Journal of Bioequivalence & Bioavailability - Open Access Expert Review JBB/Vol.1 July-August 2009
J Bioequiv Availab Volume 1(2): 052-062 (2009) - 052
ISSN:0975-0851 JBB, an open access journal
The Matrix Reloaded: New Insights from Type IV Collagen Derived
Endogenous Angiogenesis Inhibitors and their Mechanism of Action
Akulapalli Sudhakar1,2,3,*
1Cell Signaling and Tumor Angiogenesis Laboratory,
Department of Genetics, Boys Town National Research Hospital, Omaha
2 Department of Biomedical Sciences, Creighton University School of Medicine, Omaha
3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha
*Corresponding author: Akulapalli Sudhakar, MS., M.Phill & Ph.D, Assistant Professor/Staff Scientist II, Creighton
University School of Medicine and University of Nebraska Mecical Center, Director: Cell Signaling and Tumor
Angiogenesis Laboratory, Boys Town National Research Hospital, 555 N, 30th Street, Omaha NE 68131,
USA, Tel: (402) 498-6681, (402) 498-6322; Fax: (402) 498-6331; E-mail: [email protected]
Received August 19, 2009; Accepted August 21, 2009; Published August 22, 2009
Citation: Sudhakar A (2009) The Matrix Reloaded: New Insights from Type IV Collagen Derived Endogenous Angio-
genesis Inhibitors and their Mechanism of Action. J Bioequiv Availab 1: 052-062. doi:10.4172/jbb.1000009
Copyright: © 2009 Sudhakar A. This is an open-access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original
author and source are credited.
Abstract
Angiogenesis, the process of neovascularization from parent blood vessels, is a prerequisite for many physiologi-
cal and pathological conditions that is regulated by a balance between the levels of endogenous angiogenic stimu-
lators and matrix reloaded angiogenic regulators. Several non-collagenous carboxy terminal end domains in
chains of type IV collagen matrix reloaded molecules selectively interact with proliferating endothelial cells by
binding to distinct integrins and regulate intracellular signaling and inhibit angiogenesis. This review will focus on
the current understanding of extra cellular matrix type IV collagen reloaded endogenous angiogenesis inhibitors
and their mechanism of action.
Introduction
An emerging area of research in cell biology is the dis-
covery of extra cellular matrix (ECM) that is reloaded
with proteolytic fragments from the basement membrane,
which exert powerful anti-angiogenic or anti-tumarogenic
activities. Angiogenesis, the process by which new blood
vessels are originated from parent blood vessels, is essen-
tial in normal development and also pathological condi-
tions such as cancer (solid tumor growth), rheumatoid
arthritis and diabetes retinopathy (Marneros and Olsen,
2001; Ortega and Werb, 2002; Sottile, 2004; Sudhakar,
2007). In cancerous conditions, tumor cells need new
blood vessels for nourishment, local growth and escape
to remote organs sites through blood circulation, a pro-
cess called metastasis. Without angiogenesis, within the
tumor, tumor cells cannot stay alive for longer time. For
this reason, matrix reloaded endogenous inhibitors of an-
giogenesis, which might not produce the same sort of re-
sistance and intolerance as exogenous compounds, might
be important candidates for anticancer therapy, either by
themselves or in combination with other inhibitors that
are used routinely in the clinics.
The first discovered ECM reloaded endogenous angio-
genic inhibitory molecule is endostatin, a 20-kDa frag-
ment of heparan sulfate proteoglycan derived from type
XVIII collagen non-collagenous (NC1) domain is best
characterized among endogenous angiogenic inhibitors.
