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Tumor Biology |
Department of Pathology, University of Arizona, Tucson, Arizona 85724
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the importance of angiogenesis in solid tumors is well established, its role in hematopoietic tumors is not. In a study of 88 patients with B-cell non-Hodgkin’s lymphoma, Ribatti et al. (23) found an increase in the microvessel density in lymph nodes that correlated with the severity of the disease. A similar study of childhood acute lymphocytic leukemia also revealed an increase in the microvessel density, as assessed by factor VIII-related antigen staining, in the bone marrow of leukemic patients compared with that found in normal controls (24) . An increase in bone marrow microvessel density was also observed in a series of patients diagnosed with multiple myeloma compared with patients with monoclonal gammopathies of unknown significance (25) . Such findings, although not conclusive, are suggestive of a role for angiogenic growth factors in hematopoietic malignancies.
Although its expression was demonstrated previously in the HL-60 promyelocytic leukemia cell line (26) , it is not known whether VEGF or other angiogenic factors play a role in human hematopoietic malignancies. The present studies were undertaken to identify whether VEGF and its receptors were expressed in other hematopoietic malignancies in general and in multiple myeloma in particular.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Northern Blot Analysis.
Total cellular RNA was isolated from the cell lines using guanidinium isothiocyanate and cesium chloride gradient centrifugation according to the method of Chirgwin et al. (27)
. RNA (5 µg) was denatured at 65°C for 10 min in 50% formamide, 6.5% formaldehyde, 40 mM 3-(N-morpholino)propanesulfonic acid, and subjected to electrophoresis on a 1% formaldehyde-agarose gel. The RNA was transferred by capillary action to a nylon membrane (Nytran; Schleicher & Schuell, Keene, NH) and immobilized by exposure to UV light. Membranes were prehybridized in Rapid-hyb buffer (Amersham, Arlington Heights, IL) according to the manufacturer’s instructions. Hybridization was carried out at 42°C for 24 h with 32P-labeled cDNA probes generated by RT-PCR. Following high stringency washes, the filters were exposed to X-ray film (Kodak; XAR-5) at -80°C with an intensifying screen.
Detection of Angiogenic Molecules and Growth Factor Cytokines by RT-PCR.
Total RNA isolated from exponentially growing cells was treated with an enzyme reverse transcriptase (SuperScript II; Gibco BRL, Gaithersburg, MD) to generate cDNA; the cDNA was then amplified by the PCR using Taq DNA polymerase (Life Technologies, Inc., Gaithersburg, MD). The primers were designed to span intron-exon borders to distinguish amplified cDNA from genomic DNA. PCR primers used to detect VEGF were: 5'-GAA GTG GTG AAG TTC ATG GAT GTC (forward) and 5'-CGA TCG TTC TGT ATC AGT CTT TCC (reverse); flt-1, 5'- GAG AAT TCA CTA TGG AAG ATC TGA TTT CTT ACAGT-3' (forward) and 5'- GAG CAT GCG GTA AAA TAC ACA TGT GCT TCT AG-3' (reverse); and KDR, 5'-CAA-CAA-AGT-CGG-GAG-AGG-AG-3' (forward) and 5'-ATG-ACG-ATG-GAC-AAG-TAG-CC-3' (reverse; Ref. 28
). The VEGF primers detect the four spliced RNA transcripts. The primers used for bFGF were: 5'- GTG TGT GCT AAC CGT TAC CT (forward) and 5'-GCT CTT AGC AGA CAT TGG AAG (reverse; Ref. 7
). Amplification of the "housekeeping" gene, glyceraldehyde-3-phosphate dehydrogenase was used to verify mRNA isolation and RT-PCR techniques. PCR-amplified products were electrophoresed in 1.0% agarose gel and stained with ethidium bromide.
ELISA.
Supernatants were obtained from in vitro tissue culture studies and were examined for expression of VEGF using a quantitative solid-phase ELISA assay (R&D Systems, Minneapolis, MN). Samples (200 µl) or standards (200 µl) were added to a coated microtiter plate and incubated for 2 h at room temperature. The plates were then rinsed, and 200 µl of recombinant anti-VEGF165 polyclonal antibody conjugated to horseradish peroxidase were added to the wells. This ELISA assay will detect both the Mr 165,000 and Mr 121,000 VEGF isoforms. After an additional 2- incubation, the wells were again rinsed, and 200 µl of hydrogen peroxide and tetramethylbenzidine were added. The reaction was stopped by the addition of 50 µl of 2 N sulfuric acid. The absorbance of each well was measured spectrophotometrically at 450 nm and plotted against a standard curve with VEGF levels expressed as ng/ml. The lower detection limit of the ELISA assay is 5.0 pg/ml. Each cell line was analyzed in triplicate.
RNase Protection Assay.
