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[Frontiers
in Bioscience 6, d776-784, June 1, 2001] |
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BIOIMMUNOTHERAPEUTIC
TARGETS ON ANGIOGENETIC BLOOD VESSELS IN SOLID MALIGNANGIES Michele Maio, Maresa Altomonte, Luana Calabrò,
Ester Fonsatti Cancer Bioimmunotherapy
Unit, Centro di Riferimento Oncologico, Istituto Nazionale di Ricovero e Cura
a Carattere Scientifico, 33081 Aviano, Italy TABLE OF CONTENTS 1. Abstract 1. ABSTRACT Physiological angiogenesis
is a tightly regulated process that occurs mainly during reproduction, development
and wound healing. Although angiogenesis is a continuous process, different
consecutive steps can be identified, including: i) release of
pro-angiogenetic factors; ii) release of proteolytic enzymes; iii)
endothelial cell migration, morphogenesis and proliferation. Angiogenesis is
also a hallmark of malignant diseases, and an inverse correlation between
tumor vascularity and survival was demonstrated. Thus, strategies aimed at
interfering with tumor blood supply by targeting tumor vasculature, presently
represent promising new approaches for the treatment of solid malignancies.
In fact, at least 30 angiogenetic inhibitors, utilized alone or in
combination with other therapeutic agents, are currently being tested in
clinical trials in humans. In this paper, we will review current knowledges
on selected molecules expressed by endothelial cells and involved in distinct
steps of the angiogenetic process, that represent potential targets for
bioimmunotherapeutic approaches in human malignancies. 2. INTRODUCTION Angiogenesis is a complex
process that leads to new blood vessels development from pre-existing
microvessels, and involves sequential events including proteolysis and
remodeling of the extracellular matrix, as well as proliferation and
migration of endothelial cells (1). In the adult, with the exception of the
reproductive cycle in women, angiogenesis occurs in response to pathological
conditions such as inflammation, wound healing and hypoxia (2). Furthermore,
excessive or insufficient vascularization has been associated with several
non-malignant diseases (2-6), and it has long been established that
angiogenesis plays a crucial role in tumor growth and metastasis (7). In this
regard, it has been demonstrated that microvascular density correlates with
distant metastasis and prognosis in solid malignancies of different histotype
(8-13), and in hematological malignancies (14-15). Recent progresses in
identifying and characterizing physiological regulators of blood vessels
development, prompted several pre-clinical studies designed to block tumor
vessel growth in order to interrupt blood supply to neoplastic cells. In
light of these pre-clinical data, a variety of angiogenetic inhibitors are
currently being tested in clinical trials aiming to target specific molecules
involved in blood vessel neoformation, or to directly inhibit specific
biologic functions of endothelial cells or their response to angiogenetic
stimuli (16). Due to their active
involvement in angiogenesis, targeting of proliferating endothelial cells
presents several advantages compared to conventional treatment of human
malignancies; in fact, it allows: i) easy accessibility of therapeutic agents
to endothelial cells through the blood stream; ii) suitability of this
therapeutic strategy to solid tumors of different histotype; iii) targeting
of a genetically stable cell population, thereby reducing the possibility of
acquiring drug resistance. In addition, targeting of proliferating endothelia
potentially amplifies the killing of transformed cells since each blood
capillary sustains the growth of a great number of malignant cells (17). Although anti-angiogenetic
therapy currently represents one of the most promising approaches for cancer
treatment, a number of limitations must be taken into account when
anti-angiogenetic therapies are carried out in humans. In fact, angiogenesis
is highly regulated by a balance between positive and negative stimuli, that
are tightly coordinated (1). Additionally, the mechanism of action of several
angiogenetic inhibitors is poorly understood yet (1). Furthermore, cytokines
and pro-angiogenetic molecules secreted by cancer and immune cells can
modulate the phenotypic profile of tumor endothelia (1). Finally, the
quantification of angiogenesis in response to angiogenetic inhibitors
remains, to date, impractical in metastatic diseases; thus, the
identification of reliable soluble markers of angiogenesis is required to
monitor the effectiveness of anti-vascular therapies. In this regard, recent
findings suggested that measurement of serum vascular cell adhesion molecule
(VCAM)-1 might help in the assessment of anti-angiogenetic drugs currently in
clinical trials (18). 3. VASCULAR ENDOTHELIAL
GROWTH FACTOR (VEGF) VEGF is a disulphide-linked
dimeric glycoprotein, that represents a key mediator of vasculogenesis and
angiogenesis (19-21), and presents at least 5 isoforms (VEGF121, VEGF145,
VEGF165, VEGF189, VEGF206) generated by alternative splicing of a single gene
(19-20). These different isoforms show similar biological activities, but
differ for their binding to heparin and to the extracellular matrix (22). The
smaller isoforms are secreted in a soluble form, whereas the larger ones
remain cell-associated and their availability is regulated by proteolysis
(22). Many different cell types, including cancer cells, are able to produce
VEGF that exerts its biological activity predominantly on endothelial cells
(19-20). In vivo, it induces both vascular permeability and angiogenesis,
and contributes to vasculature maintenance (20, 23). In vitro, VEGF
promotes endothelial cell proliferation and it modulates the expression of
adhesion molecules such as VCAM-1 and ICAM-1 on endothelial cells (20).
