Download The Role of Tissue Factor Pathway Inhibitor

The Role of Tissue Factor Pathway Inhibitor-2
in Cancer Biology
Ewa Sierko, M.D.,1,2 Marek Z. Wojtukiewicz, M.D.,1,2 and Walter Kisiel, Ph.D.3
ABSTRACT
Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type serine
proteinase inhibitor family, is a structural homologue of tissue factor pathway inhibitor
(TFPI). The expression of TFPI-2 in tumors is inversely related to an increasing degree of
malignancy, which may suggest a role for TFPI-2 in the maintenance of tumor stability and
inhibition of the growth of neoplasms. TFPI-2 inhibits the tissue factor/factor VIIa (TF/
VIIa) complex and a wide variety of serine proteinases including plasmin, plasma kallikrein,
factor XIa, trypsin, and chymotrypsin. Aberrant methylation of TFPI-2 promoter cytosinephosphorothioate-guanine (CpG) islands in human cancers and cancer cell lines was widely
documented to be responsible for diminished expression of mRNA encoding TFPI-2 and
decreased or inhibited synthesis of TFPI-2 protein during cancer progression. Furthermore,
an aberrantly spliced variant of TFPI-2 mRNA (designated asTFPI-2) was detected, which
represents an untranslated form of TFPI-2. The levels of asTFPI-2 were very low or
undetectable in normal cells but markedly upregulated in neoplastic tissue. TFPI-2
functions in the maintenance of the stability of the tumor environment and inhibits
invasiveness and growth of neoplasms, as well as metastases formation. TFPI-2 has also
been shown to induce apoptosis and inhibit angiogenesis, which may contribute
significantly to tumor growth inhibition. Restoration of TFPI-2 expression in tumor
tissue inhibits invasion, tumor growth, and metastasis, which creates a novel possibility of
cancer patient treatment. However, more information is still needed to define the precise
role of TFPI-2 in human tumor biology.
KEYWORDS: Coagulation inhibitors, TFPI-2, cancer
T
issue factor pathway inhibitor-2 (TFPI-2) is
a homologue of tissue factor inhibitor (TFPI)—the
principal inhibitor of tissue factor–dependent blood
coagulation.1,2
STRUCTURE AND FUNCTION OF TFPI-2
The TFPI-2 molecule consists of three tandemly
arranged Kunitz-type proteinase inhibitor domains, a
1
Department of Oncology, Medical University, Bialystok, Poland;
Comprehensive Cancer Center, Bialystok, Poland; 3Department of
Pathology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico.
Address for correspondence and reprint requests: Dr. Marek Z.
Wojtukiewicz, Department of Oncology, Medical University, 12
Ogrodowa St., 15-027 Bialystok, Poland (e-mail: m.wojtukiewicz
2
negatively charged amino terminal region, and a positively charged carboxy terminal region.3 The first
Kunitz domain with arginine in its P1 reactive site is
responsible for TFPI-2 inhibitory activity.3 Recently,
other residues flanking the P1 residue, particularly at P6
and P50 , were documented to influence the inhibitory
activity and specificity of human TFPI-2.4 In 1994,
Kisiel and co-workers,5 on the basis of available data
on molecular cloning, structure, and function, revealed
@neostrada.pl).
Inhibitors of Hemostatic System in Cancer: Basic and Clinical
Aspects; Guest Editors, Marek Z. Wojtukiewicz, M.D., and Ewa
Sierko, M.D.
