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At least 343 records · Page 19Linked to original sources
PubMed2002

Insulin receptor activation inhibits insulin secretion from human islets of Langerhans.

There is no consensus on the role of insulin secreted from pancreatic beta-cells in regulating its own secretion, either in rodent islets or in human islets. We have now investigated whether there is an autocrine signalling role for insulin in human islets by determining insulin receptor expression and assessing the effects of insulin receptor activation using a non-peptidyl insulin mimetic termed L-783,281. Human insulin receptor mRNA was detected by PCR amplification of human islet cDNA, and translation of the message in human islets was confirmed by Western blotting. Perifusion experiments revealed that both glucose-stimulated and basal insulin secretion were significantly inhibited following human islet insulin receptor activation with L-783,281, and that signalling through phosphatidylinositol 3-kinase (PI 3-kinase) was responsible, at least in part, for this inhibitory effect. These studies indicate that human islets express insulin receptors and that they are functionally coupled to a PI 3-kinase-dependent inhibition of insulin secretion.

Autocrine Communication↗
PubMed2004

Autocrine release of TGF-beta by portal fibroblasts regulates cell growth.

Portal fibroblasts (PF) are a newly isolated population of fibrogenic cells in the liver postulated to play a significant role in early biliary fibrosis. Because transforming growth factor-beta (TGF)-beta is a key growth factor in fibrosis, we characterized the response of PF to TGF-beta. We demonstrate that PF produce significant amounts of TGF-beta2 and, unlike activated hepatic stellate cells (HSC), express all three TGF-beta receptors and are growth inhibited by TGF-beta1 and TGF-beta2. Fibroblast growth factor (FGF)-2, but not platelet derived growth factor (PDGF), causes PF proliferation. These data suggest a mechanism whereby HSC eclipse PF as the dominant myofibroblast population in biliary fibrosis.

Animals↗
PubMed2003

Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats.

BACKGROUND & AIMS: Numerous studies implicate transforming growth factor (TGF)-beta signaling in liver fibrogenesis. To perturb the TGF-beta pathway during this process, we overexpressed Smad7, an intracellular antagonist of TGF-beta signaling, in vivo and in primary-cultured hepatic stellate cells (HSCs). METHODS: Ligation of the common bile duct (BDL) was used to induce liver fibrosis in rats. Animals received injections of an adenovirus carrying Smad7 cDNA into the portal vein during surgery and via the tail vein at later stages. The effect of Smad7 on TGF-beta signaling and activation of HSC was further analyzed in primary-cultured cells. RESULTS: Smad7-overexpressing BDL rats displayed reduced collagen and alpha-SMA expression and reduced hydroxyproline content in the liver, when compared with animals administered AdLacZ. Such a beneficial effect was also observed when Smad7 was expressed in animals with established fibrosis. Accordingly, Smad7 arrested transdifferentiation of primary-cultured HSCs. AdSmad7 infected cells remained in a quiescent stage and retained storage of vitamin A droplets. Smad7 expression totally blocked TGF-beta signal transduction, shown by inhibiting Smad2/3 phosphorylation, nuclear translocation of activated Smad complexes, and activation of (CAGA)(9)-MLP-Luc, resulting in decreased collagen I expression. Smad7 also abrogated TGF-beta-dependent proliferation inhibition of HSC. Smad7 did not decrease expression of alpha-SMA, but immunofluorescent staining with anti alpha-SMA antibodies displayed destruction of the fibrillar organization of the actin cytoskeleton. CONCLUSIONS: In summary, gene transfer of Smad7 inhibits experimental fibrogenesis in vivo. Studies with isolated HSC suggest that the underlying mechanisms involve inhibition of TGF-beta signaling and HSC transdifferentiation.

Actins↗
PubMed1998

Intact autocrine activation and cytokine production by PMNs from injured adults with elevated Candida antigen titres.

Injured patients with Candida antigen titres have increased mortality due to sepsis. Polymorphonuclear leucocytes (PMNs) from injured patients with elevated Candida antigen titres demonstrate impaired function against Candida albicans growth when compared with PMNs from injury matched controls. To determine if PMN dysfunction is global, PMNs from patients with positive Candida antigen titres were evaluated for their ability to activate the anticandidal function of normal PMNs (autocrine activation) and to produce tumour necrosis factor (TNF) and interleukin 8 (IL8), known activators of PMN anticandidal function, this study demonstrates that the PMN dysfunction is not global, as PMN cytokine production and autocrine activation remain intact.

Adult↗
PubMed2003

Synthesis of acetylcholine by lung cancer.