Additionally, it has been recently demonstrated that VEGF prolongs the
survival of human dermal microvascular endothelial cells by inducing the
expression of the anti-apoptotic protein Bcl-2 (24). Increased levels of serum
VEGF and of VEGF expression have been found in different angiogenesis-related
diseases including malignancies of different histotype (25-26), and anti-VEGF
monoclonal antibodies (mAb) strongly inhibited the growth of human tumor
xenografts transplanted subcutaneously in nude or SCID mice (27-30). Taken
together, these studies demonstrated that treatment with anti-VEGF mAb
inhibited tumor neovascularization in animal models, and interfered with
tumor vasculature maintenance, malignant ascites fluid formation, and
metastatic spreading (27-30). However, tumor growth resumed upon cessation of
the mAb treatment, suggesting that it may not be sufficient for complete
tumor eradication (27, 31). Thus, curative therapy in cancer patients may
necessitate a combination of both anti-angiogenetic agents such as anti-VEGF
mAb and cytotoxic agents, to disrupt both tumor and endothelial cells (27).
Humanized forms of anti-VEGF mAb, which retain the same affinity and efficacy
of murine mAb, have been generated and are being tested in humans (16, 32-34,
URL: http://cancertrials.nci.nih.gov). Results emerging from Phase I clinical
trials with anti-VEGF mAb, administered alone or in association with
chemotherapy, showed that these treatments are well tolerated; thus, human
anti-VEGF mAb can be safely combined with chemotherapy without apparent
synergistic toxicity (33-34). Phase II clinical trials showed objective
responses, including one complete response, in breast cancer patients treated
with anti-VEGF mAb (33, 35). In addition, treatment of patients affected by
advanced non-small cell lung carcinoma or colorectal cancer with anti-VEGF
mAb in combination with chemotherapy, increased the clinical response rate
and prolonged the time-to-disease progression compared to chemotherapy alone
(33, 36-37). 4. VASCULAR ENDOTHELIAL
GROWTH FACTOR RECEPTORS (VEGFR) The main receptors that
initiate signal transduction cascades in response to VEGF comprise a family
of closely related receptor tyrosine-kinases VEGFR-1, VEGFR-2 and VEGFR-3.
Among these, VEGFR-1 and VEGFR-2 expression is largely restricted to the
vascular endothelium, and both receptors bind VEGF with high affinity
(19-21). VEGFR-2 seems to mediate the major growth and permeability actions
of VEGF, whereas VEGFR-1 may have a negative role, either by acting as a
decoy receptor or by suppressing signaling through VEGFR-2 (19-21). In adult
human tissues, VEGFR-3 is mainly expressed in the lymphatic endothelia and in
some high endothelial venules (38). Noteworthy, the mRNA for VEGFR-1 and -2
was found to be up-regulated in tumor-associated endothelial cells (26, 39);
thus, VEGF receptors represent attractive targets in the aim to effectively
block VEGF activity. Opposite to anti-VEGF mAb, the efficacy of SU5416, an
inhibitor of the tyrosine-kinase activity of VEGFR-2, was reported to be best
against slow-growing tumors, and more variable against fast-growing tumors
(27). In addition, it was demonstrated that SU5416 has long-lasting effects
on VEGFR-2 phosphorylation and function (40), and that it reverts tumor
resistance to radiotherapy (41). Results from Phase I clinical studies
indicated that anti-VEGF therapy with antibodies (Ab) or receptor kinase
inhibitors is well tolerated; moreover, patients with advanced disease
appeared to respond to therapy with disease stabilization or tumor shrinkage
(27). In addition, among 28 patients with metastatic colorectal cancer
enrolled in a Phase I/II clinical study, designed to investigate the safety
of SU5416 in combination with 5-fluoruracil (FU)/leucovorin, 15 patients
showed a clinical response (i.e., 1 complete response, 5 partial responses, 9
stable diseases) (42). According to these results, SU5416 is currently in
Phase III clinical trials for advanced malignancies. 5. MATRIX
METALLOPROTEINASES (MMP) The MMP are a family of
secreted and membrane-associated endopeptidases that selectively degrade
components of the extracellular matrix and basement membrane, allowing
endothelial cells migration and metastatic spread of cancer cells (43). These
enzymes are produced by a variety of cell types, including endothelial and
epithelial cells, fibroblasts, and inflammatory cells (43). The identification of
natural tissue inhibitors of MMP (TIMP), that are primarily secreted by
endothelial cells, has stimulated studies focused on MMP inhibition to reduce
the metastatic spreading of neoplastic cells. Among TIMP, TIMP-1, which is
mainly released by endothelial cells (44), was shown to inhibit angiogenesis
both in vitro and in vivo (45-46). Furthermore, TIMP-1