Semin Thromb Hemost 2007;33:653–659. Copyright # 2007 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 7
the identity of TFPI-2 with previously described placental protein 5 (PP5).6 Three types of TFPI-2 molecules (33, 31, and 27 kDa), resulting from differential
glycosylation, were identified in the extracellular matrix
of human dermal fibroblasts and human umbilical vein
endothelial cells (HUVECs).7–9
Despite the structural similarity of TFPI-2 and
TFPI, TFPI-2 serves as a weak inhibitor of tissue factor/
factor VIIa (TF/VIIa) complex, in contrast with TFPI.1–3
The dominant activity of TFPI-2 is directed at the
inhibition of a wide variety of serine proteinases
including plasmin,3,6,10,11 plasma kallikrein,3 trypsin
and chymotrypsin,3,6,12 as well as factor XIa.3 TFPI-2
failed to exhibit any inhibitory activity toward glandular kallikrein, urinary plasminogen activator, tissue
plasminogen activator, human activated protein C,
leukocyte elastase, and thrombin.3,11
The gene responsible for human TFPI-2 synthesis is localized on chromosome 7q22.13 The human
TFPI-2 gene spans 7 kb and consists of five exons and
four introns.14 The TFPI-2 gene promoter exhibits
features typical of a housekeeping gene.15
LOCALIZATION OF TFPI-2 UNDER NORMAL
CONDITIONS
TFPI-2 is synthesized in endothelial cells (ECs) of
different blood vessels (venous, arterial, and capillaries)
but predominately by the ECs of small blood vessels16
and is abundantly secreted (60 to 90%) into the extracellular matrix (ECM).16 Furthermore, expression of the
gene encoding TFPI-2 was detected in human ciliary
epithelium,17 mature placenta, heart, liver, kidneys, and
skeletal muscles.12 TFPI-2 mRNA was also demonstrated in syncytiotrophoblasts,18 whereas the product
of the gene was found both in syncytiotrophoblast and
cytotrophoblast.19 TFPI-2 protein was also immunohistochemically detected in seminal vesicles,20 colon, breast,
pancreas, stomach, larynx, kidney, endometrium, and
brain tissue.21 The plasma concentration of TFPI-2 in
men and nonpregnant women is very low (0.43 to 0.49
ng/mL).19 Moreover, TFPI-2 is present in seminal
plasma,22 preovulatory follicular fluid,23 and in the
mucus of the uterus.19
TFPI-2 PRESENCE IN NEOPLASTIC
TISSUES
Immunohistochemical studies have provided suggestive
evidence that the expression of TFPI-2 decreases with an
increasing degree of malignancy (in the case of breast,
gastric, colon, pancreatic, renal, laryngeal, and endometrial cancer and glial neoplasms).21 The highest levels of
TFPI-2 mRNA and protein were detected in normal
brain, with lesser amounts in low-grade gliomas and
anaplastic astrocytomas. In glioblastomas, TFPI-2 was
2007
undetected.24 An inverse correlation between TFPI-2
distribution and the degree of malignancy was also
observed in choriocarcinoma18 and fibrosarcoma cell
lines.25 In addition, in about one third of non–small
cell lung cancers (NSCLCs), TFPI-2 gene expression is
decreased 4- to 120-fold compared with normal lung
tissue.26,27 Neither pancreatic cancer cell lines nor primary pancreatic ductal neoplasms revealed expression of
TFPI-2 mRNA.28 Interestingly, high expression of
TFPI-2 was observed exclusively in lobular carcinoma
of the breast, which is known to be associated with a
much more favorable prognosis than ductal invasive
breast carcinoma.21 Moreover, as much as 90% of
hepatocellular carcinomas were characterized by underexpression of TFPI-2.29 Thus, there is ample evidence
that TFPI-2 production is reduced or absent during
tumor progression. However, little is known concerning
the molecular underpinnings of this phenomenon.
GENETIC AND EPIGENETIC BASIS OF
TFPI-2 EXPRESSION IN CANCER
As mentioned above, the gene for the TFPI-2 is localized
in chromosome 7,13 which is frequently associated with
genetic changes in different cancers (e.g., head and neck
carcinomas,30 gastric,18 colon,31 prostate,31 vesicular,32
ovarian18 and testicular cancer,31 malignant melanoma,
and glial neoplasms32).Several highly aggressive cancers
delete the locus for the TFPI-2 gene in chromosome 7q
region, which results in a complete lack of TFPI-2
protein expression in these cells.33–35 In human choriocarcinoma cell line, the minimal TFPI-2 promoter was
demonstrated to be located between –166 and –111 from
the translation start site, and nuclear factor-1 (NF-1),
nuclear factor-kappa B (NF-kB), and early growth response gene-1 (egr-1)/specificity protein 1 (Sp1) binding
sites were crucial for TFPI-2 inducible expression.15 The
promoter region –313 to þ 1 is critical for minimal and
inducible promoter activity of human TFPI-2 in glioma
cells.36 This region harbors sites for several transcription
