Department of Cellular and Molecular Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111
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ABSTRACT |
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Often those diseases most evasive to therapeutic intervention usurp the human body's own cellular machinery or deregulate normal physiological processes for propagation. Tumor-induced angiogenesis is a pathological condition that results from aberrant deployment of normal angiogenesis, an essential process in which the vascular tree is remodeled by the growth of new capillaries from preexisting vessels. Normal angiogenesis ensures that developing or healing tissues receive an adequate supply of nutrients. Within the confines of a tumor, the availability of nutrients is limited by competition among actively proliferating cells, and diffusion of metabolites is impeded by high interstitial pressure (Jain RK. Cancer Res 47: 3039-3051, 1987). As a result, tumor cells induce the formation of a new blood supply from the preexisting vasculature, and this affords tumor cells the ability to survive and propagate in a hostile environment. Because both normal and tumor-induced neovascularization fulfill the essential role of satisfying the metabolic demands of a tissue, the mechanisms by which cancer cells stimulate pathological neovascularization mimic those utilized by normal cells to foster physiological angiogenesis. This review investigates mechanisms of tumor-induced angiogenesis. The strategies used by cancer cells to develop their own blood supply are discussed in relation to those employed by normal cells during physiological angiogenesis. With an understanding of blood vessel growth in both normal and abnormal settings, we are better suited to design effective therapeutics for cancer.
blood vessel; growth; cancer; endothelium; pericyte
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NORMAL ANGIOGENESIS |
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The adult vasculature is derived from a network of blood vessels that is initially created in the embryo by vasculogenesis, a process whereby vessels are formed de novo from endothelial cell precursors termed angioblasts (202). During vasculogenesis, angioblasts proliferate and coalesce into a primitive network of vessels known as the primary capillary plexus. The endothelial cell lattice created by vasculogenesis then serves as a scaffold for angiogenesis.
After the primary capillary plexus is formed, it is remodeled by the sprouting and branching of new vessels from preexisting ones in the process of angiogenesis. Most normal angiogenesis occurs in the embryo, where it establishes the primary vascular tree as well as an adequate vasculature for growing and developing organs (73). Angiogenesis occurs in the adult during the ovarian cycle and in physiological repair processes such as wound healing (123). However, very little turnover of endothelial cells occurs in the adult vasculature (48).
Maturation and remodeling of newly formed microvessels is accomplished
by the coordination of several diverse processes in the
microvasculature (124) that are summarized in Fig.
1. For new blood vessel sprouts to form,
mural cells (pericytes) must first be removed from the branching
vessel. Endothelial cell basement membrane and extracellular matrix are
then degraded and remodeled by specific proteases such as matrix
metalloproteinases (161), and new matrix synthesized by
stromal cells is then laid down. This new matrix, coupled with soluble
growth factors, fosters the migration and proliferation of endothelial
cells. After sufficient endothelial cell division has occurred,
endothelial cells arrest in a monolayer and form a tubelike structure.
Mural cells (pericytes in the microvasculature, smooth muscle cells in
larger vessels) are recruited to the abluminal surface of the
endothelium, and vessels uncovered by pericytes regress. Blood flow is
then established in the new vessel.
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Under normal circumstances, angiogenesis is a highly ordered process
under tight regulation, because it requires inducing quiescent
endothelial cells in a monolayer to divide and spread the vascular
network only to the extent demanded by the demands of growing tissues.
Many positively and negatively acting factors influence angiogenesis;
among these are soluble polypeptides, cell-cell and cell-matrix
interactions, and hemodynamic effects. The soluble growth factors,
membrane-bound molecules, and mechanical forces that mediate these
signals are summarized in Table
1 and are discussed
below in terms of their contribution to the mechanism of normal
angiogenesis.
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Soluble Factors
Vascular endothelial growth factor. Perhaps the most well-characterized angiogenic factor is vascular endothelial growth factor (VEGF). Alternative splicing of a single gene generates six isoforms of VEGF composed of 121, 145, 165, 183, 189, and 206 amino acids, although VEGF165 is the most commonly expressed isoform (59, 205). Interestingly, although all isoforms demonstrate identical biological activities, VEGF121 and VEGF165 are secreted into the extracellular environment whereas VEGF189 and VEGF206, and to some extent VEGF165, remain cell- or matrix-associated via their affinity for heparan sulfates (108). VEGF is a highly conserved disulfide-bonded dimeric glycoprotein, with a molecular mass of 34-45 kDa, that loses biological activity in the presence of reducing agents (40).
A wide variety of human and animal tissues express low levels of VEGF, but high levels are produced where angiogenesis is required such as in fetal tissue, the placenta, and the corpus luteum as well as in a vast majority of human tumors (59). Many mesenchymal and stromal cells produce VEGF (70). VEGF binds to at least three known tyrosine kinase receptors: Flt-1 (VEGFR-1) (47), KDR/Flk-1 (VEGFR-2) (235), and Flt-4 (VEGFR-3) (174). Functional VEGF receptors were originally characterized as endothelial cell specific (174), but they have recently been found on other normal cell types including vascular smooth muscle cells and monocytes/macrophages (113, 192). Therefore, VEGF mediates several actions derived from varied sources and may utilize endothelial as well as other cell types as effectors. VEGF receptors belong to the "7-Ig," or flt, gene family characterized by seven extracellular immunoglobulin-like domains, one membrane-spanning segment, and a conserved intracellular tyrosine kinase domain (192, 210). VEGFR-1 has the highest affinity for VEGF (Kd = 10-30 pM) (15), and it is expressed in the endothelium of adult and embryonic mice as well as in healing skin wounds (185). VEGFR-1 also is expressed on vascular smooth muscle cells (113) and monocytes (111). Interestingly, no direct migratory, proliferative, or cytoskeletal effects appear to be mediated by VEGFR-1 (255). Nonetheless, VEGFR-2, a tyrosine kinase with lower affinity (KdAngiopoietins and tie receptors. The angiopoietins belong to a family of secreted proteins, four of which have been identified to date, that bind Tie family receptors. Angiopoietins and Tie receptors have been reported to play a major role in angiogenesis. Tie receptors were discovered before angiopoietins in attempts to characterize novel tyrosine kinases in endothelium and heart tissue (56, 179).
