be noted that pericyte coverage is not the only mechanism of vessel maturation, as indicated by the fact that the quiescent organ vasculature in some organs such as the lungs is not extensively covered by pericytes.
In summary, the present study has demonstrated that malignant human tumors are characterized by varying degrees of angiogenesis and pericyte recruitment. Furthermore, they indicate that the degree of angiogenesis in human tumors varies widely and may be very low in some types of tumors. Despite the fact that little is known about the mechanism of action of most angiogenesis inhibitors, the data suggest that the suitability of tumors for antiangiogenic therapies may differ between different tumor types and even within one type of tumor. Tumors with a low intensity of angiogenesis may not benefit much from antiangiogenic therapies that depend on the rate of endothelial cell proliferation. This stresses the importance that techniques such as those described in this study need to be implemented in clinical practice to assess the angiogenic status of a patient to identify those who will benefit most from antiangiogenic therapy. Furthermore, the data also indicate that the vasculature in most tumors is not very extensively covered by pericytes, which may reflect a functional immaturity of the tumor vascular bed. Not only may pericyte coverage of microvessels control vessel maturation, but it has also been shown to define a plasticity window for blood vessel remodeling (43) . Thus, our data provide support for the concept that in addition to antiangiogenic therapies, angioregressive therapies could be developed that are capable of selectively inducing the regression of the immature tumor vasculature with an open plasticity window (42) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Deutsche
Krebshilfe/Mildred-Scheel-Stiftung Grant 10-0986-Au3 and Deutsche
Forschungsgemeinschaft Grants SFB 500, C3 (to H. G. A.). 
2 A. E. and S. K. contributed equally to this
work.
3 To whom requests for reprints should be
addressed, at Cell Biology Laboratory, Department of Gynecology and
Obstetrics, University of Göttingen Medical School,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany. Phone:
49-551-396573; Fax: 49-551-396711; E-mail: haugust{at}med.uni-goettingen.de
4 The abbreviations used are: MVD, microvessel
density; PCI, proliferating capillary index; PTE, proliferating tumor
versus endothelial cell; MPI, microvessel pericyte
coverage index; -SMA, -smooth muscle actin; vWF, von Willebrand
factor; PCNA, proliferating cell nuclear antigen; BS-I,
Bandeiraea simplicifolia I; AEC, amino ethyl carbazole;
HPF, high power field.
Received 3/22/99. Accepted 1/ 4/00.
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