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W2024587123 abstract "The delivery of nutrients to and the removal of waste products from cells are required for the development, growth and maintenance of all tissues, including ones that have turned cancerous. Normal and tumor tissues are therefore dependent upon a functional circulatory system.1 Blood vessels, which consist of endothelial cells, support cells (smooth muscle cells or pericytes) and a basement membrane, are responsible for the efficient transport of nutrients and wastes to and from tissues.2 The concept of vascular targeting aims at developing strategies to selectively block the flow of blood in tumors, resulting in damage (e.g., coagulation) of the tumor's blood supply, while not perturbing blood flow in normal tissue.3 There has been an increased interest in finding specific markers of the vasculature of tumors that can be exploited by vascular targeting agents (VTA). Although a marker that is absolutely specific for tumor vasculature has not yet been found and may never be, there are still a variety of potentially therapeutically viable candidates under investigation. These include markers of endothelial cell activation and proliferation, markers of stress and hypoxia, ligand:receptor pairs, undefined endothelial cell antigens and proteins that are expressed in newly formed or remodeled basement membrane. In our review, we discuss some of the strategies that are being investigated to utilize these markers, which encompass endothelial cell surface molecules, basement membrane components and potential tumor cell surface antigens for the selective attack of tumor vasculature. Toward the end a small section highlights the possible application of gene therapy in targeting tumor vasculature. It is reasonable to assume that vascular targeting will not kill all the tumor cells and therefore it will need to be combined with conventional therapies. The concept of vascular targeting was originally proposed by Folkman4 and has been subsequently adopted/extended by numerous investigators such as Denekamp5, 6 as an alternative adjuvant to traditional anti-cancer therapies. The goal of the vascular targeting approach is to deliver an effector or cytotoxic agent specifically to the vasculature of a solid tumor, which would cause damage directly to the blood vessels in the tumor leading to coagulation of its blood supply. The advantages of this approach have been detailed in a number of recent reviews.7-12 First, the target cell is accessible. Tumor endothelial cells are freely accessible to targeting moieties that are delivered intravenously. This allows not only the efficient delivery but also the rapid accumulation of a VTA in the tumor vasculature. Second, unlike traditional anti-tumor cell therapy not all the target cells in a tumor vessel need to be bound by the VTA or express the target antigen to generate an occlusive thrombus that shuts down blood flow throughout the entire tumor vessel.13, 14 Third, antigen-negative mutant tumor endothelial cells are unlikely to emerge as a result of vascular targeting because the endothelium in tumors is non-malignant with stable genomes.15, 16 Fourth, vascular targeting is potent. Coagulation of the vasculature of the tumor has a built-in amplification mechanism because, as Tannock17, 18 has shown, tumor proliferation is limited by vascular density demonstrating that there is little vascular redundancy in solid tumors. This approach should be applicable to a broad spectrum of human tumors, because tumor vessels in histologically distinct tumors express common markers,5 such as those listed in Table I. In some cases VTA might also be anti-angiogenic agents depending on their target. For example, 2C3 is a monoclonal anti-VEGF antibody that blocks VEGF from binding to VEGFR2 but not VEGFR1.19 Therefore 2C3 could be utilized as a VTA through its ability to bind to VEGF bound to VEGFR1 and as an anti-angiogenic agent through its ability to block VEGF-mediated activation of VEGFR2. Vascular targeting has been validated experimentally by a number of groups as an effective way to treat solid tumors in mice. The first of these studies used a VTA directed against a genetically engineered tumor endothelial cell marker.14, 20 These studies demonstrated that large solid tumors could be dramatically and safely de-bulked by either toxin-linked or tissue factor (TF)-linked VTAs. More recent studies have utilized VTAs directed against VCAM-120 and the ED-B domain of fibronectin,22 both naturally occurring tumor endothelial cell antigens. One of the key points to come out of the study of Ran