TIE RECEPTORS. Expression patterns of the two Tie receptors identified so far, Tie1 and Tie2 (Tek), mimic those of VEGF receptors and appear to be specific for vascular endothelium (261), although cells in the hematopoietic cell lineage such as the tumor cell line K562 (178) also express Tie receptors. Tie1 mRNA is robustly expressed in embryonic angioblasts (endothelial cell precursors), vascular endothelium, and endocardium, whereas in adult tissues Tie1 mRNA is expressed weakly in endocardium but strongly in lung capillaries (130). Tie2 mRNA shows a similar embryonic localization but is detected earlier (day 7.5) than Tie1 (day 8.5), and it is expressed weakly in adult endocardium and vasculature endothelium (56). Therefore, expression patterns of both Tie receptors suggest a role in developmental angiogenesis. Genetic studies also implicate the Tie receptors in angiogenesis. Tie1-deficient mice develop extensive edema and hemorrhage and die either perinatally (209) or at embryonic day 14.5 (190). Although blood vessels are established in these mice, vascular integrity is severely compromised, suggesting that Tie1 is not necessary for endothelial cell differentiation in vasculogenesis but, rather, for integrity and survival of endothelial cells during angiogenesis (190). Tie2-deficient mice die embryonically and exhibit a reduction in the number of endothelial cells in blood vessels compared with wild-type littermates, underdeveloped hearts, vasodilation, and abnormal vascular network formation including lack of sprouting and branching vessels (57, 209). Therefore, whereas these studies suggest that both Tie1 and Tie2 are important for vascular integrity, they imply that Tie2 is crucial for sprouting and branching of vessels characteristic of angiogenesis. ANGIOPOIETINS. The angiopoietins are ~70-kDa secreted ligands for Tie2. A ligand for Tie1 has not yet been identified. mRNA for angiopoietin-1 (Ang1), the most extensively characterized member of this family, is found at embryonic days 9-11 in heart myocardium surrounding the endocardium and later in mesenchyme surrounding blood vessels (46). Although human neuroepithelioma and mouse myoblast cell lines are sources of Ang1, in situ localization studies suggest that mesenchymal cells closely associated with endothelium produce Ang1 (124). Interestingly, Ang1 does not induce endothelial cell proliferation or tube formation in vitro (46), but it does stimulate sprout formation from confluent endothelial cells cultured on microcarrier beads and embedded in three-dimensional fibrin gels (125). Accordingly, mice deficient in Ang1 exhibit many defects similar to those seen in Tie2-deficient mice: a grossly normal primary vasculature develops, but the mice die at embryonic day 12.5 because of incomplete vascular remodeling (228). The most severe defects are in the heart, where endocardial and trabecular development is notably impaired. Furthermore, branching of the vascular network and organization into large and small vessels is defective, blood vessels are dilated, and periendothelial cells are absent from underdeveloped tissue folds that are thought to be involved in normal vessel branching. When overexpressed in transgenic mice, Ang1 induces blood vessels that are more numerous, more highly branched, and larger in diameter than those in wild-type mice (229). In addition, overexpression of Ang1 causes blood vessels to be resistant to leakage induced by inflammatory agents or coexpressed VEGF (241). Hence, the vessel branching and remodeling stimulated by Ang1 signaling appears to be mechanistically related to its ability to increase the girth and stability of endothelium in newly formed angiogenic sprouts. Another angiopoietin family member, angiopoietin-2 (Ang2), was first characterized as a structural homolog of Ang1 that bound Tie2 and antagonized Ang1 (147). However, even though Ang2 blocks Ang1-mediated Tie2 autophosphorylation in endothelial cells, which express endogenous Tie2, Ang2 stimulates Tie2 autophosphorylation in NIH/3T3 cells ectopically expressing Tie2 (147). Thus Ang2 may be an Ang1 antagonist only in the context of the vasculature. Ang2 mRNA is expressed embryonically in the dorsal aorta and in punctate regions of the vasculature, and in adult tissues it is expressed in the placenta, ovary, and uterus, primary sites for angiogenesis in the adult (147). Furthermore, overexpression of Ang2 in vascular structures results in embryonic lethality with similar, yet more severe, defects (such as endothelial discontinuities) as those observed in mice lacking Ang1 or Tie2 (147). Therefore, Ang2 antagonizes Ang1 in the vasculature in vivo and may act as a check on Ang1/Tie2-mediated angiogenesis to prevent excessive branching and sprouting of blood vessels by promoting destabilization of blood vessels. In addition, vessel destabilization induced by Ang2 may allow angiogenic sprouts to be plastic and sensitive to remodeling factors. The angiogenic mechanism established by stimulation from VEGF and Ang1 and inhibition from Ang2 thus plays a major role in the regulation of normal blood vessel remodeling.Fibroblast growth factor. Basic [isoelectric point (pI) = 9.6] and acidic (pI = 5) fibroblast growth factors (bFGF and aFGF, respectively) are ubiquitously expressed 18- to 25-kDa polypeptides that are members of a large family of structurally related growth regulators (238) and have been thought to play a role in normal angiogenesis. In fact, aFGF was the first growth factor to be associated with angiogenesis. Like VEGF, both bFGF and aFGF induce processes in endothelial cells in vitro that are critical to angiogenesis. FGFs stimulate endothelial cell proliferation (90) and migration (236) as well as endothelial cell production of plasminogen activator and collagenase (158). In addition, bFGF causes endothelial cells to form tubelike structures in three-dimensional collagen matrices (160). Thus FGFs appear to induce many processes involved in angiogenesis. Nevertheless, unlike VEGF, which is mitogenic primarily for endothelial cells, FGF stimulates proliferation of most, if not all, cells derived from embryonic mesoderm and neuroectoderm, including pericytes, fibroblasts, myoblasts, chondrocytes, and osteoblasts (238).