HUVECs were plated into T-75 tissue culture flasks and allowed to grow to 
60% confluence. The cells were then exposed to 10 ng/ml VEGF for 72 h. A parallel flask of HUVEC cells was set up without VEGF exposure and maintained under identical culture conditions as a control. After VEGF exposure, total cellular RNA was isolated, and an RNase protection assay was carried out using the Riboquant system according to the manufacturer’s instructions (PharMingen, Inc., San Diego, CA). The human cytokine/chemokine set hCK-4, which included templates for the following human cytokines: hIL-3, hIL-7, human GM-CSF, human granulocyte-CSF, human macrophage-CSF, hIL-6, leukemia inhibitory factor, human stem cell factor, and human oncostatin M was used for probe generation. Probe synthesis was carried out with a reaction mixture containing [
-32P]UTP, GACU nucleotide pool, DTT, transcription buffer, RNase protection assay template, and T7 DNA polymerase. The mixture was incubated at 37°C for 1 h and purified using phenol/chloroform extraction. Five µg of total cellular RNA isolated from either the VEGF-exposed HUVEC cells or from unexposed control HUVEC cells were pipetted into a microfuge tube and dried in a vacuum concentrator. The samples were then reconstituted in hybridization buffer. Concomitantly, the probe was diluted with the same hybridization buffer to yield a concentration of 2.9 x 104 cpm/µl, with 2 µl added to the tube containing the RNA. Mineral oil was added to each tube to prevent evaporation. Samples were then denatured at 90°C and hybridized for 16 h at 56°C. After hybridization, the samples were placed at 37°C, and an RNase cocktail was added to each tube. The RNase treated samples were purified using phenol/chloroform extraction and resolved on a nondenaturing acrylamide gel. After electrophoresis, the gel was carefully removed from the glass plate and dried at 80°C for 1 h. The dried gel was then placed on X-ray film (Kodak X-AR), and autoradiography was carried out. To control for differences in sample loading, two housekeeping genes, glyceraldehyde-3-phosphate dehydrogenase and leukemia inhibitory factor were included as controls.
Immunohistochemistry.
Immunohistochemical analysis was carried out on formalin-fixed, paraffin-embedded bone marrow clots or cores as described previously (29)
. Slides were stained for expression of factor VIII-related antigen (Dako-Patts, Santa Barbara, CA), VEGF, KDR, or Flt-1 (Santa Cruz Biotechnology, Santa Cruz, CA). The anti-VEGF antibody used in these studies has been demonstrated to be specific for VEGF and does not cross-react with other known VEGF/placenta growth factor family members. Its specificity has been established through the use of VEGF-specific blocking peptides. Both the KDR and Flt-1 antibodies are also specific and do not cross-react with each other or with other protein tyrosine kinase membrane receptors. All reactions were performed using an automated immunostainer (GenII; VMS, Tucson, AZ; Ref. 29
). Detection of bound antibody was assessed through the use of immunoperoxidase methodologies with diaminobenzidine serving as the color substrate or by alkaline phosphatase methodologies using a biotinylated goat-anti-rabbit antibody (Dako-Patts) in conjunction with alkaline phosphatase-conjugated streptavidin followed by NBT/5-bromo-4-chloro-3-indolyl phosphate as the color substrate. The VMS antibody diluent was used as a negative control. Nuclei were counterstained with methyl green or hematoxylin, and sections were evaluated by light microscopy. Endogenous peroxidase was inhibited with methanol containing 0.01% H2O2.
In Situ Hybridization.
Paraffin-embedded bone marrows (clots or cores) were sectioned 3 µm thick and placed on glass slides with a "sausage" control section containing placenta, liver, spleen, colon, and pancreas. The slides were baked 1 h at 60°C and then deparaffinized in two changes of xylene for 10 min each, two changes of 100% ethanol for 2 min each, followed by a graded series of alcohols (95%, 80%, and 70%), and finally, two changes of diethylpyrocarbamate-treated H2O. They were then placed in APK wash (VMS). All additional steps were carried out using an automated in situ hybridization instrument (Gen II; VMS). The details of this procedure have been published previously (29, 30, 31)
. A 24-mer VEGF-specific oligonucleotide probe was designed based on published sequences and was synthesized with six biotins at the 3'end (Research Genetics, Inc., Huntsville, AL). Before the addition to the probe, slides were treated with Protease 1 (VMS) for 4 min. A total of 100 µl of probe, diluted to a concentration of 1 ng/µl in a hybridization solution composed of 35% formamide, 5x Denhardt’s, 10% dextran sulfate, 100 µg/ml of salmon sperm DNA, and 4x SSC (0.6 M NaCl; 0.06 M Na3 citrate, pH 7.0), was manually added to each slide. For a negative control, the hybridization solution alone was applied. The slides were then denatured at 65°C for 4 min, followed by hybridization at 45°C for 60 min. After hybridization, three stringency washes were performed for 4 min each at 50°C as follows: 1x SSC, 0.5x SSC, and 0.1x SSC to remove unbound probe. Detection was carried out at 40°C by incubating the slides in streptavidin-alkaline phosphatase (Boehringer Mannheim Biochemicals, Indianapolis, IN), followed by NBT and 5-bromo-4-chloro-3-indolyl phosphate substrate. The slides were counterstained off the instrument with contrast red (Kirkegaard & Perry Laboratories, Gaithersburg, MD). Hybridization with a d(T)30 oligonucleotide probe confirmed the integrity of the RNA (not shown). To insure that the oligonucleotide probe was recognizing mRNA and not genomic DNA, a subset of slides was incubated in either DNase or RNase before the addition of the probe.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. As shown in Fig. 1
, RT-PCR analysis revealed transcripts corresponding to the 121 and the 165 isoforms of VEGF in the cell lines examined. Fig. 2
shows RT-PCR data demonstrating the expression of bFGF transcripts. In contrast to VEGF, bFGF was found in 50% of the cell lines examined. These findings suggest that, although different angioregulatory molecules may be operating in a given tumor, VEGF appears to be expressed in all hematopoietic tumors examined and therefore is likely playing an important role in their pathogenesis (Table 2)
. Expression of VEGF was confirmed using Northern blot analysis. As shown in Fig. 3
, we observed a 4.4-kb transcript in all cell lines examined and an additional transcript of 3.7 (not shown).