Since initial discovery of endostatin as endogenous an-
giogenesis inhibitor, there has been an outburst in anti-
angiogenic research and in the number of endogenous
molecules that are known to promote or inhibit angiogen-
esis (Iozzo and San Antonio, 2001; Marneros and Olsen,
2001; Ortega and Werb, 2002; Schenk and Quaranta, 2003;
Sottile, 2004; Sudhakar, 2007) (Figure 1). Several endog-
enous anti-angiogenic protein fragments were discovered
that were derived from ECM constituents. Although they
are structurally different they have remarkable similari-
α
Journal of Bioequivalence & Bioavailability - Open Access Expert Review JBB/Vol.1 July-August 2009
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ISSN:0975-0851 JBB, an open access journal
ties that must be more than coincidental. More recently,
type IV collagen α1, α2, α3 and α6 chain carboxy ter-
minal NC1 domains were demonstrated to be anti-angio-
genic. These molecules that are needed to assemble vas-
cular basement membrane (VBM) to maintain the integ-
rity of blood vessels and to prevent the leakage of fluids
and loss of proteins can do the opposite actions under the
different circumstances (called matrix reloaded); that is,
they have both pro-angiogenic and anti-angiogenic ac-
tivities (Iozzo and San Antonio, 2001; Nakamura and
Matsumoto, 2005; Sudhakar and Boosani, 2008).
Therefore, matrix reloaded endogenous type IV collagen
derived angiogenic inhibitors mechanism of action are of
high significance and is updated in this review.
Structural Integrity and Biological Insights of Type IV
Collagen Matrix
The discovery of endostatin as an endogenous angio-
genesis inhibitor initiated researchers to hasten their in-
vestigation and to find other ECM derived components
that are antiangiogenic and anti-tumorogenic with the po-
tential to modulate angiogenesis. Type IV collagen is
ECM-specific and abundant collagen with various
isoforms whose network assembly is essential for the struc-
tural integrity and biological function of basement mem-
branes (Myllyharju and Kivirikko, 2004). Type IV col-
lagen has six α chains and exists in atleast three
heterotrimeric triple helical forms [α1(IV)]2α2(IV),
[α3(IV)]2α4(IV) and [α5(IV)]
2α6(IV) (Hudson et al.,
1993; Hudson et al., 2003; Kalluri, 2003). Each α(IV)
chain has a long, collagenous domain with Gly-X-Y re-
peats (X and Y represent any amino acids other than gly-
cine, but are often proline and hydroxyproline, respec-
tively) interrupted by short NC sequences, an N-terminal
cysteine-rich 7S domain and a C-terminal NC1 domain
of 230 amino acids. These superstructures self-associate
from triple helical monomers to form either dimers (via
NC1–NC1 interactions) or tetramers (via 7S-domain in-
Figure 1: The angiogenic balance between angiogenic activators and angiogenic inhibitors regulate vascular homeosta-
sis. Angiogenesis under physiological and pathological conditions is associated with up-regulation of angiogenic factors
and/or down-regulation of angiogenic inhibitors. Up-regulation of angiogenic inhibitors and/or down-regulation of an-
giogenic activators may be associated with impaired neovascularization capacity. VEGF, vascular endothelial growth
factor; bFGF, basic fibroblast growth factor; IGF-I, insulin-like growth factor-I; IL-8, interleukin-8; PDGF, platelet-
derived growth factor; PlGF, placenta growth factor; TGF-α and β, transforming growth factor-α and β.
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teractions) with 56 possible combinations (Kalluri, 2003;
Sudhakar and Boosani, 2008).
Type IV collagen molecules that contain different α(IV)
chains have different cellular interactions and localiza-
tions. Furthermore, proteolysis of ECM might expose cells
to new, cryptic interaction sites within type IV collagen
(Kalluri, 2003). The α1(IV) and α2(IV) chains are ubiq-
uitous and [α1(IV)]2α2(IV) heterotrimers are predomi-
nant, whereas α3(IV) chain expression is limited. Inter-
estingly, in many patients with Alport’s syndrome (either
X-linked autosomal recessive hereditary kidney disease
that is characterized by a defect in glomerular BM) muta-
tions in α5(IV) chain led to loss of α3(IV) chain which
indicates that their expression is co-dependent (Cosgrove
et al., 1996; Hudson et al., 2003). Type IV collagen is
highly conserved, structurally and functionally in verte-
brates and in invertebrates (Blumberg et al., 1987; Netzer
et al., 1998). Normally, type IV collagen promotes cell
adhesion, differentiation, migration and growth (Sarras et
al., 1993). In C. elegans two genes encoding type IV col-
lagen have been identified, emb-9 (α1-like) and let-2 (α2-
like). Mutations in these two genes might cause either in-
hibited embryonic development or variably severe tem-
perature-sensitive mutants (Myllyharju and Kivirikko,
2004). In Drosophila, type IV collagen genes DCG1 and
viking are involved in muscle attachment and pericardin
is involved in development of heart. A mutation in α1(IV)
was identified with perinatal cerebral hemorrhage stroke,
porencephaly, endoplasmic reticulum stress and geneti-
cally modifiable ocular dysgenesis (Gould et al., 2007;
Gould et al., 2005; Gould et al., 2006). In humans or in
mice, no specific disease is yet linked to mutations in
α2(IV) chains.