Perhaps the most convincing evidence for a role of FGFs in angiogenesis is the fact that, like VEGF, FGFs induce sprouting of preexisting blood vessels toward an implanted bolus in vivo in the cornea and chick chorioallantoic membrane (CAM) (77, 140). Nevertheless, FGFs do not appear to play a major role in angiogenesis in vivo because vascular development is normal in mice deficient in both aFGF and bFGF (159). A clue to the way in which FGFs are delivered and signal to cells in vivo comes from the observations that aFGF and bFGF lack a signal sequence and therefore are not secreted proteins. Most FGF remains cytoplasmic or is bound to the extracellular matrix (76, 96) because of an intrinsic affinity for heparin. Thus FGF may be released upon cell disruption by an injury and might have a role in local reparative angiogenesis following tissue injury where it is deposited in the extracellular matrix. Indeed, mice deficient in FGFs display mild defects in wound healing (159). Therefore, bFGF does not appear to play a general role in all angiogenic responses but, rather, may be necessary for blood vessel remodeling associated with tissue repair.Platelet-derived growth factor.
As its name suggests, PDGF was originally purified from platelets;
however, it has since been found in many other cell types including
fibroblasts, keratinocytes, myoblasts, astrocytes, epithelial cells,
and macrophages (for review see Ref. 97). PDGFs exist as
45-kDa homodimers (PDGF-AA or -BB) or heterodimers (PDGF-AB) composed
of PDGF chains A and B. Most cells express both PDGF A and B, although
a few express only one isoform. PDGF receptors are also dimeric in
nature; they are made up of complexes between - and
-subtypes
(97);
receptor can bind both PDGF A and B chains,
whereas
receptor can bind only PDGF B. Therefore, of the three
types of receptors (
,
, and
) only one (
) can
bind all three PDGF isoforms. PDGF receptor expression follows a
pattern similar to that of PDGF; however, a majority of cell types
express only one isoform (
or
).
Transforming growth factor-.
The transforming growth factor-
s (TGF-
) represent a family of
highly conserved 25-kDa disulfide-linked homodimeric cytokines typified
by TGF-
1 (151). Before secretion from the cell,
cleavage by a furin peptidase generates a COOH-terminal 112-amino acid peptide that noncovalently associates with the NH2-terminal
pro region (called latency-associated peptide, or LAP) and dimerizes to
form mature TGF-
(187). Secreted TGF-
cannot bind
TGF-
receptors and is biologically inactive; the latent complex is activated by proteases such as plasmin and cathepsin D, low pH, chaotropic agents such as urea, and heat (134, 142).
Exposure to low pH or protease cleavage most likely activates latent
TGF-
in vivo.
Other soluble factors.
Many other soluble factors have been proposed to function in
angiogenesis, but their effects on the vasculature are not as widespread as the above-described growth factors. For example, other
growth factors such as tumor necrosis factor- (TNF-
), epidermal
growth factor (EGF), transforming growth factor-
(TGF-
), and the
colony-stimulating factors (CSFs) exhibit angiogenic properties. TNF-
is secreted mainly by activated macrophages and some tumor cells, and although it is primarily involved in inflammation and immunity (19), it shares many properties with TGF-
.
Both stimulate angiogenesis in vivo (in the CAM and cornea for TNF-
)
(81), promote endothelial cell tube formation in vitro
(137), and inhibit endothelial cell growth (81,
123). EGF and TGF-
, both of which bind the EGF receptor
(243), are 5- to 6-kDa proteins that are mitogenic for
endothelial cells in vitro and induce angiogenesis in vivo in the
hamster cheek pouch (211). In addition, granulocyte colony
stimulating factor (G-CSF) and granulocyte/macrophage
colony-stimulating factor (GM-CSF), proteins required for growth and
differentiation of hematopoietic precursors (38), induce
migration and proliferation of endothelial cells to a limited extent
(26).
Membrane-Bound Factors
In addition to factors that are secreted from cells and act at a distance from their sites of synthesis, several membrane-bound proteins play prominent roles in angiogenesis. These molecules require close cell-cell or cell-matrix contact for their effects to be felt. Integrins, cadherins, and ephrins are endothelial membrane proteins that mediate many functions involved in blood vessel assembly. In particular,v
3-Integrin.
