Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An attractive strategy for the therapy of carcinomas and other solid tumors would be to target cytotoxic agents or host immune effectors to the endothelial cells of the tumor vasculature rather than to the tumor cells themselves. The key advantage of this approach is that the endothelial cells are freely accessible through the blood whereas the tumor cells are, for the most part, inaccessible. Also, endothelial cells are similar in different tumors, making it feasible to develop a single reagent for treating numerous types of cancer. In this chapter, we review progress in this "vascular targeting" approach, from the validation of the concept in a mouse model to the characterization of the TEC-11 antibody against endoglin, an endothelial cell proliferation marker that is upregulated on endothelial cells in miscellaneous human solid tumors. In addition, we review other tumor endothelial cell markers that are candidates for vascular targeting in man.
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PMID:Antibody-directed targeting of the vasculature of solid tumors. 887 33

A comparison was made of photodynamic therapy (PDT) mediated by two photosensitizers, the disulfonated aluminum phthalocyanine (AlPcS2) and Photofrin* (PII) with regard to their mechanism of action on murine tumors. Balb/c mice bearing intradermally growing EMT-6 tumors were injected intravenously with either 1 mumol kg-1 body weight of AlPcS2 or 5 mg/kg of PII 24 h prior to red light irradiation from a Xenon lamp (650-700 nm, 200 mW cm-2, for AlPcS2 and 600-650 nm, 400 J cm-2 for PII. Tumor cell survival following in vivo PDT was determined by an in vitro clonogenicity assay on the dissociated tumors. Immediately after the completion of light irradiation, a reduction of approximately 72% in the number of clonogenic cells was seen with AlPcS2-treated tumor versus approximately 24% of that for PII-treated tumor. Further loss of clonogenic cell survival progressed as a function of time following PDT, and was considered to be the consequence of indirect PDT action, however, the decline in cell viability was steeper in the first 6 h with PII-PDT than with AlPcS2-PDT. 24 h after PDT, the clonogenic capacity of both AlPcS2-and PII-PDT treated tumor fell to approximately 3% of the control tumor. The PDT effect on tumor blood flow as a measure of the tumor vascular damage was monitored by the retention of 99mTc-MIBI in the tumor. Little effect on tumor blood flow was seen with AlPcS2-PDT at 0 h after the completion of light treatment. Thereafter the blood flow declined slowly and remained at approximately 50% the level of the control by 24 h post-PDT. In contrast, PII provoked a approximately 40% reduction of tumor blood flow immediately after the completion of photo irradiation, which then fell to approximately 20% within 2 h and approximately 7% by 24 h post-PDT. These results indicate the involvement of both direct and indirect mechanisms in the PDT induced tumor necrosis. However, AlPcS2-PDT exerted a larger direct tumor cell phototoxic effect, whereas PII-PDT induced tumor cell death to a greater extent via an indirect effect that parallels the extensive damage to the tumor vasculature.
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PMID:Evidence for different mechanisms of EMT-6 tumor necrosis by photodynamic therapy with disulfonated aluminum phthalocyanine or photofrin: tumor cell survival and blood flow. 871 17

We have reported previously that topical administration of vascular endothelial growth factor165 (VEGF) to a microvascular bed supplied with a continuous endothelium can rapidly induce the formation of endothelial fenestrations (W. G. Roberts and G. E. Palade, J. Cell Sci., 108: 2369-2379, 1995). From these results, we hypothesized that tumor vasculature, in general, may also be fenestrated because it has been reported that tumor secretion of VEGF causes the surrounding host vasculature to invade and feed the growing tumor. Using electron microscopy to characterize the endothelial cell morphology in tumor vessels from either the periphery or the core of the tumor and immunoblotting to detect secreted VEGF, we analyzed the vasculature of human and murine neoplastic tumors grown s.c. in male nude mice. To clarify the role of VEGF165 two models were used: (a) Chinese hamster ovary (CHO) cells stably transfected with hu VEGF165 and injected into mice (VEGF:CHO tumors); and (b) slow-release pellets containing purified VEGF or basic fibroblast growth factor implanted on the rat cremaster muscle. All tumors had vessels with fenestrated endothelium, open interendothelial junctions, and clustered fused caveolae. From all of the peripheral tumor vessels observed, fenestrated endothelium was observed in 41% from EMT, 35% from M1S, 37% from U87, and 56% from VEGF:CHO tumors, whereas surrounding skin and muscle, from which tumor vessels were derived, had fenestrated endothelium in 2 and 0% of all vessels, respectively. Additionally, further analysis revealed a substantial decrease in the anionic glycocalyx on the luminal face of the fenestral diaphragms in endothelium from tumors (especially VEGF:CHO) when compared to intestine or pancreas. Because the host tissue microvascular endothelium which supplies the tumor is not fenestrated, tumors can transform nonproliferating, nonfenestrated vessels into proliferating vessels, many of which have fenestrated endothelium. These data provide evidence that chronic VEGF exposure can induce fenestrations in nonfenestrated endothelium similar to the fenestrated endothelium found in tumor vessels.
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PMID:Neovasculature induced by vascular endothelial growth factor is fenestrated. 904 58