Type IV Collagen Matrix Reloaded Angiogenesis In-
hibitors and their Mechanism of Action
Arresten: Arresten (α1(IV)NC1), a 26-kDa protein is
derived from C-terminal NC1 domain of α1 chain type
IV collagen by proteases (Boosani and Sudhakar, 2006;
Colorado et al., 2000; Sudhakar et al., 2005). Not much is
known about this angiogenesis inhibitor but its anti-
antiangiogenic actions are presumably mediated through
α1β1 integrins (Sudhakar et al., 2005). Integrin α1β1 is a
collagen binding receptor that also binds to other base-
ment membrane components such as laminin (Keely et
al., 1995; Zutter and Santoro, 1990). Blocking of α1β1
integrin interactions with ECM inhibits angiogenesis in-
dicating that the integrin α1β1 acts as a pro-angiogenic
receptor (Senger et al., 1997). Among the integrin recep-
tors for collagen, α1β1 integrin activates the Ras/Shc
mitogen activated protein kinase (MAPK) pathway pro-
moting cell proliferation (Senger et al., 1997; Sudhakar et
al., 2005). Arresten binds to α1β1 integrin in a collagen
type IV dependent manner and mediates its anti-angio-
genic and pro-apoptotic functions and inhibits angiogen-
esis by inhibiting endothelial cell proliferation, migration
and tube formation (Boosani et al., 2009; Nyberg et al.,
2008; Sudhakar et al., 2005). Significant halt in patho-
logical angiogenesis and tumor growth was reported in
α1 integrin knockout mice (Pozzi et al., 2000). Whereas
arresten had no effect in α1 integrin null endothelial cells,
on the contrary it significantly inhibited proliferation of
wild type mouse endothelial cells, which confirms the sig-
nificance of integrin α1β1 mediated signaling of arresten
(Sudhakar et al., 2005). Arresten inhibits phosphorylation
of FAK/Ras/Raf/MEK1/2 and p38 MAPK when endot-
helial cells are plated on collagen type IV matrix (Figure
2). Similar inhibition of MAPK signaling was not observed
with arresten treatment to α1 integrin null endothelial cells
(Sudhakar et al., 2005). Downstream to FAK, Akt/PKB
plays an important role in endothelial cell survival signal-
ing. Arresten does not inhibit Akt or phosphatidyl-3-ki-
nase (PI3 kinase) phosphorylation suggesting that arresten
regulates migration of endothelial cells in an Akt-inde-
pendent manner (Sudhakar et al., 2005).
Interestingly proteolysis of ECM reloaded arresten in-
hibits hypoxia (lack of oxygen) inducible factor alpha
(HIF-1α) and VEGF expression in endothelial cells in an
α1β1 and FAK/Ras/Raf/MEK1/2 and p38 MAPK depen-
dent manner (Sudhakar et al., 2005) (Figure. 2). HIF-1α
is an oxygen-dependent transcriptional factor which plays
prominent roles in tumor angiogenesis (Semenza, 2003).
HIF-1α regulates cellular responses to physiological and
pathological hypoxia, and studies so far demonstrate that
HIF-1α is a potential target to inhibit tumor angiogenesis
(Unruh et al., 2003). HIF-1α transcriptionally regulates
VEGF expression in hypoxic cells and promotes angio-
genesis in solid tumors (Carmeliet et al., 1998; Kung et
al., 2000; Sudhakar et al., 2005). These findings suggest
that HIF-1α is a prime target for anticancer therapies and
this hypoxic inhibitory activity might be exploited for
antiangiogenic therapy in the treatment of different solid
tumor cancers, but more pre-clinical laboratory studies
are needed.
