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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3334-3339
A High Pretreatment Serum Basic Fibroblast Growth Factor Concentration
Is an Independent Predictor of Poor Prognosis in Non-Hodgkin's
Lymphoma
By
Petri Salven,
Lasse Teerenhovi, and
Heikki Joensuu
From the Department of Oncology, Helsinki University Central
Hospital, Helsinki, Finland.
 |
ABSTRACT |
Basic fibroblast growth factor (bFGF) is a secreted multifunctional
cytokine and a potent stimulator of angiogenesis in vivo. Elevated bFGF concentrations have been detected in the serum and urine of cancer patients. We measured bFGF by enzyme-linked
immunosorbent assay from sera taken from 160 non-Hodgkin's lymphoma
(NHL) patients before treatment and stored at  20°C. The patients
had been observed for at least 5 years or until death. Serum bFGF
concentrations (S-bFGF) ranged from undetectable to 34.7 pg/mL (median,
3.3 pg/mL). S-bFGF was detectable with a similar frequency in all
subtypes of NHL. A high pretreatment S-bFGF was associated with poor
overall survival. The 5-year survival rate of the patients within the highest quartile of S-bFGF concentrations (S-bFGF = 5.5 pg/mL) was
only 39%, in contrast to a 60% survival rate of the patients with
lower S-bFGF (P = .019). A high S-bFGF (within the highest quartile) was associated with poor outcome also in large-cell diffuse
and immunoblastic lymphomas (5-year survival rates of 28% v
56%, respectively; P = .027), which was the largest
histologic subgroup (n = 66) within the series. In multivariate
analyses, S-bFGF was an independent prognostic factor, both when the
highest quartile was used as a cut-off value (P = .0079) and when S-bFGF and the other parameters were entered into the
model as continuous variables (P = .024). In the multivariate
analyses, S-bFGF had a noticeably stronger prognostic value than serum
lactate dehydrogenase and the number of extranodal tumor sites, both of
which are currently included as components in the International
Prognostic Index.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ANGIOGENESIS, THE sprouting of new
capillaries from pre-existing ones, is an important component in many
physiological and pathological processes (reviewed by
Folkman1). In healthy adults, extensive angiogenesis occurs
only in the female reproductive system. Angiogenesis also takes place
in conditions such as wound healing, rheumatoid arthritis, psoriasis,
and diabetic retinopathy. In cancer, active angiogenesis is a
prerequisite for tumor growth beyond a few cubic millimeters in size.
In addition, the dissemination of malignant tumors is dependent on
angiogenesis. Analyses of metastatic colonies in mouse lungs have shown
that the colonies must become neovascularized before they can grow
larger than microscopic in size.2,3
Angiogenesis is regulated by a balance of various positive and negative
angiogenic molecules (reviewed by Hanahan and Folkman4 and
Iruela-Arispe and Dvorak5). During tumorigenesis, the
vasculature becomes activated to grow new capillaries in response to
appropriate stimuli. One such stimulus is basic fibroblast growth
factor (bFGF), which is also called fibroblast growth factor-2 (FGF-2).
bFGF is a 18- to 24-kD polypeptide that is expressed widely in cells of
mesodermal and neuroectodermal origin and in a variety of malignant tumors and cancer cell lines (reviewed by Friesel and
Maciag6 and Bikfalvi et al7). bFGF is a mitogen
for endothelial cells and fibroblasts in vitro and a potent inducer of
angiogenesis in vivo. In addition to stimulating the growth of blood
vessels, bFGF has also been shown to inhibit the adhesion of activated natural killer cells to tumor vessel endothelium.8 This
suggests that the presence of bFGF at the tumor site may provide
protection to growing tumor vessels. In nude mouse transplanted with
cancer cells, tumor growth could be suppressed by using
immunoneutralizing monoclonal antibody against bFGF.9
Similarly, the inhibition of bFGF-mediated signaling in human
melanomas, using episomal vectors containing antisense-oriented bFGF
cDNA, resulted in a complete arrest of the tumor growth or the tumors
regressed as a result of blocked intratumoral angiogenesis and
subsequent necrosis.10
Using a transgenic mouse model, Kandel et al11 found that
the angiogenic swich in bovine papilloma virus-induced fibrosarcoma correlates with the export of bFGF from tumor cells. Abnormally elevated levels of bFGF have indeed been reported in
serum12-17 and urine16,18-20 of patients with
various types of cancer. A high serum concentration of bFGF (S-bFGF)
has been shown to be associated with a large primary tumor size in head
and neck cancer16 and with a short tumor volume doubling
time in advanced colorectal cancer.13 Nevertheless, little
is known about the clinical significance of S-bFGF, and there are no
studies available on the prognostic value of S-bFGF in any type of
human cancer. In the present study, we measured S-bFGF concentrations
from lymphoma patients' sera stored for years at 20°C and
found that a high S-bFGF at diagnosis was associated with poor
prognosis both in univariate and multivariate survival analyses.
