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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 29, 2001 as doi:10.1096/fj.00-0895fje. |
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Departments of
* Oncology and
Pathology, Hadassah-Hebrew University Hospital, Jerusalem 91120; and
InSight, Rabin Science Park, Rehovot 76121, Israel
2Correspondence: Department of Oncology, Hadassah Hospital, Jerusalem 91120, Israel. E-mail: vlodavsk{at}cc.huji.ac.il
SPECIFIC AIMS
Our objective was to study the involvement and mode of action of mammalian heparanase, endo-ß-D-glucuronidase-degrading heparan sulfate (HS), in angiogenesis associated with tumor progression and tissue repair. The experiments were undertaken to investigate 1) expression of heparanase in the endothelium of blood vessels that vascularize human tumors; 2) release by recombinant heparanase of HS-bound basic fibroblast growth factor (bFGF) and of HS degradation fragments that stimulate the growth-promoting activity of bFGF; and 3) heparanase-induced tumor angiogenesis and tissue neovascularization in vivo.
PRINCIPAL FINDINGS
1. Heparanase is expressed in the endothelium of angiogenic blood
vessels but not of mature quiescent vessels of human tumors
We investigated the expression of heparanase by vascular
endothelial cells (EC) in vitro and in angiogenic blood vessels. Using
RT-PCR, we demonstrate expression of the heparanase gene by
proliferating human EC. Both cultured human umbilical vein EC and human
bone marrow EC expressed the heparanase gene, as revealed by the
relevant PCR product. Next, we subjected paraffin-embedded sections of
primary human colon adenocarcinoma tissue to immunohistochemical
staining with monoclonal antiheparanase antibodies. An interesting
pattern of staining was noted in EC comprising blood vessels of
different maturation stages. It appears that the heparanase protein is
preferentially expressed in capillaries and small sprouting blood
vessels, whereas the endothelium of mature quiescent vessels exhibit no
detectable levels of heparanase. A similar expression pattern was
observed in human mammary and pancreatic carcinomas. This result
suggests a significant role of endothelial heparanase in enabling EC to
traverse basement membranes (BM) and extracellular matrix (ECM)
barriers during sprouting angiogenesis. Intense staining of heparanase
was noted in the neoplastic colonic mucosa as opposed to no detectable
expression of the enzyme in normal colon epithelium and stroma.
2. Recombinant heparanase releases active bFGF from the
subendothelial ECM
A straightforward explanation for the role of tumor- and
stroma-derived heparanase in angiogenesis is release of active bFGF and
other heparin binding angiogenic factors from their storage in the ECM.
To verify this mode of action, naturally produced subendothelial ECM
was preincubated with 125I-bFGF, washed free of
the unbound bFGF, and incubated with the processed 50 kDa active
form of recombinant heparanase. Degradation of HS in the ECM, reflected
by release of sulfate-labeled HS degradation fragments, resulted in the
release of as much as 70% of the ECM-bound
125I-bFGF. Alternatively, the enzyme was added to
native ECM that was not preincubated with
125I-bFGF. Aliquots of the incubation medium were
then tested for the presence of bFGF using a quantitative ELISA for
bFGF. Nearly 0.8 ng endogenous bFGF was released from ECM coating the
surface area of a 35 mm culture dish. The released bFGF stimulated
five- to eightfold the proliferation of 3T3 fibroblasts and bovine
aortic EC. These results clearly indicate that heparanase releases
active bFGF sequestered as a complex with HS in the ECM. Both tumor and
endothelial heparanase hence may elicit an indirect angiogenic response
by means of releasing active HS-FGF complexes from storage in the ECM
and tumor microenvironment.
