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PubMed2003

Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation.

Vascular endothelial growth factor (VEGF), a major factor mediating endothelial cell survival, migration, and proliferation during angiogenesis, is expressed as five splice variants (121, 145, 165, 189, and 206 aminoacids) encoded by a single gene. Although the three shorter isoforms are mainly diffusible, the two longer ones are sequestered in cell membranes after secretion. However, their potential role as true components of the extracellular matrix has not been investigated. We determined that endothelial cells could adhere and spread on VEGF189 and VEGF165, but not on VEGF121. Adhesion was mediated by the alpha3beta1 and alpha(v)beta3 integrins and other alpha(v) integrins but not by the cognate VEGF receptors. Cells migrated on VEGF165 and VEGF189 and displayed a stellate morphology with numerous lamellopodia and FAK staining but no actin stress fibers. Tumstatin, an antiangiogenic peptide that interacts with the alpha(v)beta3 integrin, could inhibit adhesion on VEGF, and this effect was potentiated by anti-alpha(v)beta3 blocking antibody. Immobilized VEGF almost totally abolished endothelial cell apoptosis through interactions with integrins. The inhibition of alpha(v)beta3 engagement with immobilized VEGF by tumstatin inhibited most of its survival activity. We have thus determined a new VEGF receptor-independent role for immobilized VEGF in supporting cell adhesion and survival through interactions with integrins.

Cell Adhesion↗

PubMed2006

Synthetic oligosaccharide stimulates and stabilizes angiogenesis: structure-function relationships and potential mechanisms.

To determine the proangiogenesis effect of series of saccharides and a synthetic oligosaccharide and potential mechanisms, an in vitro 3-dimensional endothelial cell sprouting (3D-ECS) assay and the chick chorioallantoic membrane (CAM) model were used. We demonstrated that a sulfated oligosaccharide significantly promotes the endothelial capillary network initiated by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). Furthermore, although the capillary network initiated by VEGF and b-FGF lasts no more than 7 days, addition of a sulfated oligosaccharide significantly amplifies angiogenesis and stabilizes the capillary network of new blood vessels. In the CAM model, sulfated oligosaccharide also stimulated angiogenesis. In both the CAM and the 3D-ECS assay, structure-function studies reveal that increased saccharide chain length up to the hexa- to decasaccharide show optimal proangiogenesis efficacy. In addition, the sulfation and molecular shape (branched vs linear) of oligosaccharide are important for sustained proangiogenesis efficacy. Data indicate that chemically defined synthetic oligosaccharides can play an important role in regulation of capillary structure and stability, which may contribute to future advances in therapeutic angiogenesis. The proangiogenesis efficacy of an oligosaccharide is mediated via integrin alphavbeta3 and involves mitogen-activated protein kinase signaling mechanisms.

Animals↗

PubMed2004

Evaluation of the role of platelet integrins in fibronectin-dependent spreading and adhesion.

BACKGROUND: Recent studies have shown that platelet adhesion and subsequent aggregation can occur in vivo in the absence of the two principal platelets adhesive ligands, von Willebrand factor and fibrinogen. These results highlight a possible role for fibronectin in supporting thrombus formation. OBJECTIVE AND METHODS: To evaluate the platelet integrins and subsequent activation pathways associated with fibronectin-dependent platelet adhesion utilizing both human and murine platelets. RESULTS: Platelets can adhere to fibronectin via the integrin alpha(IIb)beta(3), leading to formation of lamellipodia. This is mediated through an interaction with the tenth type III domain in fibronectin. Spreading on fibronectin promotes alpha(IIb)beta(3)-mediated Ca(2+) mobilization and tyrosine phosphorylation of focal adhesion kinase and phospholipase C gamma2. In contrast, studies with blocking antibodies and mice demonstrate that alpha(5)beta(1) and alpha(v)beta(3) support adhesion and promote formation of filopodia but not lamellipodia or tyrosine phosphorylation of these proteins. Further, neither alpha(5)beta(1) nor alpha(v)beta(3) is able to induce formation of lamellipodia in the presence of platelets agonists, such as collagen-related-peptide (CRP). CONCLUSIONS: These observations demonstrate that integrins alpha(5)beta(1) and alpha(v)beta(3) support platelet adhesion and the generation of filopodia but that, in contrast to the integrin alpha(IIb)beta(3), are unable to promote formation of lamellipodia.