| |
MATERIALS AND METHODS |
Patients.
S-bFGF concentration was measured in 160 randomly selected adult
patients with non-Hodgkin's lymphoma (NHL) diagnosed and treated in
the Department of Oncology, Helsinki University Central Hospital
(Helsinki, Finland), from 1981 to 1987, for whom frozen serum taken at the time of diagnosis but before lymphoma treatment was
available. Thirty-eight lymphomas (24%) had been classified as
low-grade, 80 (50%) as intermediate-grade, and 38 (24%) as high-grade
lymphoma according to the Working Formulation Scheme21 by a
pathologist with a special interest in lymphoma. Four cases (2%) were
considered unclassifiable. The histologic types of lymphomas in the
series according to the Working Formulation Scheme were small
lymphocytic, consistent with chronic lymphocytic leukemia (CLL; n = 11; 7%); small lymphocytic, plasmocytoid (n = 2; 1%); follicular, predominantly small cleaved cell (n = 19; 12%);
follicular, mixed small and large cell (n = 2; 1%); follicular,
predominantly large cell (n = 2; 1%); diffuse, small cleaved cell (n = 11; 7%); diffuse, mixed small and large cell (n = 6; 4%); diffuse,
large cell (n = 47; 29%); large cell immunoblastic (n = 19; 12%);
lymphoblastic (n = 5; 3%); small noncleaved cell, non-Burkitt (n = 6;
4%); small noncleaved cell, Burkitt's type (n = 2; 1%); mycosis
fungoides (n = 1; 1%); other (n = 23; 14%); and unclassifiable (n = 4; 2%). Clinical staging was performed according to the Ann Arbor
classification system. The examination of clinical status, chest x-ray,
computerized tomography (CT) scans of the mediastinum and
the abdomen, and a bone marrow biopsy were performed as staging
examinations. Fifty-five (34%) of the patients had stage I, 40 (25%)
stage II, 27 (17%) stage III, and 38 (24%) stage IV disease at
diagnosis. Thirty patients (19%) had B-symptoms (weight loss,
unexplained fever, or night sweats). The International Prognostic Index
(IPI)22 could be determined in all cases.
A total of 113 patients were treated with combination chemotherapy. The
patients with intermediate- or high-grade lymphoma and disseminated
disease were treated usually with bleo-CHOP (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisone), M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), or another anthracycline-containing combination chemotherapy regimen. Low-grade lymphomas were usually treated with a
single-agent chlorambucil if symptomatic. Fifty-four patients received
megavoltage radiotherapy. All patients were regularly followed-up with
intervals of a few months in an outpatient department. All
patients were observed over 5 years or until death. The median follow-up time was 86 months (range, 62 to 136 months). Eighty patients
died during the follow-up time.
Venous blood samples.
Peripheral venous blood samples were collected in sterile test tubes a
few hours or a few days before starting lymphoma therapy, centrifuged
at 2,000g for 10 minutes, and then stored at 20°C.
S-bFGF immunoassay.
S-bFGF concentrations were determined as S-bFGF immunoreactivity using
a quantitative sandwich enzyme immunoassay technique (Quantikine High
Sensitivity Human FGF basic Immunoassay; R&D Systems, Minneapolis, MN).