factors, including SP1, activiting enhancer-binding protein-1 (AP-1), NF-kB and NF-kB-like site, and lymphoid transcription factor-1 (Lyf-1).37 Mutations at
either of two AP-1 sites (–310 to –300 and –163 to
154), as well as either of two SP1 sites (–192 to 183 and –
135 to 128), lead to reduced TFPI-2 activity.37 Promoter
polymorphism of various genes is frequently responsible
for regulation of functions of particular proteins.26 However, none of 90 NSCLC patients exhibited genetic
variations in the TFPI-2 promoter region.26
Of particular interest is epigenetic inactivation of
TFPI-2 synthesis. Aberrant methylation of TFPI-2
promoter cytosine-phosphorothioate-guanine (CpG)
islands in human cancers and cancer cell lines was widely
documented to be responsible for diminished mRNA
encoding TFPI-2 and decreased or abolished synthesis
TFPI-2 ROLE IN CANCER/SIERKO ET AL
of TFPI-2 protein during cancer progression.27–30,38–41
The finding was associated with increased cancer
growth, invasion, and dissemination.27–29,38–41 Such a
mechanism of TFPI-2 gene silencing was demonstrated
in melanoma cell lines (HMV-I, MeWo, and WM-115),
as well as in 30% of metastatic tumors, but not in primary
melanoma surgical specimens.38 One third of NSCLC
patients, particularly at stage III and IV of the disease,
exhibited methylation of TFPI-2 gene promoter in
cancer cells.27 Approximately one half of NSCLC cases
with silenced TFPI-2 gene were lymph nodes positive.27
TFPI-2 methylation was observed in all cases of esophageal adenocarcinomas examined.39 Aberrant methylation of TFPI-2 was also revealed in as many as 73% of
pancreatic cancer xenografts and primary pancreatic adenocarcinomas.28 The finding was more frequently detected in older patients.28 Interestingly, TFPI-2
methylation in endoscopically aspirated pure pancreatic
juice was observed in 60% of pancreatic cancer patients in
contrast with 20% in patients with intraductal neoplasms or 5% in individuals with chronic pancreatitis.41
The incidence of the aberrant methylation of TFPI-2 in
the pure pancreatic juice reached 100% when liver
metastases were present and was as high as 90% in
patients who presented at stage IV of the disease.41
Promoter methylation was also documented to be
responsible for TFPI-2 gene silencing in SNB19 glioblastoma cell line.40 The finding was observed in 80%
of hepatocellular carcinoma cell lines and in 50% of
human hepatocellular carcinomas.29
Although methylation of the TFPI-2 gene promoter leads to its silencing, it does not seem to provide
the sole explanation for this phenomenon.42 Rao et al42
raised the hypothesis that one or more components of
pathways regulating TFPI-2 expression had also undergone methylation-associated silencing in cancer cells. In
this context, recent observations on the extracellular
signal-regulated kinase family (ERK)/mitogen-activated
protein kinase (MAPK) pathway mediation of the
TFPI-2 promoter activity is of particular interest.43 It
has also been reported that TFPI-2 expression is downregulated in cells harboring activated ras oncogenes.25
The Ras/Raf/mitogen-activity protein kinase (MAPK)/
extracellular signal-regulated kinase (ERK) signaling
cascade regulates cell proliferation and differentiation.44
Activation of components of the latter pathway, specifically oncogenic Ras and constitutively activated ERKs,
are frequent findings in various human malignancies.45–47
A novel mechanism, by which tumor cells circumvent the effects of TFPI-2, was recently discovered.48
Specifically, an aberrantly spliced variant of TFPI-2
mRNA derived from TFPI-2 pre-mRNA splicing at
exon/intron boundaries, as well as at new sites within
exons and introns (designated asTFPI-2), was detected.48 This form of TFPI-2 mRNA is untranslated.48 The levels of asTFPI-2 were very low or
negligible in normal cells but markedly upregulated in
neoplastic tissue and in several cancer cell lines.48 Based
on the latter observation, it is conceivable that quantification of asTFPI-2 mRNA levels could be a marker of
tumor progression.
Another facet of TFPI-2 regulation derives from
its cleavage by other tumor environment components.
Recently, an extracellular metalloproteinase, ADAMTS1,
was shown to modify the binding properties of TFPI-2
that alter the extracellular location of the protein and
disrupt its function.49 It is particularly noteworthy that
ADAMTS1 is expressed in human malignant tumors
and plays a significant role in structural remodeling
facilitating cancer invasion processes.50
TFPI-2 gene is becoming increasingly recognized
as a tumor suppressor gene. Marked downregulation of
TFPI-2 expression is associated with increasing malignancy.21,24 However, this observation raises an important question regarding its biological relevance in
aggressive tumors.