et al.21 was the demonstration that initiation of coagulation with a TF-linked VTA is dependent on the luminal expression of phosphatidylserine (PS) in the outer leaflet of the endothelial cell plasma membrane. Phosphatidylserine is found exclusively in the inner leaflet of the plasma membrane in healthy normal cells and therefore is not available to participate in TF-mediated coagulation under normal circumstances. Tumor endothelial cells flip PS to the outer leaflet of the plasma membrane, however, which enables TF to activate the coagulation cascade in tumor blood vessels. The study by Nilsson et al.22 demonstrated that it is possible to initiate tumor blood vessel coagulation with TF that is targeted to a basement membrane component, namely a unique domain of fibronectin. This is an important and exciting finding, as it should expand the potential target molecules that are evaluated for vascular targeting to include those expressed in the basement membrane of tumor blood vessels. In addition to targeting the known tumor endothelial antigens, a group of reagents bind to unknown EC surface antigens preferentially or specifically expressed on tumor EC and suppress angiogenesis. Examples of such reagents are CM101 and combretastatin A4. CM101, a polysaccharide exotoxin produced by the Group B streptococcus, has been shown to target tumor EC.23 Tumor regression has been observed in the early clinical studies and shows an unusually high anti-tumor activity compared to other anti-angiogenesis drugs.24 The tubulin destabilizing agent combretastatin A4 specifically destroys tumor vasculature leading to extensive tumor cell necrosis in animal models. A clinical trial is underway to evaluate its therapeutic usefulness in man.25 The endothelium lining blood vessels of normal non-pathological tissue in the adult is quiescent. The endothelial cells lining blood vessels in a tumor, however, are in an environment that is rich with pro-angiogenic factors and inflammatory cytokines.1 These factors induce endothelial cells to express activation and proliferation markers, such as CD105 (endoglin) and the vascular endothelial growth factor:VEGF receptor (VEGF:VEGFR) complex as well as other proteins listed in Table I. CD105, a 180 kDa integral membrane protein, is an accessory receptor for transforming growth factor (TGF)-β1 and 3 that is highly expressed on endothelium and functions as an important modulator of TGF-β signaling.26 The expression of CD105 is upregulated on proliferating endothelial cells in vitro and tumor endothelium in vivo27 (Fig. 1). Kumar et al.28 demonstrated tumor endothelial expression of CD105, as well as a direct correlation between CD105, vascular density and tumor prognosis in breast carcinoma patients. Interestingly, the same study showed no correlation between vascular density determined using a pan-endothelial marker (CD31) and tumor prognosis, thus, suggesting that the use of a marker of angiogenic endothelial cells (CD105) to determine vascular density is more predictive of outcome than vascular density determined by a pan-endothelial marker viz CD31. Immunostaining of vasculature in human colon carcinoma. (a) Colon carcinoma and surrounding “normal looking” colon tissue. Human colon carcinoma section was stained with a pan-endothelial cell marker (CD31) using an indirect immunoperoxidase technique. The morphological differences between the blood vessels in the bordering normal and tumor tissues are apparent. The asterisks indicate the “tumor-normal tissue border.” Arrows indicate blood vessels. (b,c) A composite tissue section containing colon cancerous lesions (b) and normal colon (c) stained by MAb to CD105. Blood vessels within the colon tumor but not in the normal tissue are stained. It has been demonstrated by a number of studies that CD105 is an attractive candidate for the selective targeting of tumor vasculature. The first such study27 showed that deglycosylated ricin A chain (dgA), an inhibitor of protein synthesis, delivered to CD105 on endothelial cells was effective at killing cells that were proliferating but did not damage CD105 positive cells that were quiescent. Two in vivo studies using anti-CD105-based immunoconjugates showed that the growth of human MCF-7 tumors was prevented in mice treated with the immunoconjugate without any apparent toxicity to normal tissues.29, 30 Furthermore, 125I-labeled mAb anti-CD105 conjugates have been used to effectively image spontaneous canine mammary adenocarcinomas with tumor:background ratios of greater than 8:1.31 These studies have important implications for the use of CD105 and other targets that may not