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and Fig. 4
). This was an unexpected finding in light of the literature reports of KDR and Flt-1 expression being restricted to vascular endothelial cells. Interestingly, the finding of VEGF receptor expression in tumor cells may not be unique to hematopoietic cell lines because we have observed expression of KDR, but not Flt-1, in a series of small cell and non-small cell lung cancers.4
The finding of Flt-1 in these cell lines suggests the possibility of an autocrine pathway in which the tumor cells may stimulate their own growth after VEGF exposure. Studies are presently under way to examine this possibility.
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. The H-460 human large cell lung carcinoma cell line was included for reference to compare the expression observed in the hematopoietic tumor cell lines with that of a known producer of VEGF. Values obtained from hematopoietic tumor cell lines in the ELISA assay ranged from a high of 2.2 ng/ml per 106 cells in the Hut 78 cell line to a low of 0.1 ng/ml in the ARH-77 cell line and compared with 2.8 ng/ml observed in the H-460 cells.
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. mRNAs for human macrophage-CSF, human granulocyte-CSF, human IL-6, human stem cell factor, and human oncostatin M were observed in both the VEGF-stimulated and control HUVEC cells. However, there was clearly an increase in these messages in response to VEGF exposure. We have repeated this experiment three times with similar results.
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. An additional patient demonstrated a heterogeneous pattern of plasma cell expression. VEGF expression in plasma cells revealed a diffuse cytoplasmic pattern of staining that varied in intensity among the individual patients. Although a gradient of VEGF expression is usually observed in solid tumors, with the strongest expression being in areas of hypoxia, we did not observe such a finding in the bone marrow core samples. This observation may reflect a relative lack of hypoxic areas in the samples chosen for analysis. Our findings in myeloma patients contrasted with those from normal bone marrow specimens, where a low level of plasma cell VEGF expression was observed in only one of six samples. In both normal and myeloma samples, strong VEGF staining was observed in myeloid and monocytic as well as in megakaryocytic cells. Such a pattern of expression is consistent with the known expression of VEGF in macrophages and platelets. Staining in erythroblastic or lymphoblastic cells was not observed in any of the specimens examined. Occasional staining of polymorphonuclear cells was also observed in both normal and myeloma samples. Fig. 7A
demonstrates cytoplasmic expression of VEGF, as evidenced by brown staining, in the neoplastic plasma cells growing in the bone marrow of one of these patients. Fig. 7B
presents the same tumor mass stained with an antibody against factor VIII-related antigen, revealing the expression of positive cells within the tumor mass, which represent the neovasculature associated with an angiogenic response. In Fig. 7
, panels C and D display the expression of the Flt-1 and KDR receptors, respectively. Although Flt-1 and KDR were not examined in all patient samples, neither of these two receptors were found to be expressed in the tumor cells; however, the normal bone marrow cells, predominantly myeloid and monocytic cells, revealed expression of both of these receptors, supporting a possible paracrine role of VEGF in this disease. Expression of VEGF in the malignant plasma cells was confirmed using in situ hybridization (Fig. 8)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have observed the expression of either VEGF, bFGF, or both by all of the hematopoietic tumor cell lines in our panel. In contrast to VEGF, which was observed in all of the cell lines, bFGF expression was observed in only 50% of the cell lines. These findings suggest that different angioregulatory molecules may be operating in hematopoietic tumors and that VEGF appears to be expressed in all hematopoietic cell lines examined. Results from our ELISA assay demonstrated that VEGF was secreted into the culture medium at concentrations that are within its range of biological activity. Concentrations of VEGF as low as 0.05 ng/ml have been demonstrated to stimulate endothelial cells in vitro (17) . Thus, concentrations produced by the ARH-77 and Jurkat cell lines, the two cell lines with the lowest observable VEGF levels in our study, potentially have the ability to stimulate endothelial cells.