3. Recombinant heparanase releases degradation fragments
of HS that stimulate the mitogenic activity bFGF
The ability of heparanase-cleaved HS degradation
fragments to promote the mitogenic activity of bFGF was investigated
using a cytokine-dependent lymphoid cell line (BaF3)
engineered to express FGF receptor 1. These cells lack cell surface HS
and respond to bFGF only in the presence of exogenously added species
of heparin or HS. We first treated both native ECM and confluent
vascular EC monolayer with recombinant 50 kDa heparanase. Aliquots of
the incubation media were then added to BaF3 cells and
tested for their ability to promote 3H-thymidine
incorporation in response to bFGF. As expected, BaF3
cells exposed to either bFGF or heparanase alone exhibited almost
no incorporation of 3H-thymidine. A marked
stimulation (
40-fold) of DNA synthesis was obtained in the presence
of HS degradation fragments released by heparanase from EC surfaces. In
contrast, HS fragments released by heparanase from the subendothelial
ECM exerted a much smaller effect. These results suggest that the
heparanase enzyme may potentiate the mitogenic activity of bFGF
and possibly other heparin binding angiogenic growth factors through
release of HS degradation fragments that promote bFGF receptor binding
and activation.
4. Effect of heparanase on tissue vascularity
The ability of recombinant 50 kDa heparanase to induce
vascularization in vivo was demonstrated in a wound healing mouse
model. Local daily application of recombinant heparanase (2 ng/
mm2) onto a full-thickness wound created in the
dorsal skin of mice resulted in a four- to sixfold increase in vascular
density and formation of a dense cellular granulation tissue
compared with control wounds treated with buffer alone.
Heparanase-induced tissue remodeling and vascularization were also
reflected by a significant acceleration of wound closure measured on
day 7 after wounding.
5. Heparanase promotes tumor angiogenesis in vivo
We applied the Matrigel plug assay to investigate whether the
heparanase enzyme can elicit tumor angiogenesis in vivo. For this
purpose, stable heparanase transfected mouse Eb lymphoma cells were
mixed at 4°C with Matrigel (reconstituted BM preparation extracted
from EHS mouse sarcoma) and injected subcutaneous (s.c.) into BALB/c
mice. Similarly treated mock-transfected Eb cells expressing no
heparanase activity served as a control. Upon injection, the liquid
Matrigel rapidly forms a solid gel plug that serves as a supporting
medium for the lymphoma cells. Similar to intact BM, its major
components are laminin, collagen type IV, and HSPGs. Matrigel also
contains bFGF and other growth factors that are found naturally in BM
and ECM. Hence, the Matrigel in this experimental system serves not
merely as an inert vehicle for the enzyme-producing cells, but
maintains the natural interactions existing between tumor cells and the
surrounding ECM, providing, among other effects, a source of
ECM-sequestered bFGF. As shown in Fig. 1
, a pronounced angiogenic response was induced by Matrigel-embedded Eb
cells overexpressing the heparanase enzyme compared with little or no
neovascularization exerted by mock-transfected Eb cells expressing no
heparanase activity. The angiogenic response was reflected by a network
of capillary blood vessels attracted toward the Matrigel plug
containing heparanase-transfected Eb cells (Fig. 1a
, left)
vs. a very small or no vascular response elicited by control
mock-transfected Eb cells (Fig. 1a
, right), and by a
respective difference in the amount of blood and vessels seen in the
isolated Matrigel plugs excised from each of the mice (Fig. 1b
, bottom vs. top, respectively). This difference was
highly significant, as also demonstrated by measuring the hemoglobin
content of Matrigel plugs removed from each mouse in the two groups
(Fig. 1c
). These findings, together with our previous
results on the increased metastatic potential of heparanase transfected
vs. mock transfected Eb cells, emphasize the significance of heparanase
in the two critical events in tumor progression.