The system uses a solid-phase monoclonal and an enzyme-linked
polyclonal antibody raised against recombinant human bFGF. For each
analysis, 100 µL of serum was used. All analyses and calibrations
were performed in duplicate. The calibrations on each microtiter plate
included recombinant human bFGF standards. Optical densities were
determined by using a microtiter plate reader (Multiscan RC Type 351;
Labsystems, Helsinki, Finland) at 490 nm. The blank was subtracted from
the duplicate readings for each standard and sample. A standard curve
was created using StatView 4.02 (Abacus Concepts Inc, Berkeley, CA) by
plotting the logarithm of the mean absorbance of each standard versus
the logarithm of the bFGF concentration. Concentrations are reported as
picograms per milliliter. When 20 serum samples were measured twice in
the same assay, the intra-assay variation ranged from 0.0 to 0.9 pg/mL.
When 20 serum samples were assayed twice in 2 separate assays, the
interassay variation ranged from 0.0 to 1.0 pg/mL. No correlation was
observed between S-bFGF concentration and the duration of the storage
(P > .1, the Mann-Whitney test). Thus, there was no evidence
of loss of bFGF on storage at 20°C.
Statistical analysis.
Statistical analysis was performed using StatView 4.02 (Abacus Concepts
Inc). All P values are 2-tailed. The Mann-Whitney test and
Kruskall-Wallis test were used to compare S-bFGF concentrations in
different groups. Cumulative survival was computed according to the
product-limit method of Kaplan-Meier from the date of diagnosis. The
Wilcoxon test was used to compare survival of the different subgroups
of patients. The relative importance of different variables on survival
was studied using the Weibull multivariate model. The prognostic
factors introduced in the model are commonly accepted and have been
previously reported by the International Non-Hodgkin's Lymphoma
Prognostic Factors Project on a large series of patients.22
| |
RESULTS |
S-bFGF in patients at diagnosis.
S-bFGF concentrations ranged from undetectable to 34.7 pg/mL (median,
3.3 pg/mL; mean, 4.3 pg/mL) among the 160 patients with NHL
(Fig 1). One third of the patients had an
S-bFGF of  4.8 pg/mL (the highest tertile), and one fourth had an
S-bFGF of 5.5 pg/mL (the highest quartile).
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| Fig 1.
Pretreatment serum concentrations of bFGF (in picograms
per milliliter) in 160 patients with NHL.
|
|
The serum concentrations of bFGF were comparable in the different
histologic subtypes of NHL by the Working Formulation Scheme (P > .1 for all comparisons). There was no significant difference in the
S-bFGF concentrations of patients with low-grade (median, 3.2 pg/mL;
range, 0 to 13.4 pg/mL), intermediate-grade (median, 3.3 pg/mL; range,
0 to 34.7 pg/mL), or high-grade (median, 3.5 pg/mL; range, 1 to 18.0 pg/mL) lymphoma (tested I v II+III; P > .1;
Fig 2). S-bFGF was not associated with age
(tested > median  60 years of age), the World Health Organization
(WHO) performance status (0-1 v 2-4), the serum lactate
dehydrogenase (LDH) level measured at the time of the diagnosis (normal
v abnormal), Ann Arbor stage (I-II v III-IV), the
number of extranodal tumor sites (1 v >1), or the presence
of B-symptoms (P > .1 for all comparisons). Because data from
animal models suggest that the clearance of bFGF may take place through
the kidney and the liver,23,24 we compared the patients'
S-bFGF levels with the results of kidney and liver function tests.
However, the analyses of these data showed that S-bFGF levels were not
elevated in the patients with high (>100 µmol/L) serum creatinine
(median, 3.7 pg/mL [range, 0 to 18 pg/mL] v median, 3.0 pg/mL
[range, 0 to 34.7 pg/mL] in patients with serum creatinine <100
µmol/L; P > .1). Similarly, patients with an elevated level
of serum 5'-nucleotidase (>8 U/L) had S-bFGF concentrations
comparable to those of the patients with normal serum
5'-nucleotidase (median, 3.7 pg/mL [range, 0 to 10.4 pg/mL]
v median, 3.2 pg/mL [range, 0 to 34.7 pg/mL], respectively; P > .1).