In addition, recently we also reported that arresten in-
hibits VEGF mediated angiogenesis by promoting
apoptosis in different endothelial cells. Arresten activates
caspase-3/PARP [Poly (ADP-ribose) polymerase] activa-
tion and negatively impacts FAK/p38-MAPK phospho-
rylation via down-regulation of anti-apoptotic Bcl-2 and
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Figure 2: Schematic illustration of distinct antiangiogenic and anti-tumorogenic signaling mediated by different type IV
collagen matrix reloaded molecules. Tumstatin, arresten and canstatin interact with αVβ3/α3β1, α1β1 and αVβ3/αVβ5
integrins, respectively, to inhibit the phosphorylation of focal adhesion kinase (FAK). Tumstatin: It binds to αVβ3 and
3β1 integrins and inhibits the pathway that includes phosphorylation of FAK, PI3-K, Akt, mTOR, 4E-BP1 and eIF4E to
decrease endothelial cell protein synthesis and proliferation. In addition tumstatin also inhibits NFκB mediated signaling
in hypoxic conditions leading to the inhibition of COX-2, VEGF and bFGF expressions, resulting in inhibition of hy-
poxic tumor angiogenesis. Arresten: It binds to α1β1 integrin and inhibit phosphorylation FAK, causes inhibition of Ras,
Raf, extra cellular signal related kinase 1 (ERK1) and p38 MAPK pathways that leads to inhibition of HIF-1α and VEGF
expression resulting in inhibition of endothelial cell migration, proliferation and tube formation. In addition arresten
initiates two apoptotic pathways, involving activation of caspase-9 and -8, leading to activation of caspase-3 and PARP
cleavage. (a) Arresten activates caspase-3 directly through inhibition of FAK/p38-MAPK/Bcl-2/Bcl-xL and activation of
caspase-9; (b) Integrin α1β1 cross talk with Fas-L through mitochondrial pathway and leads to activation of caspase-8
and-3 in proliferating endothelial cells. Canstatin: It binds to αVβ3/αVβ5 integrins and inhibits two apoptotic pathways,
involving activation of caspase-8 and casoase-9, leading to activation of caspase-3. Canstatin activates procaspase-9 not
only through inhibition of the FAK/PI3K/AKT pathways but also by integrins cross talking mitochondrial pathway
through Fas-L dependent caspase-8 activation leads to endothelial cell apoptosis. CM represents cell membrane.
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Bcl-xL expressions with no effect on pro-apoptotic Bax
expression leading to endothelial cell death (Boosani et
al., 2009; Nyberg et al., 2008). These Bcl-family mem-
bers are considerably involved in the balance of pro and
anti-apoptotic signals at the mitochondrial level. The bal-
ance of pro and anti-apoptotic protein expression deter-
mines whether cells undergo apoptosis (Cory et al., 2003).
These studies demonstrate that activation of apoptotic sig-
naling in proliferating endothelial cells is sufficient to in-
hibit new blood vessel formation. These results are in con-
sistent with earlier reports that anti-angiogenic and anti-
tumorogenic activity of arresten is mediated via integrin
cross talk with a cell-intrinsic apoptotic pathway (Boosani
et al., 2009) (Figure 2). The endothelial specific inhibi-
tory actions of ECM reloaded arresten may be of benefit
in the treatment of a variety of diseases with a neovascular
component.
Canstatin: Proteolytic degradation of type IV collagen
liberates a 24-kDa protein fragment from C-terminal NC1
domain of α2 chain, called canstatin [α2(IV)NC1] that
was reported to inhibit tumor angiogenesis and tumor
growth (Kamphaus et al., 2000; Petitclerc et al., 2000).
Canstatin binds to endothelial and tumor cells in an αVβ3
and αVβ5 integrin dependent manner (Magnon et al.,
2005). Canstatin competes with type IV collagen of ECM
for cell surface integrin binding and reverses the
proliferatory and migratory effects induced by cell-ECM
interactions. Thus, αVβ3 and αVβ5 integrins appear to
mediate the antiangiogenic and pro-apoptotic actions of
canstatin (Magnon et al., 2005; Panka and Mier, 2003).