Animals↗

PubMed2006

Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation.

Donor intra-islet endothelial cells contribute to neovascularization after transplantation. Several factors may interfere with this process and ultimately influence islet engraftment. Rapamycin, a central immunosuppressant in islet transplantation, is an mTOR inhibitor that has been shown to inhibit cancer angiogenesis. The aim of this study was to evaluate the effects of rapamycin on islet endothelium. Rapamycin inhibited the outgrowth of endothelial cells from freshly purified human islets and the formation of capillary-like structures in vitro and in vivo after subcutaneous injection within Matrigel plugs into SCID mice. Rapamycin decreased migration, proliferation and angiogenic properties of human and mouse islet-derived endothelial cell lines with appearance of apoptosis. The expression of angiogenesis-related factors VEGF, alphaVbeta3 integrin and thrombospondin-1 on islet endothelium was altered in the presence of rapamycin. On the other hand, rapamycin decreased the surface expression of molecules involved in immune processes such as ICAM-1 and CD40 and reduced the adhesion of T cells to islet endothelium. Our results suggest that rapamycin exerts dual effects on islet endothelium inducing a simultaneous inhibition of angiogenesis and a down-regulation of receptors involved in lymphocyte adhesion and activation.

Angiogenesis Inhibitors↗

PubMed2001

Ovulation induction disrupts luteal phase function.

Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin-releasing hormone (GnRH)-agonist treatment, or after GnRH-antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH-agonist cycles, mid-luteal biopsies have revealed increased glandulo-stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased alphavbeta3-integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.

Endometrium↗

PubMed2001

Taking cell-matrix adhesions to the third dimension.

Adhesions between fibroblastic cells and extracellular matrix have been studied extensively in vitro, but little is known about their in vivo counterparts. Here, we characterized the composition and function of adhesions in three-dimensional (3D) matrices derived from tissues or cell culture. "3D-matrix adhesions" differ from focal and fibrillar adhesions characterized on 2D substrates in their content of alpha5beta1 and alphavbeta3 integrins, paxillin, other cytoskeletal components, and tyrosine phosphorylation of focal adhesion kinase (FAK). Relative to 2D substrates, 3D-matrix interactions also display enhanced cell biological activities and narrowed integrin usage. These distinctive in vivo 3D-matrix adhesions differ in structure, localization, and function from classically described in vitro adhesions, and as such they may be more biologically relevant to living organisms.

3T3 Cells↗

PubMed2002

Tumstatin, an endothelial cell-specific inhibitor of protein synthesis.

Tumstatin is a 28-kilodalton fragment of type IV collagen that displays both anti-angiogenic and proapoptotic activity. Here we show that tumstatin functions as an endothelial cell-specific inhibitor of protein synthesis. Through a requisite interaction with alphaVbeta3 integrin, tumstatin inhibits activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3-kinase), protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR), and it prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4E-binding protein 1. These results establish a role for integrins in mediating cell-specific inhibition of cap-dependent protein synthesis and suggest a potential mechanism for tumstatin's selective effects on endothelial cells.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand.

The structural basis for the divalent cation-dependent binding of heterodimeric alphabeta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alphaV and beta3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in betaA, the ligand-binding domain of beta3; in the complex, betaA acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alphaV relative to beta3.

Amino Acid Sequence↗

PubMed2001

VEGF receptor signal transduction.

The family of vascular endothelial growth factors (VEGFs) currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (PlGF). Several of these factors, notably VEGF-A, exist as different isoforms, which appear to have unique biological functions. The VEGF family proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. Neuropilins, heparan-sulfated proteoglycans, cadherins, and integrin alphavbeta3 serve as coreceptors for certain but not all VEGF proteins. Moreover, the angiogenic response to VEGF varies between different organs and is dependent on the genetic background of the animal. Inactivation of the genes for VEGF-A and VEGF receptor-2 leads to embryonal death due to the lack of endothelial cells. Inactivation of the gene encoding VEGF receptor-1 leads to an increased number of endothelial cells, which obstruct the vessel lumen. Inactivation of VEGF receptor-3 leads to abnormally organized vessels and cardiac failure. Although VEGF receptor-3 normally is expressed only on lymphatic endothelial cells, it is up-regulated on vascular as well as nonvascular tumors and appears to be involved in the regulation of angiogenesis. A large body of data, such as those on gene inactivation, indicate that VEGF receptor-1 exerts a negative regulatory effect on VEGF receptor-2, at least during embryogenesis. Recent data imply a positive regulatory role for VEGF receptor-1 in pathological angiogenesis. The VEGF proteins are in general poor mitogens, but binding of VEGF-A to VEGF receptor-2 leads to survival, migration, and differentiation of endothelial cells and mediation of vascular permeability. This review outlines the current knowledge about the signal transduction properties of VEGF receptors, with focus on VEGF receptor-2.