be absolutely specific for tumor endothelium as they suggest that target molecules may be therapeutically useful even though they are expressed at a low basal level on resting endothelial cells in normal tissue. It is noteworthy that lately a few recent publications on CD105 have noted discrepancies concerning its specificity.32 Using a panel of MAbs to CD105, we have observed highly variable staining of blood vessels in tumor and normal tissues. This issue obviously requires further attention. The VEGF:VEGFR complex is another promising target on tumor vasculature. VEGF is a prominent pro-angiogenic growth factor that is expressed abundantly in most tumors. Tumor cells express and secrete VEGF owing to hypoxic conditions in the tumor mass and also as a result of genetic mutations. The increased expression of VEGF by tumor cells and the hypoxic conditions in the tumor lead to a concomitant increase in the expression of VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1) on the endothelium lining the tumor vasculature. Upregulation of both the ligand and its receptor(s) specifically in the tumor leads to a high concentration of the VEGF:VEGFR complex on tumor endothelium as compared to the endothelium in normal tissue. Initial studies using rabbit polyclonal antibodies against the NH2-terminus of VEGF demonstrated that the VEGF:VEGFR complex could be localized to tumor vasculature.33 Monoclonal antibodies namely, Gv39M, 11B5 and 3E7,34 and described recently scFvs35 that are selective for the VEGF:VEGFR complex have also demonstrated the capacity to localize to tumor vasculature while not binding to endothelium in most normal tissues. For a review of the use of these antibodies as VTAs see Brekken and Thorpe.36 These antibodies have also been utilized to mark VEGF-activated blood vessels in human and mouse tumors. Bergers et al.37 studied a transgenic mouse model (RIP1-Tag2) of multistage carcinogenesis and demonstrated that the induction of angiogenesis is a distinct step in the progression of islet tumor cell carcinogenesis38 and corresponded directly with reactivity of Gv39M with blood vessels specifically in the developing angiogenic islets and tumors. Furthermore, Koukourakis et al.39 used 11B5 reactivity as a measure of activated microvessel density (aMVD) and compared it to standard MVD (sMVD) evaluated by anti-CD31 reactivity. The authors were able to show that VEGF activation of VEGFR is a tumor-specific feature in more than 50% of non-small cell lung cancer (NSCLC) cases and is associated with poor outcome. Both Bergers et al.37 and Koukourakis et al.39 showed distinct staining of blood vessels selectively in tumor tissue with Gv39M and 11B5, respectively. In both studies blood vessel selective reactivity of Gv39M and 11B5 occurred despite a significant amount of VEGF being present in and around the extracellular matrix and tumor cells (demonstrated by non-NH2-terminal anti-VEGF antibodies. It is also of note that these antibodies performed equally well in mouse37 and human39 tumor tissue, which allows easier translation of results in the mouse tumor model systems to the human situation). It is conceivable that antibodies specific for other ligand:receptor pairs could also be markers of ‘activated’ endothelium. Other members of the VEGF family of proteins and their respective receptors, including VEGF-B bound to VEGFR1 and VEGF-C and -D bound to VEGFR3, as well as, the angiopoietin:Tie-receptor system would be especially useful to target in this manner. Other endothelial cell surface molecules of particular interest include prostate specific membrane antigen (PSMA), E-selectin (CD62E) and integrin αvβ3. PSMA is a 110 kDa type II transmembrane glycoprotein that is expressed on prostatic epithelial cells.40 The expression of PSMA is upregulated on malignant prostate cells and interestingly, also on the endothelium of many solid tumors, including renal cell carcinoma, transitional cell carcinoma of the bladder, testicular carcinoma, colonic adenocarcinoma, glioblastoma multiform, malignant melanoma, pancreatic duct carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, breast carcinoma and prostatic adenocarcinoma.41 PSMA has been shown to have enzymatic activity and is formally referred to as glutamate carboxypeptidase. Neither its function nor the reason for its expression on tumor endothelium are understood. It is also expressed in some normal tissues such as the epithelium of the prostate and large intestine as well as kidney tubules. Despite this expression on epithelium in some normal tissues, PSMA remains an attractive candidate for vascular targeting