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| Fig 2.
Pretreatment serum concentrations of bFGF (in picograms
per milliliter) in patients with NHL by the Working Formulation grade.
|
|
S-bFGF and survival.
Several factors correlated strongly with overall survival in univariate
survival analyses in the present series
(Table 1). Patients with a high S-bFGF at
diagnosis had inferior overall survival in comparison with those with
lower pretreatment concentration of S-bFGF. The 2- and 5-year survival
rates of the patients within the highest quartile of S-bFGF
concentrations (S-bFGF 5.5 pg/mL) were only 58% and 39%,
respectively, in contrast to the 78% and 60% 2- and 5-year survival
rates of those patients with an S-bFGF concentration less than 5.5 pg/mL (P = .019; Fig 3 and Table
1). Likewise, when other cut-off values were used, patients with higher S-bFGF concentrations had an inferior survival rate than those with
lower S-bFGF. When the highest tertile (S-bFGF 4.8 pg/mL) and the
median (3.3 pg/mL) of S-bFGF were used as cut-off values, the
respective 5-year survival rates were 44% versus 60% (P = .068) and 49% versus 61% (P = .072; Table 1).
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| Fig 3.
Overall survival of 160 patients with NHL by the
pretreatment S-bFGF concentration. The highest quartile (5.5 pg/mL) was
used as the cut-off value. Survival rates at 24 and 60 months are
given.
|
|
In patients with intermediate- or high-grade lymphoma (n = 118), the 2- and 5-year survival rates of the patients within the highest quartile
of S-bFGF concentrations (S-bFGF 5.7 pg/mL) were only 50% and 37%,
respectively, in contrast to the 73% and 57% 2- and 5-year survival
rates of those patients with S-bFGF lower than the highest quartile
(P = .033). Also, in the patients with a low-grade lymphoma (n = 38), the patients within the highest quartile of S-bFGF
concentrations (S-bFGF 5.1 pg/mL) had an inferior survival rate in
comparison with those with lower S-bFGF concentration (2- and 5-year
survival rates of 89% and 56% v 97% and 72%, respectively), but the difference was not statistically significant (P > .1). The association between S-bFGF and survival was also studied
separately in the subgroup of large-cell diffuse and immunoblastic
lymphomas. This was the largest histologic subgroup (n = 66) within the
present series. In the Revised European-American Classification of
Lymphoid Neoplasms (REAL),25 the probable immunophenotypic
equivalent of this group is the disease entity of diffuse large B-cell
lymphomas. A high pretreatment serum concentration of bFGF was
associated with poor overall survival also in the subgroup of
large-cell diffuse and immunoblastic lymphomas. When the highest
quartile of S-bFGF within the subgroup (S-bFGF 5.8 pg/mL) was used as the cut-off value, the patients within the highest quartile of S-bFGF
had 2- and 5-year survival rates of 61% and 28%, respectively, in
comparison to the 85% and 56% 2- and 5-year survival rates of
patients with an S-bFGF less than 5.8 pg/mL (P = .027; Fig 4).
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| Fig 4.
Overall survival of 66 patients with large-cell diffuse
or immunoblastic lymphoma by the pretreatment S-bFGF concentration. The
highest quartile (5.8 pg/mL) was used as the cut-off value. Survival
rates at 24 and 60 months are given.
|
|
To find out if S-bFGF has an independent influence on survival, S-bFGF
was entered to multivariate analyses together with the components of
the IPI. First, the parameters were introduced in the multivariate
model as discontinuous variables: S-bFGF (<5.5 v 5.5 pg/mL;
the highest quartile), age (60 v >60), the WHO performance status (1 v >1), Ann Arbor stage (I-II
v III-IV), the number of extranodal tumor sites (1 v
>1), and serum LDH at diagnosis (normal v abnormal). In
addition, the parameters were also entered to the multivariate model as
continuous variables. Multivariate analyses showed that S-bFGF was an
independent prognostic factor, both when the highest quartile (5.5 pg/mL) was used as a cut-off value (P = .0079;
relative risk, 2.0; 95% confidence interval [CI], 1.2 to 3.4) and
when S-bFGF and the other parameters were entered to the model as
continuous variables (P = .024;
Table 2). In both of the multivariate
analyses, S-bFGF had a stronger prognostic value than serum LDH at
diagnosis and the number of extranodal tumor sites, which are currently
included as components in the IPI (Table 2).