Although the requirement of tumor-stromal interactions is well established in multiple myeloma, the role of angiogenic factors, which act primarily on the stromal elements, is not understood in relation to hematopoietic malignancies. Most cancers may be considered as a two-compartment system in which tumor cells and stromal cells interact in a paracrine fashion. The role of the stromal compartment is well established in multiple myeloma, involving interactions between myeloma cells and the microenvironment of the bone marrow by means of cell-cell contact, adhesion molecules, and cytokines (32, 33, 34, 35, 36) . Endothelial cells are found in the stromal layer of long-term bone marrow cultures in close contact with hematopoietic cells and are known to produce IL-6, an important growth factor in multiple myeloma (36 , 37) . They have also been demonstrated to secrete several CSFs in response to cytokines such as IL-1 (38) . Thus, it is possible that endothelial cells may, in response to angiogenic factors, release cytokines capable of sustaining tumor growth. Indeed, porcine brain microvascular endothelial cells have been shown to support the expansion of human progenitor cells in vitro (39) . In addition to endothelial cells, macrophages are also believed to play an important role in tumor angiogenesis through their ability to release proteases, growth factors (including VEGF), and other cytokines (18) . Although we did not measure the release of growth factors into the cell culture medium, others have reported an increased secretion of GM-CSF from human endothelial cells after VEGF exposure (40) . Such findings reveal that VEGF can increase the level of message expression for several growth factors with known stimulatory effects in hematopoietic malignancies including multiple myeloma. Interestingly, GM-CSF and G-CSF have been shown to stimulate human endothelial cells in vitro to migrate and proliferate (41) .
Paracrine control mechanisms are increasingly recognized as being important for tumor growth. IL-6 is well established as a paracrine growth factor in myeloma, both in vitro and in vivo (33 , 36 , 42 , 43) . In normal bone marrow as well as in patients, the stromal cells appear to be the major producers of IL-6 (42 , 44) . We have observed that recombinant human VEGF is capable of increasing the expression of mRNA for IL-6 in a human vascular endothelial cell line. This points to the possibility that VEGF may also increase the expression of IL-6 in the bone marrow, a hypothesis we are presently examining.
To date, two high-affinity receptors for VEGF have been identified: KDR (also referred to as flk-1) and Flt-1, both of which are class III receptor tyrosine kinases (45 , 46) . Although it is generally held that the expression of these two receptors is restricted to endothelial cells, both human uterine smooth muscle cells and retinal pigment cells have been demonstrated to express both KDR and flt-1, whereas murine retinal progenitor cells have also been reported to express the KDR receptor (47, 48, 49) . In our studies, the VEGF receptor Flt-1 was found to be expressed at moderate to high levels in 5 of the 12 tumor cell lines examined. This finding alludes to the possibility of an autocrine pathway involving VEGF operating in these cells.
The expression of VEGF in patient samples with multiple myeloma suggests that this growth factor, which has previously been believed to play a role only in solid tumors, may also be playing a role in hematopoietic tumors such as myeloma. In bone marrow from myeloma patients, VEGF expression was observed in the tumor cells both by immunohistochemistry and in situ hybridization, whereas the Flt-1 and KDR receptors were observed to be expressed in the normal marrow myeloid and monocytic cells. These data raise the possibility that VEGF may play a role in the growth of multiple myeloma through a paracrine or an autocrine mechanism. Studies are presently under way in our laboratory to determine whether VEGF is indeed playing a role in the pathophysiology of this disease. By identifying a role for VEGF in multiple myeloma or other hematopoietic malignancies, the possibility of using new treatment strategies in these patients is thus opened. Traditionally, treatment of myeloma has been hampered by the development of drug resistance in this generally incurable disease. By developing treatment strategies that target both the stromal and tumor compartments, drug resistance may be overcome, and the effect on therapeutic outcome enhanced. Although such an approach appears to hold promise for solid tumors (50) , it remains to be seen whether it will be effective in hematopoietic neoplasms as well.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by Grant CA-32102 from the National Cancer Institute and Grant ESO6694 from the National Institute of Environmental Health Sciences. 
2 To whom requests for reprints should be addressed, at Department of Pathology, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724. Phone: (520) 626-6032; Fax: (520) 626-6463; E-mail: wbellamy{at}u.arizona.edu
3 The abbreviations used are: VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; HUVEC, human umbilical vein endothelial cell; RT-PCR, reverse transcription-PCR; hIL, human interleukin; CSF, colony-stimulating factor; GM-CSF, granulocyte-macrophage CSF; NBT, nitroblue tetrazolium; VMS, Ventana Medical Systems.
4 W. T. Bellamy, L. Richter, and P. Mendibles, Expression of VEGF receptors in non-small cell lung carcinomas, manuscript in preparation.
Received 7/16/98. Accepted 12/ 2/98.