because of the large differential in its expression on tumor blood vessels versus blood vessels in normal tissues, where it is rarely observed. Currently, there are multiple monoclonal antibodies that are being investigated as targeting agents directed specifically against PSMA.40, 41 CD62E is also a promising marker of activated endothelium. CD62E is a cell adhesion molecule that allows leukocytes to adhere and roll along the surface of endothelial cells. Most endothelial cells in normal, non-inflammatory tissue, however, do not express CD62E. Inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), or interferon-γ (IFNγ) stimulate endothelial cells to express CD62E on their luminal surface. A variety of human tumors including breast cancer, non-small cell lung cancer, colorectal cancer and hemangiomas have been shown to have CD62E positive blood vessels.42 The tight regulation of the expression of CD62E and its location on the luminal side of blood vessels are both important factors that make it a leading candidate for vascular targeting. CD62E is similar to VCAM-1 in its regulation and expression and because VCAM-1 has already proven to be a suitable target for vascular targeting in a mouse model21 it is expected that CD62E will also be effective as a target. The integrin αvβ3 has been shown to be instrumental in guiding endothelial cells through the angiogenic process.43 Antibodies against or peptide ligands specific for this integrin localize to angiogenic blood vessels in solid tumors and αvβ3 has therefore proven to be an effective target for imaging the vasculature of solid tumors in experimental animals.44 This integrin coordinates an activated endothelial cell's interaction with the matrix that surrounds it and at the same time serves as a docking site for matrix metalloprotinase-2 (MMP-2).45 Active MMP-2 localizes to αvβ3 on angiogenic endothelial cells, which allows the endothelial cells to degrade the immediate surroundings and migrate toward the angiogenic stimuli. Blocking αvβ3 function through the use of antibodies, peptides, or organic small molecules46 has a dramatic effect on the process of angiogenesis and leads to programmed cell death of endothelial cells. This in itself is an appropriate way to block the process of angiogenesis in tumors. If a drug that initiates blood coagulation were attached to a targeting moiety that targets αvβ3, however, the effect on solid tumors might be even greater. It is important to note that targeting moieties specific for each of these molecules, PSMA, E-selectin and αvβ3 already exist and have been shown to preferentially bind to human tumor blood vessels. All three of these candidates are abundantly expressed on angiogenic endothelium of a variety of human tumors and therefore are good candidates for the delivery of agents that could cause tumor infarction by initiating the coagulation cascade in tumor blood vessels. Another group of endothelial cell surface markers expressed on tumor vasculature has also been described recently. These molecules were discovered through the technique of in vivo phage panning. This powerful technique takes advantage of the very large number of specificities contained within a peptide phage library and the biology of the animal into which the library is injected.47, 48 By removing the tissue of interest, in this case the tumor, from an animal injected with a peptide phage library the phage that homed to that tissue can be harvested. The phage that are collected are then injected into another tumor-bearing animal and the process is repeated until a population of phage that bind selectively to tumor endothelium is isolated. One of the advantages of this technique is that the animal plays an important role in the selection of the tumor homing phage. All phage that bind to endothelium in normal tissue are presumably filtered out by blood vessels in normal tissues through which the phage pass before they get to the tumor. Aminopeptidase N (APN, also known as CD13) is an example of a molecule found to be selectively expressed on tumor endothelium using this technique.49, 50 Although this technique holds enormous promise for the identification of molecular addresses not only of tumor vasculature but also of blood vessels in normal organs as well, the genes identified remain to be evaluated in humans. By using serial analysis of gene expression, novel genes (TEM1, TEM5 and TEM8), encoding tumor endothelial markers have been found.51, 52 These genes are strongly expressed in tumor blood vessels and in the vasculature of developing embryo, but not at all or only in a small fraction of normal vessels. Such