Integrins are heterodimeric complexes composed of
- and
-subunits
that are receptors for extracellular matrix proteins and membrane-bound
polypeptides on other cells. More than 16
- and 8
-subunits can
combine to form a diverse array of >20 different integrins
(63). Extracellular matrix substrates for integrins include polysaccharide glycosaminoglycans as well as fibrous proteins such as fibronectin, vitronectin, collagen, laminin, and elastin (237). Some integrins bind short peptide sequences, such
as the RGD (Arg-Gly-Asp) sequence found in fibronectin and vitronectin, but others recognize three-dimensional conformations (8).
VE-cadherin.
Cadherins comprise a large family of Ca2+-binding
transmembrane molecules that promote homotypic cell-cell interactions
(94). These proteins serve diverse purposes in many cells.
The intracellular domain of cadherins mediates a linkage to the
cytoskeleton by binding to -catenin and plakoglobulin, two proteins
that are anchored to cortical actin by
-catenin (94).
Cadherins also mediate intracellular signaling by controlling
cytoplasmic levels of b-catenins and plakoglobulin, which, when
released from cadherins, can translocate to the nucleus and regulate
gene transcription (16).
Eph-B4/ephrin-B2. A unique class of receptor/ligand pair, eph receptors and ephrin ligands play a prominent role in blood vessel development. Eph receptors belong to the largest known family of receptor tyrosine kinases consisting of at least 14 membrane-bound proteins, and 8 transmembrane ligands (ephrins) for them have been identified (260). Interestingly, not only does an ephrin expressed on the surface of one cell bind and activate its cognate eph receptor on another cell, but through a reciprocal signaling mechanism the ephrin is also activated upon receptor engagement (107). These molecules have been well characterized in the nervous system, where they appear to assist axon guidance through repulsive signals and establish borders between neuronal compartments (72). They also are found at compartment boundaries in several other embryonic tissues, including early somites and limb precursors (85). The requirement of cell-cell contact for their engagement and activation has suggested that they are involved generally in the formation of spatial boundaries that establish the developing body plan during embryogenesis (85).
One member of the ephrin family, ephrin-B2, is expressed on arterial endothelial cells of the developing embryo, and its receptor, eph-B4, is exclusively localized to venous endothelial cells; ephrin-B2 colocalizes with eph-4B at arterial/venous interfaces after vasculogenesis has established the primary capillary plexus but before angiogenesis has remodeled it (258). Indeed, the importance of ephrin-B2 and its interaction with eph-4B during angiogenesis is highlighted by mice with a null mutation in ephrin-B2 that exhibit normal vasculogenesis but demonstrate defects in angiogenesis of the head and yolk sac vasculature and in myocardial trabeculation (258). Interestingly, ephrin-2B also is expressed in a variety of nonvascular tissues, including caudal somites (257). However, eph-4B is exclusively localized on vascular endothelial and endocardial cells, and mice with a targeted mutation in eph-4B exhibit phenotypes similar to those seen in the ephrin-2B-null mice (88). These results suggest that establishment of contact and signaling between arterial and venous compartments mediated by ephrin-B2 and eph-4B is necessary for remodeling of the established primary capillary plexus. Other ephrin/eph family members appear to play a role in angiogenesis as well. Ephrin-A1 is required for angiogenesis stimulated by TNF-Biomechanical Forces
In addition to the soluble and membrane-bound molecules described, mechanical forces acting on vascular endothelium also contribute to the pruning and remodeling processes characteristic of normal angiogenesis. The mechanical forces mediated by blood flow have profound effects on vessel growth. Vessels that are not perfused with blood eventually regress (202). This phenomenon is most apparent in the regulated cycles of angiogenesis occurring in the female reproductive system where periodic growth and regression of blood vessels cyclically remodel the ovarian, uterine, and placental tissues (199). For example, some of the highest rates of blood flow on a weight basis are observed in these tissues and are associated with extensive proliferation of vascular endothelial cells (199). On the contrary, it has been suggested that a reduction in ovarian blood flow leads to luteal regression (198), a process associated with extensive capillary bed degeneration. Furthermore, in skeletal muscle, increased blood flow induced by electrical or chemical stimulation results in capillary angiogenesis and arterial growth (5), and decreased blood flow causes a reduction in size and number of arterioles (256).Careful in vitro and in vivo characterization of the effects of blood
flow on capillary cells has revealed a mechanism by which it affects
vessel growth. In vitro, fluid shear stress induces a dramatic increase
in endothelial cell stress fiber expression (if flow is laminar)
(80), promotes endothelial cells to divide (if flow is
turbulent) (45), and stimulates the transcription of genes
for PDGF and TGF- (197), which promote angiogenesis as
described above. In vivo, increased shear stress in rabbit ear vessels
associated with enhanced blood flow correlates with an increase in
microvascular area (109). Therefore, shear stress induced
by blood flow modulates blood vessel morphogenesis. Laminar flow
stabilizes and protects the vessel wall by increasing stress fiber
expression in endothelial cells, and turbulent flow leads to further
blood vessel growth. This is an efficient mechanism of remodeling the
primary vascular plexus, because vasculogenesis results in the
overproduction of blood vessels. Nonperfused capillaries regress,
probably by endothelial cell apoptosis (201),
whereas those in which blood flow is established persist and become a stable part of the vasculature.