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S. Kumar, T. E. Witzig, M. Timm, J. Haug, L. Wellik, T. K. Kimlinger, P. R. Greipp, and S. V. Rajkumar Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression Blood, August 15, 2004; 104(4): 1159 - 1165. [Abstract] [Full Text] [PDF]
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H. X. Chen Expanding the Clinical Development of Bevacizumab Oncologist, June 1, 2004; 9(suppl_1): 27 - 35. [Abstract] [Full Text] [PDF]
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S. C. R. Santos and S. Dias Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways Blood, May 15, 2004; 103(10): 3883 - 3889. [Abstract] [Full Text] [PDF]
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K. Podar, L. P. Catley, Y.-T. Tai, R. Shringarpure, P. Carvalho, T. Hayashi, R. Burger, R. L. Schlossman, P. G. Richardson, L. N. Pandite, et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment Blood, May 1, 2004; 103(9): 3474 - 3479. [Abstract] [Full Text] [PDF]
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K. Asosingh, H. De Raeve, E. Menu, I. Van Riet, E. Van Marck, B. Van Camp, and K. Vanderkerken Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity Blood, April 15, 2004; 103(8): 3131 - 3137. [Abstract] [Full Text] [PDF]
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A. Bazarbachi, R. A. Merhi, A. Gessain, R. Talhouk, H. El-Khoury, R. Nasr, O. Gout, R. Sulahian, F. Homaidan, H. de The, et al. Human T-Cell Lymphotropic Virus Type I-Infected Cells Extravasate through the Endothelial Barrier by a Local Angiogenesis-Like Mechanism Cancer Res., March 15, 2004; 64(6): 2039 - 2046. [Abstract] [Full Text] [PDF]
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T. Kelly, H.-Q. Miao, Y. Yang, E. Navarro, P. Kussie, Y. Huang, V. MacLeod, J. Casciano, L. Joseph, F. Zhan, et al. High Heparanase Activity in Multiple Myeloma Is Associated with Elevated Microvessel Density Cancer Res., December 15, 2003; 63(24): 8749 - 8756. [Abstract] [Full Text] [PDF]
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R. Bieker, T. Padro, J. Kramer, M. Steins, T. Kessler, S. Retzlaff, F. Herrera, J. Kienast, W. E. Berdel, and R. M. Mesters Overexpression of Basic Fibroblast Growth Factor and Autocrine Stimulation in Acute Myeloid Leukemia Cancer Res., November 1, 2003; 63(21): 7241 - 7246. [Abstract] [Full Text] [PDF]
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A. Vacca, R. Ria, F. Semeraro, F. Merchionne, M. Coluccia, A. Boccarelli, C. Scavelli, B. Nico, A. Gernone, F. Battelli, et al. Endothelial cells in the bone marrow of patients with multiple myeloma Blood, November 1, 2003; 102(9): 3340 - 3348. [Abstract] [Full Text] [PDF]
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S. Colla, F. Morandi, M. Lazzaretti, P. Polistena, M. Svaldi, P. Coser, S. Bonomini, M. Hojden, E. Martella, T. Chisesi, et al. Do human myeloma cells directly produce basic FGF? Blood, October 15, 2003; 102(8): 3071 - 3073. [Full Text] [PDF]
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 A. Orecchia, P. M. Lacal, C. Schietroma, V. Morea, G. Zambruno, and C. M. Failla Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the {alpha}5{beta}1 integrin J. Cell Sci., September 1, 2003; 116(17): 3479 - 3489. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. T. Stopeck, L. R. Silverman, J. E. Lancet, M. A. Cooper, A. L. Hannah, J. M. Cherrington, A.-M. O'Farrell, H. A. Yuen, S. G. Louie, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes Blood, August 1, 2003; 102(3): 795 - 801. [Abstract] [Full Text] [PDF]
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P. Wachsberger, R. Burd, and A. P. Dicker Tumor Response to Ionizing Radiation Combined with Antiangiogenesis or Vascular Targeting Agents: Exploring Mechanisms of Interaction Clin. Cancer Res., June 1, 2003; 9(6): 1957 - 1971. [Abstract] [Full Text] [PDF]
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 Y.-L. Hu, C. Albanese, R. G. Pestell, and R. B. Jaffe Dual Mechanisms for Lysophosphatidic Acid Stimulation of Human Ovarian Carcinoma Cells J Natl Cancer Inst, May 21, 2003; 95(10): 733 - 740. [Abstract] [Full Text] [PDF]
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G. Bisping, R. Leo, D. Wenning, B. Dankbar, T. Padro, M. Kropff, C. Scheffold, M. Kroger, R. M. Mesters, W. E. Berdel, et al. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma Blood, April 1, 2003; 101(7): 2775 - 2783. [Abstract] [Full Text] [PDF]
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S. Kumar, R. Fonseca, A. Dispenzieri, M. Q. Lacy, J. A. Lust, L. Wellik, T. E. Witzig, M. A. Gertz, R. A. Kyle, P. R. Greipp, et al. Prognostic value of angiogenesis in solitary bone plasmacytoma Blood, March 1, 2003; 101(5): 1715 - 1717. [Abstract] [Full Text] [PDF]