| |
DISCUSSION |
It has been shown that solid tumors progress in concert with an
induction of tumor angiogenesis. Recent data suggest that similar
phenomenon occurs also in hematologic malignancies. When bone marrow
biopsies from children with newly diagnosed, untreated acute
lymphoblastic leukemia and from controls were evaluated, the biopsies
from children with leukemia showed significantly higher microvessel
densities, suggesting that leukemia cells induce angiogenesis in the
bone marrow and that leukemia might be angiogenesis dependent.26 In NHLs, significantly higher microvesel
counts have been found in high-grade lymphomas than in low-grade
lymphomas, implying that angiogenesis occurring in NHLs increases with
tumor progression.27,28 NHLs have been also found to
express angiogenic molecules, including vascular endothelial growth
factor (VEGF) and VEGF-C.29,30
In the present study, we could detect bFGF in the serum samples of most
patients with NHL. A high pretreatment S-bFGF concentration was
associated with poor overall survival. The 5-year survival rate of the
patients within the highest quartile of S-bFGF concentrations (S-bFGF
5.5 pg/mL) was only 39%, in contrast to the 60% survival rate of
the patients with a lower S-bFGF at diagnosis. Furthermore, S-bFGF
concentration was an independent prognostic factor in multivariate analyses. In line with this, we found no associations between S-bFGF
and any other clinicopathological variable studied. It should be noted
that, in multivariate analyses, S-bFGF had a stronger prognostic value
than the number of extranodal tumor sites and serum LDH at diagnosis,
which both are currently included as components, together with stage,
age, and the WHO performance status, in the IPI. Although first
designed for aggressive NHLs, the IPI has subsequently been shown to be
useful in all grades of lymphoma.31
The source of the elevated levels of bFGF in the serum samples of our
patients remains unknown. Various lymphoblastoid and leukemic cell
lines have been shown to secrete bFGF.32,33 In CLL,
elevated intracellular levels of bFGF were found in the CLL cells, and
a high intracellular bFGF level in the CLL cells was associated with a
high stage of the disease.34 Peripheral blood mononuclear
cells,35 T cells,36,37
macrophages,38 and granulocytes39 also have the
capacity to produce bFGF. In addition, the endothelial cells of blood
vessels express bFGF.40 Consequently, it is possible that
bFGF in sera of lymphoma patients is released mainly by malignant cells
or by a combination of cancer cells and normal cells, including the
endothelial cells and peripheral blood cells. S-bFGF may alternatively be produced by normal cells under deregulated stimulation by malignant cells. In a transgenic mouse fibrosarcoma model, there is a change in
the localization of bFGF from its normal cell-associated state to
extracellular release in the later stages of the multistep development
of fibrosarcoma. This change was concomitant with the
neovascularization seen in vivo. Thus, in this multistep tumorigenesis pathway, there appears to be a discrete switch to the angiogenic phenotype that correlates with the export of bFGF.11
Interestingly, in a tumor-bearing mouse model, the origin of elevated
bFGF levels in the urine was found to be almost exclusively from tumor
cells.24 In agreement with this finding, intravenously
administered bFGF has been found to be distributed preferentially to
the kidneys and the liver.23
Angiogenic molecules other than bFGF have also been detected in the
sera of cancer patients. Elevated serum concentrations of VEGF have
been found to be associated with various unfavorable clinical
parameters, including extensive disease17,41,42 and poor
patient survival.43-45 In a series of 82 patients with NHL, patients with lower than the median serum concentration of VEGF (S-VEGF) at diagnosis had a 71% 5-year survival rate, in comparison to
only 49% among those with an S-VEGF greater than the median (P = .01).43 Interestingly, a circulating form of human
endostatin was recently identified,46 suggesting that
various endogenous inhibitors of angiogenesis may also be found in the
bloodstream. Furthermore, Sasaki et al47 found that the
concentrations of soluble endostatin measured in serum samples of
healthy human donors were similar to the concentrations that
efficiently inhibit endothelial cell proliferation in
vitro,48 suggesting that circulating forms of endostatin
may be involved in the homeostatic control of angiogenesis. In the
future, it might be possible to obtain an angiogenic profile of a blood
sample by measuring the concentrations of several circulating
stimulators and inhibitors of angiogenesis. The use of such an
angogenic profile could perhaps be used as a monitor of cancer therapy
or as a predictor of outcome after cancer has been diagnosed.