tumor endothelial markers are attractive targets for vascular targeting in tumors and other angiogenic diseases. There has been an increased interest in the use of molecules that are not expressed on endothelial cells per se but are on either support cells or in the basement membrane of blood vessels. The most elegant example of this is the recent work of Nilsson et al.22 The authors utilize a fusion protein consisting of the L19 antibody fragment, which binds to the ED-B domain of FN, fused to TF. The fusion protein when injected into tumor-bearing mice mediated the complete and selective infarction of tumor blood vessels, which resulted in significant tumor regression.22 The success of our study should fuel the discovery of new targets that reside in the basement membrane. For example, through the use of subtractive immunization Xu et al.53 raised monoclonal antibodies that bind selectively to denatured or proteolyzed collagen type I and type IV. Collagen type IV is a major component of the basement membrane of blood vessels and must be remodeled during the angiogenic process. Remodeling of the basement membrane requires the proteolytic cleavage of collagen type IV and thus these antibodies might be very effective at targeting the basement membrane surrounding angiogenic blood vessels. They have already been shown to bind to the basement membrane of tumor blood vessels53 and could potentially be used to cause the infarction of tumor vasculature through the selective delivery of TF or other effectors. NG2 proteoglycan on the surface of pericytes has also been shown to be a useful marker of tumor vasculature. Peptides that bind specifically to NG2 were selected from a peptide phage library through the use of in vivo panning techniques in tumor-bearing mice.54 Recent discussions and investigations into the validity and frequency of tumor cells lining vascular channels, in so called ‘mosaic’ blood vessels or tumor cells displaying vasculogenic mimicry55-60 prompts the idea that tumor cell markers could be utilized as a potential target for vascular targeting in cancer. For instance, if cells of a particular type of tumor frequently line vascular channels in that tumor then the tumor cells themselves could be targeted with immunoconjugates that utilize cytotoxic drugs as their effectors. The effect could be 2-fold; killing of tumor cells and indirect coagulation of the vascular channel provided the functionality of the coagulation cascade in these vascular channels is intact. It is relevant to mention briefly here the potential usefulness of the rapidly expanding strategies for gene therapy. Because of limitation on space, the following section focuses on adenovirus mediated gene transfer to the vasculature. Gene therapy is the transfer of nucleic acids for the targeting of the mechanisms underlying physiological and pathological situations for therapeutic purposes. The viral vectors used most frequently for gene transfer are adenovirus, retrovirus, adeno-associated virus and herpes simplex type 1 virus. Each of these mammalian viruses has its advantages and limitations for therapeutic gene transfer.12 Although most initial efforts to deliver a gene into vascular endothelial cells (EC) for gene therapy were undertaken using retroviral vectors, replication-deficient adenovirus have several advantages over retrovirus. Adenovirus can carry large quantities of cDNA, do not require cell division for transfection, are known to infect human cells efficiently but with low pathogenicity and they are not associated with malignant transformation of the infected cells.78-80 In addition, adenoviruses are stable and can be produced in relatively high titers, a fact that is of considerable importance for techniques of direct gene transfer to EC. The feasibility of using adenovirus for gene transfer to EC has been assessed by a number of investigators. HUVECs were infected in vitro with adenovirus expressing human α1-antitrypsin (α1-AT) gene. The transduced HUVECs synthesized and secreted functional α1-AT for at least 2 weeks.81 A 98% transduction efficiency with HUVECs using an adenoviral vector containing green fluorescent protein was also reported.82 A number of experimental approaches, such as lipofection and retroviruses, have been developed to determine the feasibility of in vivo gene transfer to EC as a means of gene therapy for both cardiovascular and other angiogenic diseases. The most successful approach, however, has been the use of adenoviral vectors, which gives the highest transduction efficiency. The above mentioned adenovirus encoding the α1-AT gene has been efficiently