We have previously demonstrated that vascular endothelial growth factor-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chronically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772). Because the morphology and function of microvascular endothelium differs from tissue to tissue, we undertook studies to examine whether the neovasculature in tumors also differed depending upon tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251). In addition, we studied Chinese hamster ovary cells stably transfected with human VEGF165. As previously reported, tumors grown in the subcutaneous space had a microvasculature that was fenestrated and had open endothelial gaps. The identical tumors when grown in the brain also had fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps were not seen in all tumors implanted in the brain (EMT and M1S), although fenestrated endothelium was always seen. VEGF and VEGF receptors were measured in tumors from both locations by immunoblotting and competitive polymerase chain reaction, respectively. VEGF amount was not significantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels derived from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of the tumor vasculature and that endothelia from different tissues vary in their ability to express the VEGF receptors given identical stimuli.
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PMID:Host microvasculature influence on tumor vascular morphology and endothelial gene expression. 977 55

We have characterized a murine IgM monoclonal antibody, TEC-11, that recognizes endoglin and may be suitable for targeting cytotoxic agents to human tumor vasculature. TEC-11 strongly stains endothelial cells in a broad range of solid human tumors while staining endothelial cells in the majority of normal, healthy adult tissues relatively weakly. Human umbilical vein endothelial cells (HUVECs) in sections of the umbilical vein react weakly with TEC-11, whereas proliferating HUVECs in tissue culture react strongly and uniformly. HUVEC cultures grown to confluence and then rested contain two subpopulations having high and low levels of endoglin expression. Flow cytometry revealed that a significant proportion of cells with high endoglin expression are cycling, having markedly increased levels of cellular protein, RNA, and DNA by comparison to low endoglin-expressing cells, which appear to be noncycling. Taken together, the increased binding of TEC-11 to tumor vasculature and to dividing as opposed to noncycling HUVECs in vitro suggests that endoglin is an endothelial cell proliferation-associated marker. An immunotoxin [TEC-11.deglycosylated ricin A chain (dgA)] composed of TEC-11 and dgA was 3000-fold more potent at inhibiting protein synthesis in proliferating HUVEC cultures than in confluent cultures. The confluent cells were no more sensitive to TEC-11.dgA than they were to an isotype-matched immunotoxin of irrelevant specificity. These findings suggest that TEC-11.dgA might have therapeutic value in the treatment of solid tumors in humans by selectively killing dividing endothelial cells which are prevalent in such tumors.
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PMID:Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. 981 65

Angiogenesis is a key process in a variety of human diseases, including cancer. The ability to target selectively the tumor vasculature is potentially useful for the diagnosis and treatment of cancer. Still, little information is available regarding markers that are restricted to the ECs of tumor vessels. cDNA array technology allows simultaneous analysis of relative expression levels of a broad spectrum of genes in 2 related cell populations. We used this technology with the aim of identifying markers specific for TECs. TECs were isolated by CD31-mediated immunomagnetic separation from tumors induced by s.c. injection of NF9006 breast carcinoma cells into syngeneic mice. NECs were isolated from lactating mammary glands. The endothelial nature of isolated cells was confirmed by RT-PCR using CD31-specific primers and by uptake of DiI-Ac-LDL. Macrophage contamination in the EC isolations could be reasonably ruled out by assessing the expression of the macrophage marker c-fms. (32)P-labeled cDNA probes generated by reverse transcription from total RNA were hybridized to mouse-specific gene arrays. Several genes consistently showed differential expression between TECs and NECs. However, expression of only 1 of these genes, IGFBP-3, was restricted exclusively to ECs. Semiquantitative RT-PCR revealed 22- to 33-fold differential expression of IGFBP-3 in the TEC fraction. IGFBP-3 was overexpressed by a factor of 5 in an additional mouse model of breast carcinoma induced by 4T1.2 tumor cells. These results indicate that IGFBP-3 is a potential novel marker of angiogenesis. Elucidation of its role in tumor neovascularization may open the possibility of IGFBP-3 as a therapeutic target for antiangiogenesis.
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PMID:Insulin-like growth factor binding protein-3 is overexpressed in endothelial cells of mouse breast tumor vessels. 1249 64