Canstatin inhibits the growth of many tumors in mouse
xenograft models and histological studies revealed de-
creased CD31 positive vasculature. Canstatin binds to
αVβ3 and αVβ5 integrins and inhibits endothelial migra-
tion and proliferation (Kamphaus et al., 2000; Magnon et
al., 2005; Panka and Mier, 2003; Roth et al., 2005). More-
over, these events are mediated by inhibiting phosphory-
lation of FAK, Akt, mammalian target of rapamycin
(mTOR), eukaryotic initiation factor 4E binding protein-
1 (4E-BP1) and ribosomal S6 kinase (Panka and Mier,
2003). Canstatin binds to αVβ3 and αVβ5 integrins and
initiates two apoptotic pathways that includes (a) activa-
tion of caspase-8 and -9 and leads to activation of caspase-
3 and (b) activation of caspase-8 by downregulation of
Flip levels (Magnon et al., 2005; Narazaki and Tosato,
2006). Upregulation of Fas/Fas ligand triggers not only
cell death directly through caspase-3 activation but also
indirectly through mitochondrial damage via activation of
caspase-9 within the apoptosome (Magnon et al., 2005;
Magnon et al., 2008; Wang et al., 2008). On the other
hand, phosphorylated FAK/PI3K is known to inactivate
the mitochondrial apoptotic pathway by inhibition of
caspase-9 (Figure. 2). Canstatin directly activates
procaspase-9 through inhibition of FAK/PI3K pathway
and amplifies the Fas-dependent pathway in mitochondria.
An intravitreous injection of canstatin causes selective
apoptosis in endothelial cells resulting in inhibition of
neovascularization when given prior to the onset of new
vessel sprouting (Magnon et al., 2005; Roth et al., 2005).
Importantly, when canstatin was given after
neovascularization had already developed, it caused the
new vessels to regress.
In tumor cells canstatin activates caspase-3 only in the
mitochondrial pathway (Figure. 2). Canstatin suppresses
tumor angiogenesis in different mice xenograft models
and also laser induced choroidal nonvascular (CNV) in
mice, indicating it as a strong antiangiogenic agent in the
choroid and as a therapeutic candidate for treatment of
CNV in age related macular degeneration (Lima et al.,
2006). These results demonstrate that canstatin binds to
αVβ3 and αVβ5 integrins and inactivates FAK down
stream signaling leading to inhibition of cell proliferation
and migration, and thus leading to activation of apoptosis
and inhibition of tumor angiogensis.
Tumstatin: Physiological proteolysis of α3 chain type
IV collagen by MMP-9 results in tumstatin (α3(IV)NC1)
a 28-kDa C-terminal NC1 domain (Hamano et al., 2003).
The anti-angiogenic activity of tumstatin was observed
with pharmacological doses of this protein associated with
inhibition of protein synthesis in endothelial cells
(Maeshima et al., 2002; Sudhakar et al., 2003). The ex-
pression of tumstatin is down-regulated in renal carcinoma
growth (Xu et al., 2009). Inhibition of melanoma and fib-
rosarcoma cell migration using tumstatin peptide (185-
205 amino acids) was reported with a decrease in expres-
sion of membrane-bound metalloproteinase (MT1-MMP)
and activated MMP-2 (Han et al., 1997). Tumstatin in-
hibits tube formation in mouse aortic endothelial cells
embedded in Matrigel plugs and inhibits tumor growth in
different mouse models [renal cell carcinoma (786-O),
CT26 (colon adenocarcinoma), prostate carcinoma (PC3),
lewis lung carcinoma (LLC), human lung cancer (H1299),
human prostate cancer (DU145), human fibrosarcoma
(HT1080), teratocarcinoma (SCC-PSA1) and lymphatic
metastasis in an orthotopic oral squamous cell carcinoma
model] (Boosani et al., 2007; Chung et al., 2008; Hamano
et al., 2003; Maeshima et al., 2000b; Miyoshi et al., 2006;
Pedchenko et al., 2004; Petitclerc et al., 2000; Sudhakar
and Boosani, 2008). In addition tumstatin gene therapy
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enhanced anti-tumor effect of gemcitabine in murine mod-
els (Yao et al., 2005). But what integrins are engaged in
these antiangiogenic and anti-tumorogenic actions of
tumstatin? It is clear that different integrins are key tar-
gets of tumstatin to mediate its antiangiogenic and anti-
tumorogenic actions. Tumstatin interacts with endothelial
cell via αVβ3 integrin in a vitronectin and RGD indepen-
dent fashion (Maeshima et al., 2000a). Integrin αVβ3 in-
teracts with tumstatin through two separate regions. The
first region 54-132 amino acids is involved in the
antiangiogenic activity, whereas the second region 185-
203 amino acids is involved in anti-proliferative activity
in cancer cell lines (Boosani et al., 2007; Eikesdal et al.,
2008; Maeshima et al., 2000a; Pedchenko et al., 2004).