delivered to the carotid arteries and jugular veins of sheep. After 24 hr, 100% of ECs were transduced and gene expression was easily detectable, being maximal at Day 7, after which it declined.83 Although adenoviruses have been used widely as vectors to deliver genes to a number of tissues in vivo, including vascular tissues,79, 84-87 a major improvement to this system would be the ability to target the vector to receptors on specific cell types. Efforts to this end have utilized bi-specific conjugates. These conjugates have been used to target adenovirus type 5 (Ad5) to growth factor receptors that are upregulated during tumor development or inflammation.88-90 Ad5 targeting was also demonstrated using ligands for CD3, αv integrins91, 92 or phage-displayed peptide to EC.93 These targeting approaches have improved both transduction efficiency and selectivity.93, 94 As mentioned earlier, CD105 is an angiogenesis-associated protein that is strongly expressed in activated and proliferating EC. Antibodies to CD105 show highly selective binding to the neovasculature, but react weakly or not at all with quiescent endothelium. Thus a bi-specific conjugate constructed using antibody to CD105 can be utilized for selective vascular targeting. A recent publication demonstrates that this is a promising and feasible strategy for vascular targeting. Nettelbeck et al.95 have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to CD105 on the surface of EC for vascular targeting of adenoviruses. This bispecific molecule mediated enhanced selective adenovirus transduction of HUVECs. These results reveal the utility of bispecific single-chain antibodies, which can be produced in large quantities in bacteria, for vascular targeting. In addition to bispecific conjugates, it is worth emphasizing that the CD105 promoter is blood vessel specific, thus a vector constructed with the CD105 promoter can be used for vascular targeting (Fig. 2). 96 Human CD105 gene expression driven by CD105 promoter in mouse skin blood vessels. Blood vessels (↑) were strongly positive for CD105 as compared to a negative staining of adipocytes (*) and striated muscle (▴).96 Antisense adenovirus mediated gene delivery is a novel form of gene therapy that is likely to have major impact on the treatment of angiogenic diseases in man. The expression of an antisense mRNA is able to specifically block the targeted gene translation thereby exerting its therapeutic effects. The successful delivery of adenovirus containing an antisense cDNA to malignant cells or endothelium has been recently reported. An adenoviral vector encoding antisense VEGF effectively blocked angiogenesis and glioma growth in athymic mice.97 Antisense mRNA to bFGF expressed in an adenovirus inhibited bFGF synthesis in the vein graft wall of rabbits and decreased tangential stress of the graft.98 Kallistatin, a serine proteinase inhibitor, induced neointima formation in balloon-injured artery. Adenovirus-mediated transfer of kallistatin antisense cDNA significantly reduced kallistatin mRNA levels and attenuated neointima formation in rat arteries in vivo.99 These studies conclusively demonstrate that antisense adenoviral vectors represent a novel and promising approach for the therapy of human vascular diseases including cancer. A tumor's absolute dependence on its blood supply makes the vasculature of the tumor a target for therapy that has attracted the attention of both researchers and clinicians. The realization of the goal of vascular targeting namely, the targeted delivery of a drug that will cause coagulation of the tumor's blood vessels is waiting for the identification and development of suitable targeting moieties. The list of potential targets and agents that can selectively bind to these targets has increased markedly over the past few years. This list includes candidates that encompass not only markers of endothelial cell activation but also proteins that are expressed in the basement membrane or on support cells in angiogenic blood vessels. It is worth noting that there have been no reported toxicities associated with use of VTA for therapy in tumor-bearing mouse models. This is most probably attributable to the fact that VTA are used at low doses that represent approximately 10% of the maximum tolerated dose. How VTA will effect the progression of other pathologies that are associated with changes in endothelial cells, such as inflammation or wound healing, that in a cancer patient may not be prominent, is unknown. The targeting moiety and effector utilized to construct the VTA will certainly influence whether there is any non-tumor endothelial