In conclusion, the results of the present study indicate that S-bFGF is
elevated in a subgroup of patients with NHL and correlates with a poor
outcome. Notably, the pretreatment S-bFGF surfaced as an independent
prognostic variable in multivariate analyses, having a stronger
predictive value than 2 of the components of the IPI. A high S-bFGF
content may reflect active angiogenesis and lymphoma growth, and it is
possible that similar associations with unfavorable survival can be
found in other types of human cancer as well. Studies are now needed to
find out if lymphoma therapy can be monitored by measuring bFGF
concentrations in consecutive serum samples. It will be of particular
interest to study if the clinical significance of S-bFGF could be
further improved using an angiogenic profile obtained by measuring the
serum concentrations of several circulating angiogenic and
antiangiogenic molecules.
| |
ACKNOWLEDGMENT |
The authors thank Kati Konola for technical assistance.
| |
FOOTNOTES |
Submitted March 2, 1999; accepted July 12, 1999.
Supported by grants from the Finnish Academy of Sciences, the Finnish
Cancer Foundation, and the Helsinki University Central Hospital
Research Funds.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Petri Salven, MD, PhD, Department of
Oncology, Helsinki University Central Hospital, PO Box 180, FIN-000290
HYKS, Finland; e-mail: petri.salven{at}helsinki.fi.
| |
REFERENCES |
1.
Folkman J:
Angiogenesis in cancer, vascular, rheumatoid and other disease.
Nat Med
1:27, 1995[Medline]
[Order article via Infotrieve]
2.
O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J:
Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.
Cell
79:315, 1994[Medline]
[Order article via Infotrieve]
3.
Holmgren L, O'Reilly MS, Folkman J:
Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression.
Nat Med
1:149, 1995[Medline]
[Order article via Infotrieve]
4.
Hanahan D, Folkman J:
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
Cell
86:353, 1996[Medline]
[Order article via Infotrieve]
5.
Iruela-Arispe ML, Dvorak HF:
Angiogenesis: A dynamic balance of stimulators and inhibitors.
Thromb Haemost
78:672, 1997[Medline]
[Order article via Infotrieve]
6.
Friesel RE, Maciag T:
Molecular mechanisms of angiogenesis: Fibroblast growth factor signal transduction.
FASEB J
9:919, 1995[Abstract]
7.
Bikfalvi A, Klein S, Pintucci G, Rifkin DB:
Biological roles of fibroblast growth factor-2.
Endocr Rev
18:26, 1997[Abstract/Free Full Text]
8.
Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK:
During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium.
Nat Med
2:992, 1996[Medline]
[Order article via Infotrieve]
9.
Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y:
Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor.
Cancer Res
51:6180, 1991[Abstract/Free Full Text]
10.
Wang Y, Becker D:
Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth.
Nat Med
3:887, 1997[Medline]
[Order article via Infotrieve]
11.
Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D:
Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma.
Cell
66:1095, 1991[Medline]
[Order article via Infotrieve]
12.
Fujimoto K, Ichimori Y, Kakizoe T, Okajima E, Sakamoto H, Sugimura T, Terada M:
Increased serum levels of basic fibroblast growth factor in patients with renal cell carcinoma.