Animals↗

PubMed2003

Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5.

Rotavirus infection seems to be a multistep process in which the viruses are required to interact with several cell surface molecules to enter the cell. The virus spike protein VP4, which is cleaved by trypsin into two subunits, VP5 and VP8, is involved in some of these interactions. We have previously shown that the neuraminidase-sensitive rotavirus strain RRV initially attaches to a sialic acid-containing cell molecule through the VP8 subunit of VP4 and subsequently interacts with integrin alpha2beta1 through VP5. After these initial contacts, the virus interacts with at least two additional proteins located at the cell surface, the integrin alphavbeta3 and the heat shock cognate protein Hsc70. In this work, we have shown that rotavirus RRV and its neuraminidase-resistant variant nar3 interact with Hsc70 through a VP5 domain located between amino acids 642 and 658 of the protein. This conclusion is based on the observation that a recombinant protein comprising the 300 carboxy-terminal amino acids of VP5 binds specifically to Hsc70 and a synthetic peptide containing amino acids 642 to 658 competes with the binding of the RRV and nar3 viruses to the heat shock protein. The VP5 peptide also competed with the binding to Hsc70 of the recombinant VP5 protein, and an antibody to Hsc70 reduced the binding of the recombinant protein to the surface of MA104 cells. The fact that the synthetic peptide blocks the infectivity of rotaviruses RRV and nar3 but not their binding to cells indicates that the interaction of VP5 with Hsc70 most probably occurs at a postattachment step during the virus entry process.

Amino Acid Sequence↗

PubMed2005

Analysis of a foot-and-mouth disease virus type A24 isolate containing an SGD receptor recognition site in vitro and its pathogenesis in cattle.

Foot-and-mouth disease virus (FMDV) initiates infection by binding to integrin receptors via an Arg-Gly-Asp (RGD) sequence found in the G-H loop of the structural protein VP1. Following serial passages of a type A(24) Cruzeiro virus (A(24)Cru) in bovine, via tongue inoculation, a virus was generated which contained an SGD sequence in the cell receptor-binding site and expressed a turbid plaque phenotype in BHK-21 cells. Propagation of this virus in these cells resulted in the rapid selection of viruses that grew to higher titers, produced clear plaques, and now contained an RGD sequence in place of the original SGD. To study the role of the SGD sequence in FMDV receptor recognition and bovine virulence, we assembled an infectious cDNA clone of an RGD-containing A(24)Cru and derived mutant clones containing either SGD with a single nucleotide substitution in the R(144) codon or double substitutions at this position to prevent mutation of the S to an R. The SGD viruses grew poorly in BHK-21 cells and stably maintained the sequence during propagation in BHK-21 cells expressing the bovine alpha(V)beta(6) integrin (BHK3-alpha(V)beta(6)), as well as in experimentally infected and contact steers. While all the SGD-containing viruses used only the bovine alpha(V)beta(6) integrin as a cellular receptor with relatively high efficiency, the revertant RGD viruses utilized either the alpha(V)beta(1) or alpha(V)beta(3) bovine integrins with higher efficiency than alpha(V)beta(6) and grew well in BHK-21 cells. Replacing the R at the -1 SGD position with either K or E showed that this residue did not contribute to integrin utilization in vitro. These results illustrate the rapid evolution of FMDV with alteration in receptor specificity and suggest that viruses with sequences other than RGD, but closely related to it, can still infect via integrin receptors and induce and transmit the disease to susceptible animals.

Amino Acid Sequence↗

PubMed1998

Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development.