Thus microvascular blood vessels are remodeled in angiogenesis through several diverse mechanisms. Growth factors secreted from distant cells, transmembrane proteins binding to extracellular matrix components or to receptors on other cells, and hemodynamic forces all act in concert to regulate normal angiogenesis. In a physiological setting, these factors exert both positive and negative influences on blood vessel growth to ensure that angiogenesis is confined to metabolic demands of growing and healing tissues. However, certain pathological conditions usurp these mechanisms to enhance the spread of disease. One of the most characterized of these is tumor angiogenesis, which is discussed below in terms of its relation to normal angiogenesis.
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TUMOR-INDUCED ANGIOGENESIS |
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Tumors are populations of host-derived cells that have lost the ability to regulate growth and therefore proliferate aberrantly. Though several features distinguish them from their nontransformed counterparts, many aspects of tumor cells are similar to those of normal ones. One major similarity is the requirement for an adequate supply of oxygen and nutrients and an effective means to remove wastes in order for metabolic processes to occur and survival to be maintained. Proximity to a vascular supply fulfills these requirements for mammalian cells. Normal cells and tissues rely on physiological vasculogenesis and angiogenesis (described in detail above) to provide them with a vasculature that fulfills their metabolic demands. Tumor cells, on the other hand, can induce their own blood supply from the preexisting vasculature in a process that mimics normal angiogenesis.
The Tumor Vasculature
Tumors can establish their own blood supply by several means. Figure 2 is a schematic of tumor-induced neovascularization. In a process very similar to normal angiogenesis, a tumor may elicit the formation of blood vessels from preexisting capillaries. In addition, tumor cells are able to grow around an existing vessel and hence, at least initially, do not need to induce angiogenesis for adequate vascularization (105). Furthermore, circulating endothelial precursors, angioblast-like cells derived from bone marrow but reported to be present in the adult circulation, have recently been suggested to contribute to tumor-derived blood vessels (193). Though tumor-induced vessels form a conduit for the delivery of metabolites, ultrastructurally they are abnormal. Many lack functional pericytes (18), they are dilated and convoluted, and they are exceptionally permeant due to the presence of fenestrae and transcellular holes and lack of a complete basement membrane (32) (see Fig. 2). Furthermore, tumor vessel walls may be made up of both endothelial cells and tumor cells (35). These structural abnormalities in tumor vessels reflect the pathological nature of their induction, yet their ability to support cell growth also underlies the use of physiological mechanisms of angiogenesis that tumors commandeer for their propagation.
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Factors Involved in Tumor Angiogenesis
The induction of new blood vessel growth by a tumor is mediated through the action of many molecules, some of which are involved in normal angiogenesis. Those substances that are well characterized in tumor neovascularization are summarized in Table 2 and are described below.
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Vascular endothelial growth factor. As in normal angiogenesis, tumor angiogenesis appears to rely heavily on VEGF. Many tumor cell lines secrete VEGF in vitro (215), and by in situ hybridization VEGF mRNA is highly upregulated in most human cancers including lung, breast, gastrointestinal tract, kidney, bladder, ovary, and endometrial carcinomas, intracranial tumors, glioblastomas, and capillary hemangioblastomas (68). Both VEGF and its receptor (Flk-1) are highly expressed in metastatic human colon carcinomas and their associated endothelial cells, respectively, and production of these two proteins correlates directly with the degree of tumor vascularization (231). Furthermore, increased VEGF expression is closely associated with increased intratumoral microvessel density and poor prognosis in breast cancer patients (244). In addition to producing VEGF themselves, tumors may induce the production of VEGF in their surrounding stromal tissue (84). In this study, green fluorescent protein driven by the VEGF promoter was robustly expressed for weeks in fibroblasts surrounding both implanted and spontaneous tumors. Therefore, high levels of VEGF production in a wide variety of tumor and tumor-associated cells and robust expression of its receptor in tumor-associated blood vessels suggest that VEGF plays an important role in tumor angiogenesis.
A causative role for VEGF in tumor angiogenesis is suggested by inhibition studies. Intraperitoneal administration of anti-VEGF antibody in nude mice harboring tumors derived from injected sarcoma and glioblastoma cells significantly decreases tumor vessel density and suppresses tumor cell growth (118). By intravital examination of blood vessels stimulated by tumor spheroids administered to mice, anti-VEGF was shown to almost completely inhibit tumor neovascularization (21). These observations indicate that a general inhibition of VEGF activity in vivo results in reduced tumor angiogenesis and tumor growth. A more direct role of tumor cell-derived VEGF in stimulating angiogenesis in vivo was suggested by the dramatically impaired ability of embryonic stem (ES) cells with a targeted inactivation of the VEGF gene to form teratocarcinomas in nude mice compared with control ES cells (69). Interestingly, blood vessels induced by the VEGFFibroblast growth factor. The first tumor-derived factor known to stimulate endothelial cell proliferation and induce neovascularization in vivo was isolated by Folkman et al. (78) in the early 1970s. However, purification of this factor was difficult because of a lack of suitable bioassays, and the angiogenic activity was simply known as "tumor angiogenesis factor" (78). The advent of heparin-affinity chromatography facilitated the identification of FGF as the first known tumor-derived angiogenic factor (75, 217, 218).