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CONCLUSIONS
We have previously reported the cloning of mammalian heparanase, an endo-ß-D-glucuronidase-degrading heparan sulfate, and provided a direct evidence for its role in tumor metastasis. We now demonstrate that heparanase is tightly involved in angiogenesis and clarify its mode of action. Immunohistochemical staining of human colon carcinoma tissue revealed a high expression of the heparanase protein in the endothelium of sprouting capillaries, but not of mature quiescent vessels, suggesting up-regulation of the heparanase gene and protein in the endothelium of angiogenic blood vessels. As described previously, intense preferential expression of heparanase was noted in the carcinoma cells, which hence can be regarded as the main source of heparanase in the tumor microenvironment. At a later stage of tumor progression, heparanase could also be found in the tumor stroma.
Apart from its direct involvement in ECM degradation and
endothelial cell migration (vascular sprouting), heparanase was found
to release active bFGF from the subendothelial ECM as well as
bFGF-stimulating HS-degradation fragments from the endothelial cell
surface. HS fragments released from ECM induced little or no
potentiation of the growth-promoting activity of bFGF, suggesting that
HS in the ECM is primarily involved in sequestration, protection, and
stabilization of heparin binding growth factors, whereas the cell
surface HS plays a more active role in promoting the angiogenic
activity of the growth factor by means of stimulating receptor binding,
dimerization, and activation (Fig. 2
). In preliminary studies (in
collaboration with E. Buddecke and A. Schmidt), EC were cultured in the
presence of
Na2[35S]O4,
washed extensively, and both the cells and ECM were treated with
bacterial heparinase III. Sulfate-labeled degradation fragments were
then subjected to size fractionation on Biogel P6. Different elution
profiles were obtained, showing a three- to eightfold higher ratio of
disaccharides to oligosaccharides in material released from cells vs.
ECM. This and other structural differences may be held responsible for
the observed difference in biological activity. A more detailed
analysis (i.e., mass and NMR spectroscopy, sequencing) of ECM- and cell
surface-derived species of HS and their interaction with bFGF is under
way.
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Altogether, it appears that apart from direct involvement in BM
invasion by EC, heparanase elicits an indirect angiogenic response by
releasing HS-bound angiogenic growth factors (i.e., bFGF, VEGF) from
ECM and BM and by generating HS fragments that can potentiate bFGF
receptor binding, dimerization and signaling (Fig. 2)
. Using the mouse
matrigel plug angiogenesis assay, we observed an increased angiogenic
response to heparanase-transfected T lymphoma cells, embedded in
Matrigel and implanted s.c., vs. a small or no response to the parental
mock-transfected cells. This result is a clear demonstration of the
involvement of heparanase in tumor angiogenesis. Increased tissue
vascularity was also observed in a mouse wound healing model in
response to a topical administration of recombinant heparanase. Thus,
cooperative interactions between heparanases from tumor, inflammation
and endothelial sources appear to play a significant role in the
angiogenic cascade.
The ability of heparanase to promote tumor angiogenesis together with its involvement in tumor metastasis make it a promising target for cancer therapy. In other words, compounds that inhibit the heparanase enzyme are expected to exert an anticancerous effect through inhibition of both tumor cell metastasis and angiogenesis. In fact, nonanticoagulant species of heparin and various sulfated polysaccharides that inhibit experimental metastasis also inhibit tumor cell heparanase. Among these is phosphomannopentaose sulfate (PI-88), whose continuous administration inhibits the growth, vascularity, and lymph node metastasis of mammary adenocarcinoma tumors in rats. This compound is being evaluated in a multicenter phase II clinical trial. The unexpected identification of a single predominant functional heparanase suggests that if its activity can be inhibited, other heparanases may not be available to cover for it. On the other hand, taking into account the normal roles of the enzyme, heparanase-inhibiting compounds might, for example, interfere with physiological functions such as immune surveillance, tissue repair, anticoagulant activity, and HS turnover. It is hoped that identification of the sugar residues in HS adjacent to the heparanase cleavage site, as well as crystallization and analysis of the 3D-structure of the enzyme, will lead to a rational design of highly specific heparanase inhibitors.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0895fje ; to cite this
article, use FASEB J. (May 29, 2001) 10.1096/fj.00-0895fje 
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