Stanniocalcin 1 (STC1) is a secreted glycoprotein originally described as a hormone involved in calcium and phosphate homeostasis in bony fishes. We recently identified the mammalian homolog of this molecule to be highly up-regulated in an in vitro model of angiogenesis, as well as focally and intensely expressed at sites of pathological angiogenesis (e.g. tumor vasculature). In the present study, we report that STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation. STC1 did not inhibit proliferative or migratory responses to vascular endothelial growth factor or basic fibroblast growth factor. The mechanism of STC1 inhibitory effects on HGF-induced endothelial migration seem to occur secondary to receptor activation because STC1 did not inhibit HGF-induced c-met receptor phosphorylation, but did block HGF-induced focal adhesion kinase activation. In the mouse femoral artery ligation model of angiogenesis, STC1 expression closely paralleled that of the endothelial marker CD31, and the peak level of STC1 expression occurred after an increase in HGF expression. We propose that STC1 may play a selective modulatory role in angiogenesis, possibly serving as a "stop signal" or stabilizing factor contributing to the maturation of newly formed blood vessels. HGF is a mesenchyme-derived pleiotropic factor with mitogenic, motogenic, and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c-met, and aberrant HGF and c-met expression are frequently observed in a variety of tumors. Recent studies have shown HGF to be a potent growth factor implicated in wound healing, tissue regeneration, and angiogenesis.
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PMID:Stanniocalcin 1 is an autocrine modulator of endothelial angiogenic responses to hepatocyte growth factor. 1450 Jul 21

The phosphatidylinositol 3'-kinase (PI3k)/protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The delta isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110delta specific inhibitor IC486068, which abrogated radiation-induced phosphorylation of Akt. IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in Matrigel following irradiation. In vivo tumor growth delay was studied in mice with Lewis lung carcinoma and GL261 hind limb tumors. Mice were treated with daily i.p. injections (25 mg/kg) of IC486068 during 6 days of radiation treatment (18 Gy). Combined treatment with IC486068 and radiation significantly reduced tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the tumor vascular window model and showed IC486068 significantly enhanced radiation-induced destruction of tumor vasculature as compared with either treatment alone. IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. These findings suggest that p110delta is a therapeutic target to enhance radiation-induced tumor control.
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PMID:A specific antagonist of the p110delta catalytic component of phosphatidylinositol 3'-kinase, IC486068, enhances radiation-induced tumor vascular destruction. 1525 60

In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.
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PMID:Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects. 1789 20

Integrin-linked kinase (ILK) was assesed as a therapeutic target in glioblastoma xenograft models through multiple endpoints including treatment related changes in the tumor microenvironment. Glioblastoma cell lines were tested in vitro for sensitivity toward the small-molecule inhibitors QLT0254 and QLT0267. Cell viability, cell cycle, and apoptosis were evaluated using MTT assay, flow cytometry, caspase activation, and DAPI staining. Western blotting and ELISA were used for protein analysis (ILK, PKB/Akt, VEGF, and HIF-1alpha). In vivo assessment of growth rate, cell proliferation, BrdUrd, blood vessel mass (CD31 labeling), vessel perfusion (Hoechst 33342), and hypoxia (EF-5) was done using U87MG glioblastoma xenografts in RAG2-M mice treated orally with QLT0267 (200 mg/kg q.d.). ILK inhibition in vitro with QLT0254 and QLT0267 resulted in decreased levels of phospho-PKB/Akt (Ser473), secreted VEGF, G2-M block, and apoptosis induction. Mice treated with QLT0267 exhibited significant delays in tumor growth (treated 213 mm3 versus control 549 mm3). In situ analysis of U87MG tumor cell proliferation from QLT0267-treated mice was significantly lower relative to untreated mice. Importantly, VEGF and HIF-1alpha expression decreased in QLT0267-treated tumors as did the percentage of blood vessel mass and numbers of Hoechst 33342 perfused tumor vessels compared with control tumors (35% versus 83%). ILK inhibition with novel small-molecule inhibitors leads to treatment-associated delays in tumor growth, decreased tumor angiogenesis, and functionality of tumor vasculature. The therapeutic effects of a selected ILK inhibitor (QLT0267) should be determined in the clinic in cancers that exhibit dysregulated ILK, such as PTEN-null glioblastomas.
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PMID:Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK). 1820 10


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