over-expression induced on endothelial cells by gene transfer, strongly
decreased their migration and invasion of the extracellular matrix (47);
furthermore, levels of TIMP-1 expression correlated with prognosis in
patients with gastric carcinoma (48). Extensive pre-clinical data
generated in animal models have shown that the administration of synthetic
MMP inhibitors (MMPI) reduces primary tumor growth as well as the number and
size of metastatic lesions. Based on these promising results, synthetic MMPI
have been developed and taken into clinical trials (49). Among these,
Marimastat, BAY- 129566, CGS-27023A, Prinomastat (AG-3340), BMS-275291 and
Metastat (COL-3) are in different stages of clinical development, ranging
from Phase I to Phase III trials (50). Furthermore, with the aim to
potentiate tumor cytotoxicity, as well as to reduce the size and number of
metastatic lesions, several MMPI are being administered in clinical trials in
combination with chemotherapy (49-51). 6. ALPHA V BETA 3
INTEGRIN (CD51/CD61) The integrin family member
alpha v beta 3 is an adhesion receptor, strongly implicated in the response
of endothelial cells to angiogenetic stimuli. Its expression on angiogenetic
endothelial cells is thought to facilitate their adhesion to the
extracellular matrix during migration; in fact, alpha v beta 3 integrin was
shown to bind directly to the MMP-2 on the surface of vascular endothelial
cells during angiogenesis, suggesting a possible functional link between
these endothelial cells surface proteins (52). Furthermore, alpha v beta 3
integrin has been described as a marker for angiogenetic blood vessels, as it
has been found predominantly expressed in wound healing and in
tumor-associated blood vessels (53-54). Although the vasculature within
apparently normal tissues also stained for alpha v beta 3 integrin, the
percentage of stained vessels and their staining intensity were lower
compared to neoplastic tissues (55). The relevance of this integrin in
neovascularization was strongly supported by the ability of the anti-alpha v
beta 3 integrin mAb LM609 to induce endothelial cells apoptosis within
angiogenetic blood vessels (56), and to promote tumor regression by
inhibiting tumor angiogenesis (57). Clinical trials utilizing a
humanized version of mAb LM609 (Vitaxin) have been initiated, to evaluate its
safety and pharmacokinetics in late stage cancer patients (58). Results
emerging from a pilot study have shown that Vitaxin was generally well
tolerated; however, no objective regressions or significant stabilizations of
disease were observed in 15 patients with advanced leiomyosarcomas (59). 7. ENDOSTATIN Endostatin is a 20 kDa
terminal fragment of collagen XVIII, that was originally isolated as an
inhibitor of endothelial cells proliferation from the culture medium of the
EOMA hemangioendothelioma cell line (60). Endostatin shows a widespread
distribution in blood vessel walls and basement membrane zones, and a strong
association with elastic fibers of aorta and with large arteries was found in
adult mouse tissues (61). Functional studies
demonstrated that Endostatin inhibits endothelial cell proliferation (60) and
migration (62), and that it induces endothelial cell apoptosis (63). The
action of Endostatin seems to be endothelium-specific since it has no
activity on fibroblasts and smooth muscle cells (60, 63-64); however, its
mechanism(s) of action remain to be elucidated. It has been suggested that
Endostatin inhibits the proteolytic activation of pro-MMP-2 and the catalytic
activities of Membrane Type (MT)1-MMP and MMP-2 (65). In addition, most recent
findings indicated that Endostatin down-regulates many genes involved in
proliferation, apoptosis and migration of growing endothelial cells,
resulting in a potent anti-migratory effect (66). In vitro, Endostatin significantly reduced
endothelial and malignant cells invasion into reconstituted basement membrane
(65), while in vivo, it regressed established syngeneic Lewis lung
carcinoma, T241 fibrosarcoma, and B16 melanoma tumors in xenograft models
(60). Moreover, repeated cycles of Endostatin therapy prolonged tumor
dormancy in mice, suggesting that it does not generate drug resistance (67);
however, anti-angiogenetic therapy with Endostatin in tumor-bearing mice
required prolonged administration and high doses of protein (60, 64). Further
support to the potential usefulness of Endostatin for cancer therapy, has
recently derived from the demonstration that intratumoral delivery of the
Endostatin gene efficiently suppressed MCa-4 murine mammary carcinoma growth
in immunodeficient mice (68). In this study, it was also demonstrated that
the observed reduction of tumor growth was associated with a marked reduction
in vascular density as assessed by CD31, CD105 and DiOC7 staining.
