Abstract
Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-alpha (IFN-alpha) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro- and anti-angiogenic factors, including bFGF (23.9 pg/ml +/- 7.9; mean +/- s.e.m.), VEGF (12.5 pg/ml +/- 2.3) and TSP-1 (1.9 ng/ml +/- 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both pro- and anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation.
MeSH terms
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Angiogenesis Inhibitors / biosynthesis*
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Antigens, CD
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Autocrine Communication
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Clone Cells / metabolism
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Clone Cells / pathology
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Cohort Studies
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Collagen / analysis
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Collagen / metabolism
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Endoglin
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Endostatins
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Endothelial Growth Factors / analysis
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Endothelial Growth Factors / metabolism
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Fibroblast Growth Factor 2 / analysis
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Fibroblast Growth Factor 2 / metabolism
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Germ-Line Mutation
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Growth Substances / biosynthesis*
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Humans
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Interferon-alpha / analysis
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Interferon-alpha / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphokines / analysis
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Lymphokines / metabolism
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Peptide Fragments / analysis
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Peptide Fragments / metabolism
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Proto-Oncogene Proteins / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / genetics
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Receptors, Cell Surface
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Receptors, Growth Factor / biosynthesis
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Receptors, Growth Factor / genetics
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Receptors, Thrombin / genetics
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Receptors, Vascular Endothelial Growth Factor
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Thrombospondin 1 / analysis
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Thrombospondin 1 / metabolism
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Tumor Cells, Cultured
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Vascular Cell Adhesion Molecule-1 / genetics
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Angiogenesis Inhibitors
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Antigens, CD
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ENG protein, human
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Endoglin
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Endostatins
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Endothelial Growth Factors
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Growth Substances
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Interferon-alpha
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Lymphokines
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Peptide Fragments
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Growth Factor
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Receptors, Thrombin
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Thrombospondin 1
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Vascular Cell Adhesion Molecule-1
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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Collagen
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1