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G. Schuch, M. Machluf, G. Bartsch Jr, M. Nomi, H. Richard, A. Atala, and S. Soker In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo Blood, December 15, 2002; 100(13): 4622 - 4628. [Abstract] [Full Text] [PDF]
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 J. M.L. Ebos, J. Tran, Z. Master, D. Dumont, J. V. Melo, E. Buchdunger, and R. S. Kerbel Imatinib Mesylate (STI-571) Reduces Bcr-Abl-Mediated Vascular Endothelial Growth Factor Secretion in Chronic Myelogenous Leukemia Mol. Cancer Res., December 1, 2002; 1(2): 89 - 95. [Abstract] [Full Text] [PDF]
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H. F. Dvorak Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy J. Clin. Oncol., November 1, 2002; 20(21): 4368 - 4380. [Abstract] [Full Text] [PDF]
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B. Lin, K. Podar, D. Gupta, Y.-T. Tai, S. Li, E. Weller, T. Hideshima, S. Lentzsch, F. Davies, C. Li, et al. The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Inhibits Growth and Migration of Multiple Myeloma Cells in the Bone Marrow Microenvironment Cancer Res., September 1, 2002; 62(17): 5019 - 5026. [Abstract] [Full Text] [PDF]
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S. J. Welsh, W. T. Bellamy, M. M. Briehl, and G. Powis The Redox Protein Thioredoxin-1 (Trx-1) Increases Hypoxia-inducible Factor 1{alpha} Protein Expression: Trx-1 Overexpression Results in Increased Vascular Endothelial Growth Factor Production and Enhanced Tumor Angiogenesis Cancer Res., September 1, 2002; 62(17): 5089 - 5095. [Abstract] [Full Text] [PDF]
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A. Stopeck, M. Sheldon, M. Vahedian, G. Cropp, R. Gosalia, and A. Hannah Results of a Phase I Dose-escalating Study of the Antiangiogenic Agent, SU5416, in Patients with Advanced Malignancies Clin. Cancer Res., September 1, 2002; 8(9): 2798 - 2805. [Abstract] [Full Text] [PDF]
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E. S. J. M. de Bont, V. Fidler, T. Meeuwsen, F. Scherpen, K. Hahlen, and W. A. Kamps Vascular Endothelial Growth Factor Secretion Is an Independent Prognostic Factor for Relapse-free Survival in Pediatric Acute Myeloid Leukemia Patients Clin. Cancer Res., September 1, 2002; 8(9): 2856 - 2861. [Abstract] [Full Text] [PDF]
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J L Xu, R Lai, T Kinoshita, N Nakashima, and T Nagasaka Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade J. Clin. Pathol., July 1, 2002; 55(7): 530 - 534. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, R. A. Mesa, R. Fonseca, G. Schroeder, M. F. Plevak, A. Dispenzieri, M. Q. Lacy, J. A. Lust, T. E. Witzig, M. A. Gertz, et al. Bone Marrow Angiogenesis in 400 Patients with Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Primary Amyloidosis Clin. Cancer Res., July 1, 2002; 8(7): 2210 - 2216. [Abstract] [Full Text] [PDF]
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M. Ratta, F. Fagnoni, A. Curti, R. Vescovini, P. Sansoni, B. Oliviero, M. Fogli, E. Ferri, G. R. Della Cuna, S. Tura, et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6 Blood, June 17, 2002; 100(1): 230 - 237. [Abstract] [Full Text] [PDF]
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M. E. El-Sabban, R. A. Merhi, H. A. Haidar, B. Arnulf, H. Khoury, J. Basbous, J. Nijmeh, H. de The, O. Hermine, and A. Bazarbachi Human T-cell lymphotropic virus type 1-transformed cells induce angiogenesis and establish functional gap junctions with endothelial cells Blood, May 1, 2002; 99(9): 3383 - 3389. [Abstract] [Full Text] [PDF]
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S. Lentzsch, M. S. Rogers, R. LeBlanc, A. E. Birsner, J. H. Shah, A. M. Treston, K. C. Anderson, and R. J. D'Amato S-3-Amino-phthalimido-glutarimide Inhibits Angiogenesis and Growth of B-Cell Neoplasias in Mice Cancer Res., April 1, 2002; 62(8): 2300 - 2305. [Abstract] [Full Text] [PDF]
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M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]
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S. Dias, M. Choy, K. Alitalo, and S. Rafii Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy Blood, March 15, 2002; 99(6): 2179 - 2184. [Abstract] [Full Text] [PDF]
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 K. Podar, Y.-T. Tai, B. K. Lin, R. P. Narsimhan, M. Sattler, T. Kijima, R. Salgia, D. Gupta, D. Chauhan, and K. C. Anderson Vascular Endothelial Growth Factor-induced Migration of Multiple Myeloma Cells Is Associated with beta 1 Integrin- and Phosphatidylinositol 3-Kinase-dependent PKCalpha Activation J. Biol. Chem., March 1, 2002; 277(10): 7875 - 7881. [Abstract] [Full Text] [PDF]
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Y.-T. Tai, K. Podar, D. Gupta, B. Lin, G. Young, M. Akiyama, and K. C. Anderson CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells Blood, February 15, 2002; 99(4): 1419 - 1427. [Abstract] [Full Text] [PDF]