These results substantiate exact regulatory sub-domains
in tumstatin controlling adhesion and proliferation in vari-
ous cell types. The functional specificity of these two sub
domains from tumstatin in cancer or endothelial cells is
very interesting. Indeed published 3D crystal structure of
type IV collagen NC1 domain reveals N and C-homolo-
gous sub-domains (Than et al., 2002). The major differ-
ence between these sub-domains for each chain is in the
region from residues 86-95 in the N-sub-domain and 196-
209 in the C-sub-domain. These regions overlap two se-
quences that were previously identified to be having
antiangiogenic and anti-proliferative effects in cancer cells
(Borza et al., 2006). Tum-1, a tumstatin peptide, gene de-
livery into hepatocellular carcinoma cells suppressed tu-
mor growth by inhibiting angiogenesis (Goto et al., 2008).
Tumstatin or its peptides interaction with integrins seems
to be involved in the disruption of contacts between en-
dothelial or tumor cells leading to apoptosis in these cells,
but the mechanism of apoptosis activation is still not clear.
Tumstatin also binds to endothelial cells through other
integrins α6β1 and αVβ5, but the significance of these
integrins interaction is not yet clear (Boosani et al., 2007;
Maeshima et al., 2000a).
Tumstatin induces endothelial cell apoptosis by inter-
acting with integrin αVβ3 and inhibits VEGF adhesion to
matrix, and this effect was overturned by integrin αVβ3
blocking antibody. The antiangiogenic activity of tumstatin
is conferred by its interaction with integrin αVβ3 and in-
hibiting activation of focal adhesion kinase (FAK),
phosphatidylinositol 3-kinase (PI-3K), serine/threonine
kinase (Akt/protein kinase B), mammalian target of
rapamycin (mTOR) and prevents dissociation of eukary-
otic translation initiation factor 4E (eIF4E) from 4E bind-
ing protein (4E-BP1) leading to the inhibition of Cap-de-
pendent translation in proliferating endothelial cells
(Maeshima et al., 2002; Sudhakar et al., 2003) (Figure.
2). PTEN/Akt pathway dictates the direct αVβ3 integrin
dependent growth inhibitory action of T7 peptide of
tumstatin in glioma cells in-vitro and in-vivo (Kawaguchi
et al., 2006). Furthermore, these results conforms a spe-
cific function for integrins in mediating endothelial cell
specific inhibition of cap-dependent translation, signify-
ing a possible specific mechanism of tumstatin. Whereas
α3β1 integrins bind to C-terminal region 185-203 resi-
dues associated with antiangiogenic and anti-tumorogenic
activity (Borza et al., 2006), 17426256}. These results
compare earlier findings that tumstatin binds to α3β1
integrin and transdominantly inhibits expression of αVβ3
integrin (Boosani et al., 2007). Interestingly recent stud-
ies clearly show tumor suppressive action of tumstatin or
its peptide (T3; C-terminal end comprising amino acid
residues 133-244 region of the tumstatin) that directly
inhibits growth of glioma cells (Kawaguchi et al., 2006).
In addition a cyclopeptide derived from tumstatin
(YSNSG) was also shown to inhibit human melanoma
cell proliferation (Thevenard et al., 2006).