A direct role for FGF in tumor angiogenesis has been suggested in an inhibition study using a soluble form of the bFGF receptor. Administration of a soluble form of the FGF receptor to mice injected with pancreaticAng2. Recent evidence strongly implicates Ang2 in tumor angiogenesis. As mentioned above, the angiopoietins play prominent roles in normal angiogenesis. Ang1 signaling through the Tie2 receptor remodels newly formed capillary tubes and stabilizes them through interactions between endothelial cells and surrounding support cells (228, 229, 241). Ang2 is an antagonist of Ang1 and destabilizes blood vessels (147). In the absence of VEGF production, Ang2 mediates blood vessel regression; however, in the presence of VEGF, Ang2-induced destabilization of vessels renders them plastic and more responsive to VEGF-mediated growth (147).
Based on Ang2 and VEGF functions in normal angiogenesis, an interesting model has been proposed for angiogenesis induced by several tumors. Contrary to initial reports that most tumors, especially metastases, originate in an environment devoid of blood vessels, many tumors start growing around existing vessels and initially do not need to induce angiogenesis to survive (261). As the tumor grows larger, however, mural cells progressively disengage from the endothelium of these co-opted vessels, and the blood vessels regress (106) by endothelial cell apoptosis. Interestingly, Ang2 is induced in the endothelium of these vessels even before they regress (105). Furthermore, robust expression of VEGF in the growing tumor cells then results in angiogenesis, and the newly formed vessels also express high levels of Ang2 mRNA (105). Therefore, Ang2 plays a dual role in tumor angiogenesis. In the early stages of tumor cell growth around an existing blood vessel, tumor cells do not produce VEGF. Instead, they induce Ang2 expression in the blood vessel, which results in vessel destabilization and regression. As the tumor grows and its metabolic demands become greater, VEGF production by the tumor induces neovascularization, and Ang2 induction by tumor cells in endothelial cells of newly formed vessels facilitates this process by rendering endothelium unstable and plastic. Indeed, by in situ hybridization, Ang2 mRNA is expressed in endothelial cells of tumor vessels but not in normal blood vessels, and it is one of the earliest markers of tumor-induced neovascularization (265). Block of the stabilizing effect of Ang1 on newly formed blood vessels by Ang2 is probably a major contribution to leakiness and fragility of tumor vessels (32). Therefore, Ang2 contributes significantly to tumor angiogenesis. Like FGF, it cooperates with VEGF to induce blood vessel growth.Interleukin-8 and matrix metalloproteinase-2. A growth factor that is not well characterized in normal angiogenesis but has attracted attention in tumor neovascularization is interleukin-8 (IL-8). An angiogenic role for IL-8 in angiogenesis was first suggested by the observation that macrophages produce IL-8 and mediate angiogenesis in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis (126, 127). Subsequently, it was shown that not only is IL-8 mitogenic and chemotactic for HUVECs in vitro, but it also stimulates angiogenesis in the rat cornea (127).
A role for IL-8 in tumor angiogenesis is suggested by the findings that IL-8 mRNA is upregulated in neoplastic tissues, such as non-small cell lung cancer (264) and melanoma (141), vs. normal ones in vivo and that its expression correlates with the extent of neovascularization. In addition, overexpression of IL-8 in nonmetastatic, IL-8-negative melanoma cells not only increases their ability to invade Matrigel-coated filters but also renders them highly tumorigenic and metastatic in nude mice (12). Also, stable transfection of gastric carcinoma cells that produce low amounts of endogenous IL-8 with the IL-8 gene allows them to produce rapidly growing, highly vascular neoplasms that are not seen with control-transfected cells (121). Furthermore, conditioned medium from the IL-8-transfected cells stimulates HUVEC proliferation (121). Although these results suggest a role for IL-8 in the induction of endothelial cell proliferation in the tumor vasculature, another mechanism may mediate the role of IL-8 in tumor angiogenesis. An important observation made in the studies using IL-8-transfected melanoma cells was that the cells exhibit an increase in MMP-2 mRNA and activity and an increase in MMP-2 promoter-driven reporter gene activity (141). Therefore, angiogenesis induced by IL-8 may have been mediated in part by its ability to stimulate production of MMP-2, which degrades basement membranes and remodels the extracellular matrix for cell invasion and migration. One of the first steps in angiogenesis, normal or pathogenic, is degradation of the extracellular matrix (124). Indeed, MMP-2 has been shown to directly modulate melanoma cell adhesion and spreading on extracellular matrix (196), and an inhibitor of MMP-2 significantly inhibits growth and neovascularization of tumors implanted into CAMs (23). Thus MMP-2 plays an important role in tumor angiogenesis. Interestingly, although MMP-2 expression is increased in cells transfected with IL-8, VEGF and bFGF mRNA levels are unchanged (12, 121). Therefore, the IL-8-mediated stimulation of tumorigenicity and blood vessel growth is independent of upregulated VEGF and bFGF activity in the tumor cells. These results suggest that IL-8-induced MMP-2 production is a major mechanism by which tumor cells induce angiogenesis. The other factors outlined above that mediate normal angiogenesis, such as PDGF, TGF-Inhibitors of Tumor Angiogenesis
In addition to the numerous factors that stimulate angiogenesis, both physiologically and pathologically, many substances including those mentioned above can inhibit blood vessel growth. More than 40 endogenous angiogenesis inhibitors have been characterized, and these can be divided into 4 major groups: interferons, proteolytic fragments, interleukins, and tissue inhibitors of metalloproteinases (TIMPs) (66). Many of these agents are in clinical trials as cancer therapeutics because inhibition of angiogenesis usually results in suppression of tumor growth. Representative members of each of the four classes of inhibitors are highlighted below.Interferons.