THE ROLE OF TFPI-2 IN MALIGNANCY
TFPI-2, an ECM-derived inhibitor, may function in the
maintenance of the stability of the tumor environment
and inhibit the growth of neoplasms. It has been shown
to suppress invasion of choriocarcinoma tumor cells both
in vitro and in vivo.51 Similarly, TFPI-2 decreases
invasion of human lung cancer A549cell line,52 glioblastoma SNB19 cell line,24,53 fibrosarcoma HT-1080 cell
line,54 prostate cancer LNCaP cell line,55 and amelanotic melanoma C-32 cell line.56 The invasive potential
of cancer derives from proteolytic activity driven by
tumor cells, which results in ECM and basement membrane degradation.57 In fact, TFPI-2 is thought to play a
pivotal role in the regulation of plasmin-mediated ECM
proteolysis. Downregulation of TFPI-2 protein concentration enhances cancer cell ability to degrade the ECM
because TFPI-2 is a potent inhibitor of plasmin regardless of whether the enzyme is associated with the tumor
cells or ECM.3,58 TFPI-2 exerts inhibitory effect on
plasmin- or trypsin-dependent activation of pro-matrix
metalloproteinase (MMP)-1 and pro-MMP-3, which
subsequently leads to diminished ECM degradation and
decreased invasion of HT-1080 fibrosarcoma cell
lines.54,59 In addition, it is conceivable that TFPI-2
may inhibit the plasmin-mediated release of proangiogenic molecules from the ECM components. Moreover,
TFPI-2 has been demonstrated to inhibit MMP-2
formation in HT-1080 fibrosarcoma cell line25 and to
directly inhibit MMP-1, MMP-13, MMP-2, and
MMP-9 in experimental models.60 However, recently
performed studies revealed that native TFPI-2 failed to
form complexes with MMP-2, MMP-9, and MMP-1.61
TFPI-2 also failed to inhibit the proteolytic activity of
MMP-1 toward triple-helical collagen.61 Experimental
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 7
studies focused on the effect of restoration of TFPI-2
revealed inhibition of invasion and tumor growth of
several cancer lines.28,62,63
A unique characteristics of TFPI-2 were observed
in human hepatocellular carcinoma cell line.64 The
serine proteinase inhibitor was demonstrated to promote
invasion, an effect that was suggested to be a result of
TFPI-2 binding to TF-VIIa complex on cancer cells.64
It is not obvious if this phenomenon represents the
mechanism by which TFPI-2 exerts its activity in vivo
because the results of another study revealed that hypermethylation of its gene promoter was detected in as
many as 50% of human hepatocellular carcinomas,
and ectopic overexpression of TFPI-2 markedly reduced
the proliferation and invasiveness of hepatocellular carcinoma cells.29 Significantly higher amounts of TFPI-2
gene promoter hypermethylation occurs in metastatic
disease, in relation to its expression in localized cancer,38,41 suggesting that silencing of the TFPI-2 gene
is involved in the process of metastases formation.
Tumor growth depends on the balance between
the ratio of proliferation of cancer cells and their apoptosis. Recently, the role of TFPI-2 in the induction of
apoptosis was described.65,66 Highly invasive human
glioblastoma cells either lack or contain undetectable
amounts of TFPI-2, whereas normal brain tissue and
low-grade glial tumors express this protein abundantly.21,24 An increase in apoptosis was shown in
aTFPI-2–positive multiforme glioblastoma cell line
(SNB-19) and in low-grade glioma cell line (Hs683).65
Restoration of TFPI-2 in human glioblastoma cell line
(U-251) activates both intrinsic and extrinsic caspasemediated, proapoptotic signaling pathways and induces
apoptosis.66
It is thoroughly documented that activation of
blood coagulation contributes to local progression of
cancer and facilitates metastatic spread as well.67–84
Tissue factor plays a key role in the initiation of coagulation activation in malignancy.62,82 The presence of
TF was observed in loco in many tumors and resulted in
increased invasiveness and higher rate of metastases
formation.67–84 The essential role in TF/VIIa inactivation is played by TFPI.1,2 Another inhibitor of TFdependent pathway of blood coagulation is TFPI-2. It
may inhibit tumor growth via interfering with TF
activity. However, data on the influence of TFPI-2 on
cancer biology by such a mechanism are scanty and will
require additional studies. Nonetheless, it seems that
there exists a regulatory self-restricting mechanism that,
to some extent, counteracts TF influence on cancer
progression. Namely, TF activity leads to thrombin
generation, which upregulates TFPI-2 synthesis.85 In
this way, thrombin may contribute to suppression of the
extrinsic pathway of blood coagulation and subsequently
facilitate the maintenance of ECM and may attenuate
TF-mediated impact on cancer progression.