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M. B. Steins, T. Padro, R. Bieker, S. Ruiz, M. Kropff, J. Kienast, T. Kessler, T. Buechner, W. E. Berdel, and R. M. Mesters Efficacy and safety of thalidomide in patients with acute myeloid leukemia Blood, February 1, 2002; 99(3): 834 - 839. [Abstract] [Full Text] [PDF]
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 F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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R. Koomagi, F. Zintl, A. Sauerbrey, and M. Volm Vascular Endothelial Growth Factor in Newly Diagnosed and Recurrent Childhood Acute Lymphoblastic Leukemia as Measured by Real-Time Quantitative Polymerase Chain Reaction Clin. Cancer Res., November 1, 2001; 7(11): 3381 - 3384. [Abstract] [Full Text] [PDF]
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J. L. Gabrilove Angiogenic Growth Factors: Autocrine and Paracrine Regulation of Survival in Hematologic Malignancies Oncologist, October 1, 2001; 6(2008): 4 - 7. [Abstract] [Full Text] [PDF]
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A. F. List Vascular Endothelial Growth Factor Signaling Pathway as an Emerging Target in Hematologic Malignancies Oncologist, October 1, 2001; 6(2008): 24 - 31. [Abstract] [Full Text] [PDF]
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F. J. Giles The Vascular Endothelial Growth Factor (VEGF) Signaling Pathway: A Therapeutic Target in Patients with Hematologic Malignancies Oncologist, October 1, 2001; 6(2008): 32 - 39. [Abstract] [Full Text] [PDF]
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T. Hayashibara, Y. Yamada, T. Miyanishi, H. Mori, T. Joh, T. Maeda, N. Mori, T. Maita, S. Kamihira, and M. Tomonaga Vascular Endothelial Growth Factor and Cellular Chemotaxis: A Possible Autocrine Pathway in Adult T-Cell Leukemia Cell Invasion Clin. Cancer Res., September 1, 2001; 7(9): 2719 - 2726. [Abstract] [Full Text] [PDF]
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M. H. Mangi, W. T. Bellamy, T. M. Grogan, and A. F. List Misleading information about ALIP and VEGF in myelodysplasia Blood, August 15, 2001; 98(4): 1272 - 1273. [Full Text] [PDF]
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J. De Vos, G. Couderc, K. Tarte, M. Jourdan, G. Requirand, M.-C. Delteil, J.-F. Rossi, N. Mechti, and B. Klein Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays Blood, August 1, 2001; 98(3): 771 - 780. [Abstract] [Full Text] [PDF]
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K. Podar, Y.-T. Tai, F. E. Davies, S. Lentzsch, M. Sattler, T. Hideshima, B. K. Lin, D. Gupta, Y. Shima, D. Chauhan, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration Blood, July 15, 2001; 98(2): 428 - 435. [Abstract] [Full Text] [PDF]
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 M. S. Irwin and W. G. Kaelin p53 Family Update: p73 and p63 Develop Their Own Identities Cell Growth Differ., July 1, 2001; 12(7): 337 - 349. [Full Text] [PDF]
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R. M. Mesters, T. Padro, R. Bieker, M. Steins, M. Kreuter, M. Goner, S. Kelsey, P. Scigalla, W. Fiedler, T. Buchner, et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia Blood, July 1, 2001; 98(1): 241 - 243. [Abstract] [Full Text] [PDF]
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A. R. Kini, L. C. Peterson, M. S. Tallman, and M. W. Lingen Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid Blood, June 15, 2001; 97(12): 3919 - 3924. [Abstract] [Full Text] [PDF]
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 S. Wellmann, T. Taube, K. Paal, H. Graf v. Einsiedel, W. Geilen, G. Seifert, C. Eckert, G. Henze, and K. Seeger Specific Reverse Transcription-PCR Quantification of Vascular Endothelial Growth Factor (VEGF) Splice Variants by LightCycler Technology Clin. Chem., April 1, 2001; 47(4): 654 - 660. [Abstract] [Full Text] [PDF]
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A. Ferrajoli, T. Manshouri, Z. Estrov, M. J. Keating, S. O’Brien, S. Lerner, M. Beran, H. M. Kantarjian, E. J. Freireich, and M. Albitar High Levels of Vascular Endothelial Growth Factor Receptor-2 Correlate with Shortened Survival in Chronic Lymphocytic Leukemia Clin. Cancer Res., April 1, 2001; 7(4): 795 - 799. [Abstract] [Full Text]
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D. J. Brat and E. G. Van Meir Glomeruloid Microvascular Proliferation Orchestrated by VPF/VEGF : A New World of Angiogenesis Research Am. J. Pathol., March 1, 2001; 158(3): 789 - 796. [Full Text] [PDF]
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B. D. Smolich, H. A. Yuen, K. A. West, F. J. Giles, M. Albitar, and J. M. Cherrington The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts Blood, March 1, 2001; 97(5): 1413 - 1421. [Abstract] [Full Text] [PDF]
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W. T. Bellamy, L. Richter, D. Sirjani, C. Roxas, B. Glinsmann-Gibson, Y. Frutiger, T. M. Grogan, and A. F. List Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes Blood, March 1, 2001; 97(5): 1427 - 1434. [Abstract] [Full Text] [PDF]