Recently we discovered that tumstatin inhibits hypoxia
induced cyclo-oxygenase-2 (COX-2) expression in endot-
helial cells via FAK/Akt/NFkB (nuclear transcription fac-
tor-kappa B) pathway leading to decreased
tumorangiogenesis and tumor growth in a α3β1 integrin
dependent manner (Figure 2). In addition to COX-2 inhi-
bition, the down stream VEGF and bFGF protein expres-
sion was also inhibited upon tumstatin treatment to en-
dothelial cells (Boosani et al., 2007). Moreover, research-
ers have confirmed that inhibition of COX-2 signaling
serves as a therapeutic benefit in different cancer models
and potential target for tumor angiogenesis (Boosani et
al., 2007; Harris, 2002). These findings indicate that there
may be several targets for the inhibitory effects of tumstatin
in tumor-angiogenesis. All these studies support that the
antiangiogenic and anti-tumorogenic activity of tumstatin
is mediated through αVβ3 and α3β1 integrins. Astonish-
ingly, aberrant tumor growth and tumor vasculature is
observed in tumstatin knockout mice, demonstrating that
tumstatin is playing a prominent role in pathological an-
giogenesis to decrease tumor progression (Hamano and
Kalluri, 2005; Hamano et al., 2003). However in a con-
trolled physiological angiogenic process such as wound
healing, tumstatin does not affect the physiological an-
giogenesis and /or neovascularization. The amino acids
residues 185-191 that contain the sequence CNYYSNS
in which the YSNS motif forms a β-turn have the same
anti-tumor activity compared to intact tumstatin
(Thevenard et al., 2006). Furthermore, replacing Cys185
with Asp, but not Met prevents the anti-tumor activity,
which indicates the importance of a sulfur atom in its struc-
ture and function (Thevenard et al., 2006; Thevenard et
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al., 2009). Although tumstatin is efficient in reducing
tumorangiogenesis and /or tumor neovascularization, its
exact role needs to be deciphered.
Signaling Convergence and Complementarities Be-
tween Arresten, Canstatin and Tumstatin
The carboxy terminal localization might be necessary
for different proteases to access and liberate the
antiangiogenic domains from type IV collagen that are
embedded in the ECM. These protease-generated domains
exert their effects by binding to different integrins that
help modulate how cells interact with and are affected by
matrix components. The functional integrin receptor for
each anti-angiogenic molecule liberated from type IV col-
lagen are different and specific; α1β1 for arresten, αVβ5/
αVβ3 for canstatin and αVβ3/α3β1/αVβ5/α6β1 for
tumstatin. This indicates that the mechanism of integrin
receptors engagement and downstream signaling mecha-
nism might also be different and specific for matrix re-
loaded endogenous angiogenesis inhibitors, although some
common intracellular signaling components vary between
these angiogenic inhibitors. Arresten and canstatin seem
to exert their effects on the endothelial cytoskeleton that
is essential for the cells to migrate and form capillary like
structures. Canstatin and tumstatin function by inhibiting
protein synthesis and growth and survival of proliferating
endothelial cells. Arresten, canstatin and tumstatin can
directly affect the integrin receptor complement and have
functional consequences (Table 1). Finally, these three
antiangiogenic domains are different structurally, which
explains why they interact with different integrins and have
different effects on angiogenesis. By limiting our focus to
these three antiangiogenic domains, we hope to highlight
similarities that might also apply to other undiscovered
antiangiogenic ECM fragments and further our under-
standing of angiogenesis inhibition with potential thera-
peutic implications against cancer.
Significance of Bioavailability of ECM Reloaded En-
dogenous Angiogenesis Inhibitors
At present there are several ECM derived endogenous
angiogenesis inhibitors in pre-clinical trails including type
IV collagen derived arresten, canstatin and tumstatin
(Table 1). These endogenous matrix reloaded molecules
were found available in patients at nano molar levels.
Owing to their strong anti-angiogenic and anti-
tumorogenic actions and their availability in meager quan-
tities, these endogenous molecules have been synthesized,
expressed and purified from different heterologus systems
to increase their bioavailability and to treat patients with
neovascular diseases such as cancer, rheumatoid arthritis
and diabetic retinopathy.
Concluding Remarks
Angiogenesis is a dynamic process. In-vivo, endogenous
molecules have been identified that stimulate, inhibit and
modulate this process. A common, revolutionary theme
has gradually emerged for endogenous, ECM derived anti-
Table 1: Type IV collagen matrix reloaded angiogenesis inhibitors and their mechanisms of action.
Angiogenesis
inhibitors name Arresten Canstatin Tumstatin
Origin α1 chain Type IV collagen NC1 domain
α2 chain Type IV collagen NC1 domain
α3 chain Type IV collagen NC1 domain
Generated Matrix metalloprotensae-9 Matrix metalloprotensae-9 and-2 Matrix metalloprotensae-9,-3 and -13
Integrin
binding α1β1,? αVβ3, αVβ5,? αVβ3, α3β1, α6β1, αVβ5,?