Biochem Biophys Res Commun
180:386, 1991[Medline]
[Order article via Infotrieve]
13.
Dirix LY, Vermeulen PB, Hubens G, Benoy I, Martin M, De Pooter C, Van Oosterom AT:
Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer.
Ann Oncol
7:843, 1996[Abstract/Free Full Text]
14.
Dirix LY, Vermeulen PB, Pawinski A, Prove A, Benoy I, De Pooter C, Martin M, Van Oosterom AT:
Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.
Br J Cancer
76:238, 1997[Medline]
[Order article via Infotrieve]
15.
Cronauer MV, Hittmair A, Eder IE, Hobisch A, Culig Z, Ramoner R, Zhang J, Bartsch G, Reissigl A, Radmayr C, Thurnher M, Klocker H:
Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate.
Prostate
31:223, 1997[Medline]
[Order article via Infotrieve]
16.
Leunig A, Tauber S, Spaett R, Grevers G, Leunig M:
Basic fibroblast growth factor in serum and urine of patients with head and neck cancer.
Oncol Rep
5:955, 1998[Medline]
[Order article via Infotrieve]
17.
Landriscina M, Cassano A, Ratto C, Longo R, Ippoliti M, Palazzotti B, Crucitti F, Barone C:
Quantitative analysis of basic fibroblast growth factor and vascular endothelial growth factor in human colorectal cancer.
Br J Cancer
78:765, 1998[Medline]
[Order article via Infotrieve]
18.
Chodak GW, Hospelhorn V, Judge SM, Mayforth R, Koeppen H, Sasse J:
Increased levels of fibroblast growth factor-like activity in urine from patients with bladder or kidney cancer.
Cancer Res
48:2083, 1988[Abstract/Free Full Text]
19.
Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J:
Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers.
J Natl Cancer Inst
86:356, 1994[Abstract/Free Full Text]
20.
O'Brien TS, Smith K, Cranston D, Fuggle S, Bicknell R, Harris AL:
Urinary basic fibroblast growth factor in patients with bladder cancer and benign prostatic hypertrophy.
Br J Urol
76:311, 1995[Medline]
[Order article via Infotrieve]
21.
National Cancer Institute sponsored study on classification of non-Hodgkin's lymphomas. Summary and description of a working formulation for clinical usage.
Cancer
49:2112, 1982[Medline]
[Order article via Infotrieve]
22.
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project.
N Engl J Med
14:987, 1993
23.
Hondermarck H, Courty J, Boilly B, Thomas D:
Distribution of intravenously administered acidic and basic fibroblast growth factors in the mouse.
Experientia
46:973, 1990[Medline]
[Order article via Infotrieve]
24.
Soutter AD, Nguyen M, Watanabe H, Folkman J:
Basic fibroblast growth factor secreted by an animal tumor is detectable in urine.
Cancer Res
53:5297, 1993[Abstract/Free Full Text]
25.
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC:
A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84:1361, 1994[Free Full Text]
26.
Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J:
Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia.
Am J Pathol
150:815, 1997[Abstract]
27.
Ribatti D, Vacca A, Nico B, Fanelli M, Roncali L, Dammacco F:
Angiogenesis spectrum in the stroma of B-cell non-Hodgkin's lymphomas. An immunohistochemical and ultrastructural study.
Eur J Haematol
56:45, 1996[Medline]
[Order article via Infotrieve]
28.
Vacca A, Ribatti D, Ruco L, Giacchetta F, Nico B, Quondamatteo F, Ria R, Iurlaro M, Dammacco F:
Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin's lymphomas.
Br J Cancer
79:965, 1999[Medline]
[Order article via Infotrieve]
29.
Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Van de Water L, Senger DR:
Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.
J Exp Med
174:1275, 1991[Abstract/Free Full Text]
30.
Salven P, Lymboussaki A, Heikkila P, Jaaskela-Saari H, Enholm B, Aase K, von Euler G, Eriksson U, Alitalo K, Joensuu H:
Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors.
Am J Pathol
153:103, 1998[Abstract/Free Full Text]
31.