Noteworthy, radiation has been shown to increase the production of
Endostatin; in fact, plasma levels of Endostatin were twice as high in mice
that underwent tumor irradiation as compared to mice that underwent tumor
resection (69). In addition, a significant tumor growth inhibition was
observed in mice bearing radio-resistant tumors following combined treatment
with Endostatin and radiotherapy, compared to mice treated with irradiation
alone (70). Altogether, these findings suggest that the efficacy of combined
anti-angiogenetic and conventional anti-cancer therapies should be further
investigated for their potential implications in the treatment of human
cancer. Interestingly, Ab to Endostatin were detected in the serum and in the
tumor tissue of a patient with a multifocal glioblastoma, suggesting that
Endostatin over-expression might induce a humoral immune response (71). At present, Phase I clinical
trials are ongoing to test the efficacy and toxicity of Endostatin in
patients with advanced solid tumors (i.e., breast cancer, melanoma, head and
neck cancer, colon cancer, renal carcinoma and sarcoma) for which no other
standard therapy exists (URL: http://cancertrials.nci.nih.gov). 8. PLATELET ENDOTHELIAL
CELL ADHESION MOLECULE-1 (PECAM-1/CD31) CD31 is a 130 kDa
glycoprotein that belongs to the immunoglobulin (Ig) superfamily (72), and
that is mainly expressed on endothelial cells of large and small vessels
(73). In cultured endothelial cells, and in continuous endothelia of blood
vessels in human tissues, CD31 was found predominantly localized at
intercellular junctions (73-74); additionally, CD31 is constitutively
expressed on platelets, monocytes and leukocytes (75). The role of CD31 in
angiogenesis has not been fully clarified yet, however, several experimental
findings suggest that it is involved in neovascularization. In this respect,
CD31 was found to play a role in endothelial cell migration (76), endothelial
cell-cell adhesion (77), and in the development of the cardiovascular system
(72). Additionally, it was reported that high levels of CD31 inhibited
endothelial cells morphogenesis (78), and anti-CD31 Ab inhibited tube
formation in Matrigel by human umbilical vein endothelial cells (HUVEC)
(79-80). In vivo, CD31 has proven to represent an useful
immunohistochemical marker of blood vessels, and it is currently considered
as the "golden standard" for the assessment of angiogenetic
activity in tumors (81); however, it was recently demonstrated that opposite
to Endoglin, levels of CD31 expression inversely
correlate with HUVEC proliferation (82). 9. ENDOGLIN (CD105) CD105 is a homodimeric cell
membrane glycoprotein of approximately 180 kDa, composed of disulphide-linked
subunits of 95 kDa (83), which has limited species-specificity (84-85). Two
different isoforms of CD105, L-CD105 and S-CD105 have been characterized (86-87).