The role of fibrillin-1 in metanephrogenesis was investigated. Fibrillin-1 cDNA was isolated from the rat kidney cDNA library and sequenced, and its spatiotemporal expression was studied. It had approximately 88% homology with human fibrillin-1 and had Ca2+ binding epidermal growth factor-like domains, transforming growth factor-beta binding protein motifs, and an RGD binding site. Northern blot analysis revealed an approximately 10-kb transcript, and fibrillin-1 expression was developmentally regulated. In situ hybridization and immunofluorescence studies indicated that at day 15 of gestation, fibrillin-1 is expressed in the metanephric mesenchyme. At day 18, its expression was confined to nascent blood vessels and glomeruli, and it increased in the newborn and neonatal kidneys. Immunoprecipitation revealed an approximately 300-kDa band by SDS-PAGE. Treatment with fibrillin-1 antisense oligodeoxynucleotide induced marked dysmorphogenesis of the embryonic metanephroi. Concomitantly, the fibrillin-1 mRNA, antibody reactivity in the metanephroi, and fibrillin-1-specific radioincorporation were reduced. These data indicate that, like alphavbeta3 integrin, a known morphogen and a putative receptor of fibrillin-1, the fibrillin-1 modulates events related to early organogenesis and possibly also the vascularization of the rat kidney.

Amino Acid Sequence↗

PubMed2004

Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice.

Tumor growth, tumor angiogenesis, and vascular endothelial growth factor (VEGF)-specific angiogenesis are all enhanced in beta(3)-integrin-null mice. Furthermore, endothelial cells isolated from beta(3)-null mice show elevated levels of Flk1 (VEGF receptor 2) expression, suggesting that beta(3)-integrin can control the amplitude of VEGF responses by controlling Flk1 levels or activity. We now show that Flk1 signaling is required for the enhanced tumor growth and angiogenesis seen in beta(3)-null mice. Moreover, beta(3)-null endothelial cells exhibit enhanced migration and proliferation in response to VEGF in vitro, and this phenotype requires Flk1 signaling. Upon VEGF stimulation, beta(3)-null endothelial cells exhibit higher levels of phosphorylated Flk1 and extracellular-related kinases 1 and 2 than wild-type endothelial cells. Furthermore, signaling via ERK1/2 is required to mediate the elevated responses to VEGF observed in beta(3)-null endothelial cells and aortic rings in vitro. These data confirm that VEGF signaling via Flk1 is enhanced in beta(3)-integrin-deficient mice and suggests that this increase may mediate the enhanced angiogenesis and tumor growth observed in these mice in vivo.

Animals↗

PubMed2005

Dentin matrix protein 1 enhances invasion potential of colon cancer cells by bridging matrix metalloproteinase-9 to integrins and CD44.

The up-regulation of various matrix metalloproteinases (MMP), certain cell receptors such as integrins and CD44, and the SIBLING family of integrin-binding glycophosphoproteins have been reported separately and in various combinations for many types of tumors. The mechanisms by which these different proteins may be interacting and enhancing the ability of a cancer cell to survive and metastasize have become an interesting issue in cancer biology. Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence-dependent integrins. This SIBLING was recently shown to be able to specifically bind and activate proMMP-9 and to make MMP-9 much less sensitive to inhibition by tissue inhibitors of metalloproteinases and synthetic inhibitors. In this study, we used a modified Boyden chamber assay to show that DMP1 enhanced the invasiveness of the MMP-9 expressing colon cancer cell line, SW480, through Matrigel in a dose-dependant manner. DMP1 (100 nmol/L) increased invasion 4-fold over controls (86.1 +/- 13.9 versus 22.3 +/- 9.8, P < 0.001). The enhanced invasive potential required the presence of MMP-9 and at least one of the cell surface receptors, CD44, alpha(v)beta(3), or alpha(v)beta(5) integrin. The bridging of MMP-9 to the cell surface receptors was shown by both pull-down and fluorescence activated cell sorting experiments. Because all of these proteins were also shown by immunohistochemistry to be expressed in serial sections of a colon adenocarcinoma, we have hypothesized that the MMP-9/DMP1/cell surface complexes observed to enhance cell invasion in vitro may be aiding metastatic events in vivo.

Adenocarcinoma↗

PubMed2004

Conditionally replicative adenovirus with tropism expanded towards integrins inhibits osteosarcoma tumor growth in vitro and in vivo.