Hermans J, Krol AD, van Groningen K, Kluin PM, Kluin-Nelemans JC, Kramer MH, Noordijk EM, Ong F, Wijermans PW:
International Prognostic Index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades.
Blood
86:1460, 1995[Abstract/Free Full Text]
32.
Vacca A, Ribatti D, Iurlaro M, Albini A, Minischetti M, Bussolino F, Pellegrino A, Ria R, Rusnati M, Presta M, Vincenti V, Persico MG, Dammacco F:
Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis.
Int J Clin Lab Res
28:55, 1998[Medline]
[Order article via Infotrieve]
33.
Allouche M, Bayard F, Clamens S, Fillola G, Sie P, Amalric F:
Expression of basic fibroblast growth factor (bFGF) and FGF-receptors in human leukemic cells.
Leukemia
9:77, 1995[Medline]
[Order article via Infotrieve]
34.
Menzel T, Rahman Z, Calleja E, White K, Wilson EL, Wieder R, Gabrilove J:
Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine.
Blood
87:1056, 1996[Abstract/Free Full Text]
35.
Gu XF, Bikfalvi A, Chen YZ, Caen JP, Han ZC:
Constitutive and selective expression of basic fibroblast growth factor in human leukaemia cell lines.
Eur J Haematol
55:189, 1995[Medline]
[Order article via Infotrieve]
36.
Peoples GE, Blotnick S, Takahashi K, Freeman MR, Klagsbrun M, Eberlein TJ:
T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: A potential pathologic role.
Proc Natl Acad Sci USA
92:6547, 1995[Abstract/Free Full Text]
37.
Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M:
T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: Differential production and release by CD4+ and CD8+ T cells.
Proc Natl Acad Sci USA
91:2890, 1994[Abstract/Free Full Text]
38.
Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J, Furie MB, Torcia G, Cozzolino F, Kamada T, Stern DM:
Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells.
Proc Natl Acad Sci USA
92:4606, 1995[Abstract/Free Full Text]
39.
Brunner G, Nguyen H, Gabrilove J, Rifkin DB, Wilson EL:
Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells.
Blood
81:631, 1993[Abstract/Free Full Text]
40.
Schulze-Osthoff K, Risau W, Vollmer E, Sorg C:
In situ detection of basic fibroblast growth factor by highly specific antibodies.
Am J Pathol
137:85, 1990[Abstract]
41.
Fujisaki K, Mitsuyama K, Toyonaga A, Matsuo K, Tanikawa K:
Circulating vascular endothelial growth factor in patients with colorectal cancer.
Am J Gastroenterol
93:249, 1998[Medline]
[Order article via Infotrieve]
42.
Kumar H, Heer K, Lee PW, Duthie GS, MacDonald AW, Greenman J, Kerin MJ, Monson JR:
Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer.
Clin Cancer Res
4:1279, 1998[Abstract]
43.
Salven P, Teerenhovi L, Joensuu H:
A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin's lymphoma.
Blood
90:3167, 1997[Abstract/Free Full Text]
44.
Salven P, Ruotsalainen T, Mattson K, Joensuu H:
High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer.
Int J Cancer
79:144, 1998[Medline]
[Order article via Infotrieve]
45.
Tempfer C, Obermair A, Hefler L, Haeusler G, Gitsch G, Kainz C:
Vascular endothelial growth factor serum concentrations in ovarian cancer.
Obstet Gynecol
92:360, 1998[Medline]
[Order article via Infotrieve]
46.
Standker L, Schrader M, Kanse SM, Jurgens M, Forssmann WG, Preissner KT:
Isolation and characterization of the circulating form of human endostatin.
FEBS Lett
420:129, 1997[Medline]
[Order article via Infotrieve]
47.
Sasaki T, Fukai N, Mann K, Gohring W, Olsen BR, Timpl R:
Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin.
EMBO J
17:4249, 1998[Medline]
[Order article via Infotrieve]
48.
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J:
Endostatin: An endogenous inhibitor of angiogenesis and tumor growth.
Cell
88:277, 1997[Medline]
[Order article via Infotrieve]
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ABSTRACT
INTRODUCTION