L-CD105 is predominantly expressed on endothelial cells and shares regions of
sequence identity with betaglycan, a component of the Transforming Growth
Factor (TGF)-beta receptor complex, that is weakly expressed or absent on
endothelial cells (88). CD105 is an accessory
component of the TGF-beta receptor complex (89-90), and it binds several
factors of the TGF-beta superfamily including TGF-beta 1 and -beta 3 (90-91),
activin-A, BMP-7, and BMP-2 (90). The exact role of CD105 in TGF-beta
signaling remains unclear. However, CD105 over-expression on different cell
types modulates several cellular responses to TGF-beta 1, including
inhibition of cellular proliferation and down-regulation of c-myc mRNA,
stimulation of fibronectin synthesis, cellular adhesion, platelet-endothelial
cell adhesion molecule-1 phosphorylation, and homotypic aggregation (89,
92-93). On the contrary, using an antisense approach, it was shown that the
inhibition of CD105 expression in cultured endothelial cells enhanced the ability
of TGF-beta 1 to suppress their growth and migration (93). Concerning its tissue
distribution, CD105 was found mostly expressed on cellular lineages within
the vascular system, and preferentially and strongly expressed on endothelial
cells (83, 94-95). Noteworthy, highest levels of CD105 expression were
identified on cultured endothelial cells with protein, RNA, and DNA levels
consistent with cellular activation and proliferation (96). In agreement with
this observation, a significant correlation was found between levels of CD105
expression and endothelial cells proliferation and density in culture (82,
97), as well as with markers of cell proliferation (i.e., cyclin A and Ki-67)
in tumor endothelia (98). Consistently, a stronger intensity of staining for
CD105 was detected on vascular endothelial cells in tissues undergoing active
angiogenesis, such as regenerating and inflamed tissues or tumors (96,
98-99), compared to normal tissues. In solid malignancies of different
histotype investigated, anti-CD105 mAb reacted almost exclusively with venous
and arterial endothelium of both peritumoral and intratumoral vessels (96-97,
100). Additional support to the involvement of CD105 in angiogenesis derives
by the demonstration that mutations in the coding region of CD105 gene are
associated with hereditary hemorrhagic telangiectasia type 1 (HHT), a
dominantly inherited vascular disorder characterized by multisystemic
vascular dysplasia and recurrent hemorrhage (101). In addition, mice
heterozygous for CD105 showed signs of HHT (102), and CD105 knockout mice
died of defective vascular development at gestational day 10-11 (102-103). The identification of CD105
as an optimal marker of endothelial cells proliferation has encouraged
studies designed to test the clinical usefulness of anti-CD105 mAb for the in
vivo diagnosis and treatment of malignant diseases. Consistently, CD105
was shown to represent an ideal marker to quantify tumor angiogenesis (104);
furthermore, microvessel density assessed by using an anti-CD105 mAb, was
found to be an independent prognostic factor in breast cancer patients (104).
Additionally, using in vivo models of spontaneous canine mammary
adenocarcinoma (82) or human melanoma xenografts in C57BL/6 mice (105), it
has been recently demonstrated that targeting of endothelial CD105 by
radiolabeled mAb is an efficient procedure to image solid malignancies,
regardless of their histological origin. Most interestingly, in vivo
studies conducted in SCID mice bearing human breast carcinomas, demonstrated
that radiolabeled or immunotoxin-coniugated anti-CD105 mAb had a highly
effective anti-tumor efficacy (106-108). In light of these findings, Phase I
clinical trials have been initiated to evaluate the therapeutic efficacy and
toxicity of anti-CD105 mAb in cancer patients (109). 10. CONCLUSIONS AND
FUTURE DIRECTIONS Agents that target the tumor
vasculature by killing and/or interfering with biological functions of
endothelial cells (i.e., proliferation, migration and differentiation),
represent promising candidates to set up new therapeutic approaches in solid
malignancies, regardless of their histotype. The pre-clinical and clinical
experiences so far obtained demonstrate that a more in-depth knowledge of the
endothelial cell molecules playing a role in angiogenesis, and of the
molecular mechanism(s) regulating angiogenesis in tumors, may allow to design
more specific and eventually more effective therapeutic approaches to cancer.
Furthermore, these anti-vascular therapeutic strategies, that potentially do
not induce drug resistance, might represent useful approaches for the
long-term maintenance of cancer treatment, following or in association with
conventional therapeutic strategies such as surgery, chemotherapy,
radiotherapy and immunotherapy. 11. ACKNOWLEDGEMENTS This work was supported by
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Today 22, 129 (2001) Key Words: VEGF, MMP, alpha v beta 3 integrin,
endostatin, CD31, CD105, Tumor, Endothelial Cells, Angiogenesis, Review Send correspondence to: Michele Maio, MD, Cancer
Bioimmunotherapy Unit, Centro di Riferimento Oncologico-I.R.C.C.S., Via
Pedemontana Occ.le, 12, Aviano, Italy 33081 Tel: +39-0434-659342, Fax:
+39-0434-659566, E-mail: [email protected] |