Interferons (INF-, -
, and -
) are members of a family of
secreted glycoproteins that were initially characterized for their antiviral effect (13). Nonetheless, one of the first
pieces of evidence showing that endogenous angiogenesis inhibitors
exist was demonstrated by the ability of IFN-
to inhibit endothelial cell chemotaxis in vitro (25). Tumor cell extracts induce
motility of endothelial cells across gold-plated coverslips, and
IFN-
suppresses this activity in a dose-dependent manner
(25). More recently, interferons have been shown to
inhibit angiogenesis in vivo: IFN-
suppresses the vascularization of
the chick embryo area vasculosa (200). It is possible that
the ability of IFN-
and IFN-
to downregulate bFGF mRNA and
protein levels in bladder, renal, colon, breast, and prostate carcinoma
cells (220) as well as the inhibitory effect of IFN-
on
endothelial cell migration (208) underlies this in vivo suppression.
Interleukins. Interleukins are proteins secreted from leukocytes that mediate a wide spectrum of activities ranging from lymphocyte activation and proliferation (165) to stimulation of IgE release from B cells (180). A subset of these lymphokines has been found to affect blood vessel growth. Interestingly, interleukins having a Glu-Leu-Arg (ELR) motif at the NH2 terminus, such as IL-8, enhance angiogenesis, and those that lack this sequence, such as IL-4, inhibit it (226).
IL-4 is well characterized to inhibit tumor growth (191). Although it may directly inhibit proliferation of some tumor cells (245) or induce a host immune reaction against the tumor (234), some tumors are inhibited by other means (101). Inhibition of neoplastic angiogenesis is another likely mechanism by which IL-4 inhibits tumor growth. IL-4 inhibits in vivo neovascularization induced by bFGF in the rat cornea and blocks the migration of microvascular endothelial cells toward bFGF in vitro (251). Therefore, inhibition of neovascularization is an important mechanism mediated by IL-4 in suppressing tumor growth.Tissue inhibitors of metalloproteinases. An important theme that has emerged in the angiogenesis field is that not only are direct effects on endothelial cell growth and migration important in regulating blood vessel growth, but a wide variety of additional interactions is crucial. In particular, the extracellular matrix is an essential component of the angiogenic response (195). Remodeled extracellular matrix components comprise a scaffold upon which endothelial cells can adhere, migrate, and form tubes, and deposition of these components forms the basal lamina that ensheaths endothelium and mural cells. As mentioned above, many proteases, including those of the metalloproteinase family, are important in effecting this remodeling necessary for progression of angiogenesis. Accordingly, the TIMPs have been found to inhibit angiogenesis. For example, transfection of the highly metastatic B6F10 murine melanoma cell line with TIMP-2 cDNA inhibited its invasive potential in vitro as well as its growth, associated neovascularization, and metastatic potential in vivo (248). Furthermore, conditioned medium from these cells exhibited a reduced ability to induce endothelial cell migration and invasion through Matrigel, and the transfected tumor cells were also suppressed in vitro invasive potential (248). In addition, in vitro migration of endothelial cells through gelatin is significantly inhibited by overexpressed TIMP-1 (67). The multiple effects of TIMPs on both endothelial and tumor cell migration render MMPs attractive targets for tumor therapy.
Proteolytic fragments. Numerous potent antiangiogenic agents are proteolytic fragments of larger, naturally occurring proteins. Interestingly, most of these cleavage products are derived from extracellular matrix components, such as collagen or fibronectin, or from enzymes such as plasminogen and MMP-2 that remodel extracellular matrix. Perhaps the most characterized inhibitors in this class are angiostatin and endostatin.
Interestingly, angiostatin was discovered as a factor somehow produced or generated by a primary tumor that circulates and inhibits the growth of remote metastases (167). Angiostatin is a 38-kDa internal fragment of plasminogen that potently inhibits capillary endothelial cell growth in vitro (28, 167). In addition, intraperitoneal administration of angiostatin potently inhibits the neovascularization and metastasis formation in mice observed after a primary tumor has been removed (28). Furthermore, by engineering various cell lines, including those derived from melanoma (6) and glioma (232), to express angiostatin, tumors induced by them in mice are significantly inhibited in growth and neovascularization. Although the mechanism by which angiostatin is produced or generated from plasminogen in vivo, human prostate carcinoma cells have been reported to express a serine protease that generates biologically active angiostatin from purified human plasminogen or plasmin (86). However, the identity of this protease is unknown. Endostatin is a 20-kDa fragment of type XVIII collagen that has been identified as a factor produced by hemangioendothelioma cells that specifically inhibits endothelial cell proliferation (166). Similar to angiostatin, endostatin dramatically inhibits angiogenesis in vivo in the CAM assay, potently inhibits the growth of metastases of a primary Lewis lung tumor, and induces almost complete regression of a wide variety of primary tumors (166). Interestingly, repeated administration (2-6 treatment cycles) of endostatin to mice bearing tumors derived from Lewis lung carcinoma, T241 fibrosarcoma, or B16F10 melanoma induces no drug resistance in the host and results in tumor dormancy that requires no further treatment (20). These results indicate that endostatin can irreversibly halt tumor progression, most likely through its antiangiogenic effects.Other antiangiogenic molecules. Several other factors mediate inhibition of tumor angiogenesis, but their effects have not been extensively characterized, perhaps because they are not as potent or as amenable to therapeutic delivery as the agents mentioned above. One of these molecules is thrombospondin-1 (TSP-1). The antiangiogenic activity of TSP-1 was discovered during a screen for genes that promote (tumor promoters) or inhibit tumorigenesis (tumor suppressors). One screen for such regulatory genes revealed that a nontumorigenic hamster cell line became tumorigenic upon mutational inactivation of a tumor suppressor gene (194). Interestingly, the nontumorigenic cell line secreted a potent inhibitor of endothelial cell chemotaxis in vitro and corneal neovascularization in vivo, and the tumorigenic cell lines secreted much less of this activity (194). The inhibitory activity was shown to be due to TSP-1, and purified TSP-1 was shown to be a potent inhibitor of in vitro as well as in vivo neovascularization (89). Subsequent work has indicated that the tumor suppressor gene p53 regulates TSP-1 expression in certain cell lines (44). Furthermore, thrombospondin-2 (TSP-2), which shares high structural similarity with TSP-1 but has a distinct expression pattern (110), is a potent inhibitor of angiogenesis in vitro and in vivo (252) and inhibits tumor growth and neovascularization (225).