Proliferation Inhibits endothelial
proliferation Inhibits endothelial proliferation Inhibits endothelial proliferation
Migration Inhibits endothelial
migration Inhibits endothelial migration No effect on endothelial migration
Tube formation Inhibits endothelial tube
formation
Inhibits endothelial tube
formation Inhibits endothelial tube formation
Antiangiogenic
activity
Inhibits endothelial
migration and promoted
apoptosis
Inhibits protein synthesis by
activating endothelial apoptosis
Inhibits endothelial growth and
protein synthesis
Pathways
affected
FAK/MAPK/HIF1α and FasL/Bcl-2/Bcl-xL mediated
signaling
FAK/Akt/PI3/mTOR/eIF-4E/4E-
BP1 and FasL mediated
signaling
FAK/Akt/PI3K/mTOR/eIF-4E/4E-
BP1 and NFkB/COX-2 mediated
signaling
Journal of Bioequivalence & Bioavailability - Open Access Expert Review JBB/Vol.1 July-August 2009
J Bioequiv Availab Volume 1(2): 052-062 (2009) - 059
ISSN:0975-0851 JBB, an open access journal
angiogenic molecules: C-terminal end fragments of many
type IV collagen matrix exert their inhibitory effects (at
least in part) by interacting with integrins. It is feasible
that proteases that degrade ECM or VBM and enable en-
dothelial cell migration during angiogenesis also gener-
ate C-terminal anti-angiogenic peptides. In pathological
conditions such as cancer, anti-angiogenic signals might
be overwhelmed by pro-angiogenic (growth factors) sig-
nals that are produced by tumor cells.
Arresten canstatin and tumstatin are antiangiogenic and
are also potent anti-tumorogenic molecules that are de-
rived from the C-terminal end of type IV collagen seem
to have diverse complementary effects. In addition to di-
rect functional interactions among these type IV collagen
NC1 domains, the antiangiogenic activity of these NC1
domains is modulated by partially overlapping signal
transduction pathways. However, till date several ques-
tions remain to be answered and numerous issues need to
be solved like how these antiangiogenic NC1 domains
are reloaded from matrix? Are these domains regulating
different signaling mechanisms? Is it significant that these
domains are C-terminally derived? Are there any other
cellular receptors for these domains in addition to cell
surface integrins? To what extent does the overlap in sig-
naling affect the anti-angiogenic potencies of the indi-
vidual domains in-vivo? Are the physiological blood lev-
els of these domains generated from type IV collagen (all
are in nano-molar range) sufficient to exert anti-tumor
activity? Is the presence of these domains in the circulat-
ing blood a mere indicator of turnover of the ECM re-
loaded? Should their in-vivo activity be viewed as a phar-
macological effect? Most importantly, will any of these
collagen type IV derived endogenous angiogenesis inhibi-
tors be a successful clinical tool in the fight against can-
cer and other vascular diseases such as choroidal
neovascularization of age related macular degeneration?
Whatever the final results, by recognizing the common-
alities of type IV collagen ECM derived endogenous anti-
angiogenic domains, we should gain invaluable, clinically
significant insights for optimal therapeutic interventions.
Acknowledgements
This work was supported by Flight Attendant Medical
Research Institute Young Clinical Scientist Award Grant
FAMRI 062558 (AS); Dobleman Head and Neck Cancer
Institute Grant 61905 (AS); startup funds of Cell Signal-
ing and Tumor Angiogenesis Laboratory at Boys Town
National Research Hospital (AS). I thank Dr. Chandra S.
Boosani for critical reading of the review.
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TitleAuthorsAffiliationsCorresponding authorDatesCitationCopyright
AbstractIntroductionStructural Integrity and Biological Insights of Type IVCollagen MatrixType IV Collagen Matrix Reloaded Angiogenesis Inhibitorsand their Mechanism of ActionCanstatinTumstatin
Signaling Convergence and Complementarities BetweenArresten, Canstatin and TumstatinSignificance of Bioavailability of ECM Reloaded EndogenousAngiogenesis InhibitorsConcluding Remarks
AcknowledgementsFiguresFigure 1Figure 2
TablesTable 1
References
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