cell binding by the VTA and if so, however, what the result of that binding is. Vascular targeting approaches should work well in combination with traditional anticancer chemotherapy or radiation treatments. In fact, vascular targeting might be even more effective shortly after more traditional treatments because the tumor will presumably be under more stress after being attacked by drugs that act directly on the tumor cells. This should lead to a heightened dependence on its blood supply and thus an amplification of the damage that could be caused to the tumor by cutting off its supply lines with a VTA. In a recent publication, Folkman's group has advocated a novel use for the antiangiogenic agent, angiostatin. These authors found that after irradiation of cancerous mass, tumor cells began to metastasize. Intriguingly this irradiation-induced tumor spread could be controlled by the injection of angiostatin into the mice.100 The subject of other targeting strategies based on those antigens that have low density or are expressed abluminally on EC was excluded from this short review but merit a mention. Unfortunately there have been no therapeutic vascular targeting studies published that utilize an antigen of lower antigen density such as that recognized by the antibody 11B5. Therefore it is unclear whether a potent effector, such as truncated tissue factor (tTF) linked to 11B5 would be therapeutically effective or not. The antigen recognized by the targeting agent L19 has been shown recently to be a suitable target for the delivery of tTF despite the fact that it is located abluminally.21 It is appropriate to conclude this review by adding 2 cautionary notes, one related to tumor angioarchitecture and the other about the much neglected role of lymphatics in tumor spread, as both have a profound bearing on anti-angiotherapies. It is generally assumed that as all solid tumors grow, newly formed microvessels continuously penetrate the tumor mass. One only has to consider an ovarian cancer that lies on the interstitial surface, however, where it can form quite large exophytic masses. These tumors have little tendency to infiltrate deeply unless they are growing in confined spaces for instance between the liver and diaphragm, paracolic regions and pouch of Douglas. Therefore such a tumor can happily survive by acquiring its nutrients from the existing vasculature of its host without any necessity to induce angiogenic blood vessels. Such tumors naturally would respond poorly to anti-angiotherapies. With regard to lymphatics, it should be remembered that especially in carcinomas the major route for tumor spread is through lymphatics. Only recently a few studies have began to consider how tumor lymphatics can be targeted to control its growth and spread (Fig. 3).101-105 By fortuitous coincidence, CD105 is expressed on both endothelium of blood vessels and lymphatics, which clearly enhances its potential usefulness in anti-tumor strategies. Thompson et al.106 and Madhusudan et al.107 have given very informative critical reviews on antiangiogenic therapies in man, especially their side-effects and future opportunities in this rapidly expanding field that holds a great deal of promise not only in cancer but also in numerous other angiogenesis-dependent disease states. Note added in proof: In αvβ3 knockout mice, tumour growth was significantly enhanced compared with normal mice. This is an unexpected finding, as antibodies to αvβ3 have been used to control tumour growth (Reynods et al., Nat Med 2002;8:27–34). Increase in lymphatic density in tumor tissues: visualization of the vasculature by immunohistochemistry in a human cutaneous melanoma (a) and in a squamous cell carcinoma of the larynx (b) demonstrates differential staining of capillary and venous blood vessels on one hand and lymph vessels on the other. Blood vessels are stained red by blood vessel marker PAL-E and lymph vessels blue by the pan-endothelial marker CD31. Blue blood vessel endothelial staining by the anti-CD31 MAb is overruled by the red staining by PAL-E and thereby not visible. The arrows indicate staining of the basal membrane by MAb PAL-E (figure courtesy of Prof. R. Clarijs, Nijmegen, The Netherlands). Magnification ×100. R.A.B. is supported by NIH grant HL10352. S.K. is particularly grateful to Dr. K. Narayan for lively discussions on potential usefulness of antiangiogenesis therapies in man. C.L. is a Wellcome Trust fellow." @default.
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W2024587123 title "Strategies for vascular targeting in tumors" @default.
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