2007
The process of angiogenesis is a rate-limiting step
in cancer progression.85 Several studies highlight the role
of TFPI-2 in the regulation of new blood vessel formation. In this regard, TFPI-2 was shown to inhibit
angiogenesis in experimental models.86,87 The inhibitor
is synthesized by ECs, particularly small blood vessels,
and secreted abundantly into the ECM.16 It may facilitate the maintenance of integrity of ECM and basement
membrane of small blood vessels, thus preventing initiation of angiogenesis. Moreover, TFPI-2 plays a role in
EC adhesion as anti-TFPI-2 IgG treatment of ECs
leads to their detachment from the ECM.16 Of interest,
TFPI-2 in ECs is upregulated by the essential proangiogenic growth factor vascular endothelial growth factor
(VEGF), which suppress proliferation of ECs.88 This
may represent the mechanism for negative-feedback
regulation of VEGF activity.
Several highly aggressive neoplasms (melanoma
as well as breast, lung, prostate, and ovarian cancer)
develop a vessel-like network formed by cancer cells
themselves; the process known as vasculogenic mimicry.89–95 The structures play a role in sustained blood
supply of the nascent tumor, and their formation was
correlated with tumor progression.89–95 In experimental
melanoma, TFPI-2 was demonstrated to strongly contribute to vasculogenic mimicry plasticity.96
The presence of TFPI-2 was demonstrated in
tumor-infiltrating macrophages in gastric and renal carcinomas.21 Cancer cells are able to synthesize and release
several different cytokines that exert multidirectional
influences on normal host cells97 and inflammatory
mediators, such as tumor necrosis factor-a (TNF-a),
endotoxin, and phorbol esters, which stimulate synthesis
and secretion of TFPI-2 by HUVECs.9 The precise role
of TFPI-2 localized in tumor-associated macrophages in
cancer biology is still unknown.
On the basis of gene profiling and protein
detection, it is tempting to speculate that TFPI-2
expression is attenuated during cancer progression,
which facilitates invasion, tumor growth, angiogenesis,
as well as metastases formation. Restoration of TFPI-2
in the tumor tissue inhibits the above-mentioned
processes suggesting a novel therapeutic target for the
treatment of cancer patients. However, additional information on the precise role of TFPI-2 in the tumor
biology of particular types of human cancer is needed
to design therapeutic options based on TFPI-2 structure and function.
ACKNOWLEDGMENTS
This work was supported in part by research grant 6
P05A 096 21 from the Polish Committee of Scientific
Research (KBN) to M.Z.W. and by research grant
HL64119 from the National Institutes of Health
(to W.K.).
TFPI-2 ROLE IN CANCER/SIERKO ET AL
ABBREVIATIONS
ADAMTS1 a disintegrin and metalloproteinase with
thrombospondin motifs
AP-1
activating enhancer-binding protein 1
CpG
cytosine-phosphorothioate-guanine
egr-1/Sp1
early growth response gene-1/specificity
protein 1
ECs
endothelial cells
ECM
extracellular matrix
ERK
extracellular signal-regulated kinase
HUVECs
human umbilical vein endothelial cells
Lyf-1
lymphoid transcription factor-1
MAPK
mitogen-activated protein kinase
MEK
MAPK/ERK
MMP
matrix metalloproteinase
NF-1
nuclear factor-1
NF-kB
nuclear factor-kappa B
NSCLC
non–small cell lung cancer
PP5
placental protein 5
SP1
specificity protein 1
TF
tissue factor
TFPI
tissue factor pathway inhibitor
TNF-a
tumor necrosis factor-a
VEGF
vascular endothelial growth factor
10.
11.
12.
13.
14.
15.
16.
17.
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