PURPOSE: The clinical course of osteosarcoma (OS) demands the development of new therapeutic options. Conditionally replicative adenoviruses (CRAds) represent promising agents for the treatment of solid tumors, because CRAds have an intrinsic replication capacity that allows in situ amplification and extensive tumor infection through lateral spread. The CRAd AdDelta24 has been developed to replicate selectively in cells with a defective retinoblastoma (Rb) pathway. Because genetic alterations in the Rb pathway are frequently observed in OS, AdDelta24 might be useful in the treatment of this cancer. EXPERIMENTAL DESIGN: Because the lack of Coxsackie adenovirus receptor on OS cells limits the efficacy of CRAd treatment, we explored alternative target molecules on OS. Insertion of an Arg-Gly-Asp (RGD-4C) integrin-targeting motif into the adenovirus fiber knob expanded tropism toward the alpha(nu)beta(3) and alpha(nu)beta(5) integrins. The oncolytic capacity of the CRAd Ad5-Delta24RGD was tested on primary OS cells in vitro and in vivo. RESULTS: The alpha(nu)beta(3)and alpha(nu)beta(5) integrins are abundantly expressed on OS cells. RGD-mediated infection augmented adenovirus infection of primary OS cells by two orders of magnitude. Ad5-Delta24RGD was shown to be highly active in killing human OS cell lines, as well as primary cell cultures. Furthermore, intratumoral injections with Ad5-Delta24RGD into established human OS xenografts that were derived directly from a patient with OS refractory for chemotherapeutic treatment caused a significant tumor-growth delay. Furthermore, adenoviral particles could be detected in tumor cells 25 days posttumor injection. CONCLUSIONS: Targeting adenovirus toward integrins rendered OS cells more sensitive to killing by Ad5-Delta24RGD. These findings suggest that Ad5-Delta24RGD has potential for use in OS treatment.

Adenoviridae↗

PubMed2005

Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist.

The aim of the present study was to identify specific alpha(v)beta3/alpha(v)beta5 integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta3 and alpha(v)beta5 integrins with negligible interacting with alpha5beta1 integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-d-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of alpha(v)beta3/alpha(v)beta5-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of alpha(v)beta3-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-alpha(v)beta3 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta3 integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta3/alpha(v)beta5 integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.

Animals↗

PubMedDate not supplied

The disintegrin kistrin inhibits neurite extension from spiral ganglion explants cultured on laminin.

The influence of laminin-1 (LN) and tenascin-C (TN), extracellular matrix molecules expressed spatially and temporally along the neural growth route from spiral ganglion (SG) neurons to the cochlear sensory cells, was evaluated in cultured SG explants from postnatal day 4 rats. Increasing concentrations of LN resulted in a strong, dose-dependent increase in the length of neurites and in a higher number of neural processes, while varying TN concentrations had relatively minor effects on both parameters. The results suggest differential receptor activation by LN and TN. When explants grown on LN were treated with Kistrin, an inhibitor of the alphavbeta3 integrin, the LN-induced increase in neurite length was reduced in a dose-dependent manner. However, the number of extending neurites was not affected, indicating that different receptors mediate this response, perhaps by increasing neuronal survival.

Animals↗

PubMedDate not supplied

A novel snake venom disintegrin that inhibits human ovarian cancer dissemination and angiogenesis in an orthotopic nude mouse model.

OVCAR-5 is a human epithelial carcinoma cell line of the ovary, established from the ascitic fluid of a patient with progressive ovarian adenocarcinoma without prior cytotoxic treatment. The unique growth pattern of ovarian carcinoma makes it an ideal model for examining the anticancer activity of contortrostatin (CN), a homodimeric disintegrin from southern copperhead venom. FACS analysis revealed that OVCAR-5 is integrin alphavbeta3 negative, but alphavbeta5 positive. CN effectively blocks the adhesion of OVCAR-5 cells to several extracellular matrix proteins and inhibits tumor cell invasion through an artificial basement membrane. In a xenograft nude mouse model with intraperitoneal introduction of OVCAR-5 cells, intraperitoneal injection of CN was used for therapy. Tumor dissemination in CN-treated versus control groups was studied by gross examination, and antiangiogenic potential was examined by factor VIII immunohistochemistry and image analysis. CN not only significantly inhibited ovarian cancer dissemination in the nude mouse model, but it also dramatically prevented the recruitment of blood vessels to tumors at secondary sites.

Agkistrodon↗