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W. S. Dalton, P. L. Bergsagel, W. M. Kuehl, K. C. Anderson, and J. L. Harousseau Multiple Myeloma Hematology, January 1, 2001; 2001(1): 157 - 177. [Abstract] [Full Text] [PDF]
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R. J. Klasa, A. F. List, and B. D. Cheson Rational Approaches to Design of Therapeutics Targeting Molecular Markers Hematology, January 1, 2001; 2001(1): 443 - 462. [Abstract] [Full Text] [PDF]
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R. A. Mesa, C. A. Hanson, S. V. Rajkumar, G. Schroeder, and A. Tefferi Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia Blood, November 15, 2000; 96(10): 3374 - 3380. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, Y. Shima, N. Raje, F. E. Davies, Y.-T. Tai, S. P. Treon, B. Lin, R. L. Schlossman, P. Richardson, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy Blood, November 1, 2000; 96(9): 2943 - 2950. [Abstract] [Full Text] [PDF]
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A. Aguayo, H. Kantarjian, T. Manshouri, C. Gidel, E. Estey, D. Thomas, C. Koller, Z. Estrov, S. O'Brien, M. Keating, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes Blood, September 15, 2000; 96(6): 2240 - 2245. [Abstract] [Full Text] [PDF]
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G. J. Roboz, S. Dias, G. Lam, W. J. Lane, S. L. Soignet, R. P. Warrell Jr, and S. Rafii Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis Blood, August 15, 2000; 96(4): 1525 - 1530. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, T. Leong, P. C. Roche, R. Fonseca, A. Dispenzieri, M. Q. Lacy, J. A. Lust, T. E. Witzig, R. A. Kyle, M. A. Gertz, et al. Prognostic Value of Bone Marrow Angiogenesis in Multiple Myeloma Clin. Cancer Res., August 1, 2000; 6(8): 3111 - 3116. [Abstract] [Full Text]
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A. Aguayo, S. O'Brien, M. Keating, T. Manshouri, C. Gidel, B. Barlogie, M. Beran, C. Koller, H. Kantarjian, and M. Albitar Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia Blood, July 15, 2000; 96(2): 768 - 770. [Abstract] [Full Text] [PDF]
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F. Bertolini, L. Fusetti, P. Mancuso, A. Gobbi, C. Corsini, P. F. Ferrucci, G. Martinelli, and G. Pruneri Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma Blood, July 1, 2000; 96(1): 282 - 287. [Abstract] [Full Text] [PDF]
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L. Fusetti, G. Pruneri, A. Gobbi, C. Rabascio, N. Carboni, F. Peccatori, G. Martinelli, and F. Bertolini Human Myeloid and Lymphoid Malignancies in the Non-Obese Diabetic/Severe Combined Immunodeficiency Mouse Model: Frequency of Apoptotic Cells in Solid Tumors and Efficiency and Speed of Engraftment Correlate with Vascular Endothelial Growth Factor Production Cancer Res., May 1, 2000; 60(9): 2527 - 2534. [Abstract] [Full Text]
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B. Dankbar, T. Padro, R. Leo, B. Feldmann, M. Kropff, R. M. Mesters, H. Serve, W. E. Berdel, and J. Kienast Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma Blood, April 15, 2000; 95(8): 2630 - 2636. [Abstract] [Full Text] [PDF]
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L. Rosen Antiangiogenic Strategies and Agents in Clinical Trials Oncologist, April 1, 2000; 5(90001): 20 - 27. [Abstract] [Full Text]
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N. Munshi, J. E. Groopman, P. S. Gill, and R. K. Ganju c-Src Mediates Mitogenic Signals and Associates with Cytoskeletal Proteins upon Vascular Endothelial Growth Factor Stimulation in Kaposi's Sarcoma Cells J. Immunol., February 1, 2000; 164(3): 1169 - 1174. [Abstract] [Full Text] [PDF]
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K. Kuramoto, T. Uesaka, A. Kimura, M. Kobayashi, H. Watanabe, and O. Katoh ZK7, a Novel Zinc Finger Gene, Is Induced by Vascular Endothelial Growth Factor and Inhibits Apoptotic Death in Hematopoietic Cells Cancer Res., January 1, 2000; 60(2): 425 - 430. [Abstract] [Full Text]
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E. Hellstrom-Lindberg, C. Willman, A. J. Barrett, and Y. Saunthararajah Achievements in Understanding and Treatment of Myelodysplastic Syndromes Hematology, January 1, 2000; 2000(1): 110 - 132. [Abstract] [Full Text] [PDF]
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J. W. Hussong, G. M. Rodgers, and P. J. Shami Evidence of increased angiogenesis in patients with acute myeloid leukemia Blood, January 1, 2000; 95(1): 309 - 313. [Abstract] [Full Text] [PDF]
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 N. Raje and K. Anderson Thalidomide -- A Revival Story N. Engl. J. Med., November 18, 1999; 341(21): 1606 - 1609. [Full Text]
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