The experiments with TSP-1 were among the first that demonstrated the significance of an angiogenesis inhibitor in suppressing tumor growth. The list of angiogenesis inhibitors is expanding even today, and their clinical use in cancer therapy (1) is becoming evident. As more angiogenesis inhibitors are discovered it will be easier to delineate a common mechanism underlying their actions and perhaps eventually design a highly effective cancer therapeutic. ![]() |
SUMMARY |
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Angiogenesis is a complex process that relies on the coordination of many different activities in several cell types. Endothelial cells, pericytes, fibroblasts, and immune mediators express many different cytokines and growth factors that react with other cells or extracellular matrix components to effect endothelial cell migration, proliferation, tube formation, and vessel stabilization. Under physiological conditions, angiogenesis is a highly ordered process required for the normal remodeling of the primary vascular plexus formed during vasculogenesis. Not only are chemical mediators such as cytokines and membrane proteins essential for remodeling the vascular tree, but biomechanical forces such as blood flow and shear stress are also critical angiogenic factors. The reliance of a newly formed vessel on a flow of blood for survival ensures that only those vessels supporting a physiological function become a part of the vascular network. Because any nonfunctional component is eliminated from the system early in development, such a mechanism is an extremely efficient use of resources, space, and energy.
In pathological states such as cancer, mechanisms of normal angiogenesis are used to promote disease. The fact that tumors use the same angiogenic molecules to commandeer a blood supply as those utilized by the host to develop a functional blood vessel network is advantageous for the tumor is several ways. First, angiogenesis is a highly effective means of establishing a system to deliver nutrients and remove wastes from a source of metabolic demand. Normal mammalian tissues thrive because blood vessel growth meets their metabolic needs (4), and tumors rely on a similar highly effective mechanism to promote survival. Also, because the tumor vasculature relies on a system created by the host, it evades host defenses. Immunologic attack on this system is prevented by recognition of it as self. Furthermore, its pathological nature also makes it abnormally plastic and renders normally quiescent endothelial cells proliferative. In the adult, angiogenesis does not occur in most tissues (123, 202), but tumors establish conditions that foster continued blood vessel growth for their propagation.
The discovery of endogenous angiogenesis inhibitors not only reveals another aspect of exquisite neovascular regulation but also reinforces the notion that tumors are indeed dependent on angiogenesis (74). Angiogenesis is a dynamic process driven by many positive factors but also curtailed by several negatively-acting molecules, and at any time it can be seen as an equilibrium between these stimulators and inhibitors. Tumors rely on the creation of angiogenic stimulators for their survival (74). Angiogenesis inhibitors push the equilibrium in favor of vessel quiescence and thus deprive tumors of a means to grow.
Because tumors are dependent on a blood supply, antiangiogenic therapy of cancer (66) theoretically represents a highly effective strategy for destroying tumors. Multiple agents that target individual factors involved in blood vessel growth as well as endogenous angiogenesis inhibitors demonstrate promise in eradicating established tumors, and several of these are in the process of being tested in the clinic (66). Endogenous angiogenic inhibitors probably represent the most effective approach to tumor therapy to date because not only have they shown efficacy in destroying established tumors (66), but at least one of these agents, endostatin, does not promote resistance to therapy upon repeated administration, a common drawback to conventional chemotherapy (20). Antiangiogenic agents, if administered before a tumor develops or becomes dependent on a vascular supply, would therefore theoretically act similarly to a vaccine in preventing tumor development, not just tumor growth. It is important to note, however, that antiangiogenic therapy represents a treatment, not a cure, for cancer. Only by targeting agents and mechanisms that cause normal cells to become tumorigenic can a cure for cancer be realized. Angiogenesis inhibitors, nonetheless, take great strides toward that goal because they block a fundamental requirement of tumor growth.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants EY-09033, GM-55110, and P30-DK-34928 to I. Herman.
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FOOTNOTES |
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Present address of M. Papetti: Dept. of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461.
Address for reprint requests and other correspondence: I. M. Herman, Dept. of Cellular and Molecular Physiology, Tufts Univ. School of Medicine, 136 Harrison Ave., Boston, MA 02111 (E-mail: ira.herman{at}tufts.edu).
10.1152/ajpcell.00389.2001
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