The role of autocrine growth factors in the stimulation of lung cancer growth is well established. Nicotine is an agonist for acetylcholine receptors and stimulates lung cancer growth. This suggests that if lung cancers synthesize acetylcholine (ACh), then ACh may be an autocrine growth factor for lung cancer. Analysis of normal lung demonstrated that the cells of origin of lung cancers express the proteins necessary for non-neuronal ACh storage and synthesis. Analysis of mRNA from squamous cell lung carcinoma, small cell lung carcinoma (SCLC) and adenocarcinoma showed synthesis of choline acetyltransferase (ChAT) and nicotinic receptors. Immunohistochemical analysis of a retrospective series of SCLC and adenocarcinomas showed that more than 50% of the lung cancers screened expressed ChAT and nicotinic receptors. To study the effect of endogenous ACh synthesis on growth, SCLC cell lines were studied. SCLC cell lines were found to express ChAT mRNA and to secrete ACh into the medium as measured by HPLC separation and enzymatically-coupled electrochemical detection. The SCLC cell line NCI-H82 synthesized highest levels of ACh. Showing that the endogenously synthesized ACh interacted with its receptors to stimulate cell growth, addition of muscarinic and nicotinic antagonists slowed H82 cell proliferation. These findings demonstrate that lung cancer cell lines synthesize and secrete ACh to act as an autocrine growth factor. The existence of a cholinergic autocrine loop in lung cancer provides a basis for understanding the effects of nicotine in cigarette smoke on lung cancer growth and provides a new pathway to investigate for potential therapeutic approaches to lung cancer.

Acetylcholine↗
PubMed1999

Alpha-fetoprotein enhances the proliferation of human hepatoma cells in vitro.

Although the biological functions of alpha-fetoprotein ( AFP ) have been extensively studied, little is known about its effect on tumor cell growth. Our previous work has found that human AFP significantly stimulates the growth of mouse hepatoma cells in vitro. The purpose of the present study is to observe the effect of AFP on the proliferation of human hepatoma cells in vitro. Using a MTT- microculture tetrazolium assay, we found that the proliferation of human hepatoma cells was enhanced by in vitro treatment of AFP. However, the same concentrations of AFP had no effect on HL - 60 human leukemia cell proliferation, indicating that the human hepatoma cell proliferation - promoting role of AFP was not simply due to non-specific addition of exogenous protein and the proliferation enhancement of AFP showed certain tumor cell specificity. On the other hand, the growth stimulation of AFP could be diminished by rabbit anti - human AFP antibody. The anti- AFP antibody alone suppressed the growth of BEL - 7404 human hepatoma cells, not affecting HL - 60 cell proliferation. BEL - 7404 cell proliferation was not inhibited by normal rabbit immunoglobulins to demonstrate the specificity of anti-AFP effect. Taken together, it is concluded that AFP enhances the proliferation of human hepatoma cells in vitro, and this effect is seemingly mediated by an AFP/receptor autocrine pathway.

Antibodies↗
PubMedDate not supplied

24,25-(OH)(2)D(3) regulates cartilage and bone via autocrine and endocrine mechanisms.

The purpose of this paper is to summarize recent advances in our understanding of the physiological role of 24(R),25(OH)(2)D(3) in bone and cartilage and its mechanism of action. With the identification of a target cell, the growth plate resting zone (RC) chondrocyte, we have been able to use cell biology methodology to investigate specific functions of 24(R),25(OH)(2)D(3) and to determine how 24(R),25(OH)(2)D(3) elicits its effects. These studies indicate that there are specific membrane-associated signal transduction pathways that mediate both rapid, nongenomic and genomic responses of RC cells to 24(R),25(OH)(2)D(3). 24(R),25(OH)(2)D(3) binds RC chondrocyte membranes with high specificity, resulting in an increase in protein kinase C (PKC) activity. The effect is stereospecific; 24R,25(OH)(2)D(3), but not 24S,25-(OH)(2)D(3), causes the increase, indicating a receptor-mediated response. Phospholipase D-2 (PLD2) activity is increased, resulting in increased production of diacylglycerol (DAG), which in turn activates PKC. 24(R),25(OH)(2)D(3) does not cause translocation of PKC to the plasma membrane, but activates existing PKCalpha. There is a rapid decrease in Ca(2+) efflux, and influx is stimulated. 24(R),25(OH)(2)D(3) also reduces arachidonic acid release by decreasing phospholipase A(2) (PLA(2)) activity, thereby decreasing available substrate for prostaglandin production via the action of cyclooxygenase-1. PGE(2) that is produced acts on the EP1 and EP2 receptors expressed by RC cells to downregulate PKC via protein kinase A, but the reduction in PGE(2) decreases this negative feedback mechanism. Both pathways converge on MAP kinase, leading to new gene expression. One consequence of this is production of new matrix vesicles containing PKCalpha and PKCzeta and an increase in PKC activity. The chondrocytes also produce 24(R),25(OH)(2)D(3), and the secreted metabolite acts directly on the matrix vesicle membrane. Only PKCzeta is directly affected by 24(R),25(OH)(2)D(3) in the matrix vesicles, and activity of this isoform is inhibited. This effect may be involved in the control of matrix maturation and turnover. 24(R),25(OH)(2)D(3) causes RC cells to mature along the endochondral developmental pathway, where they become responsive to 1alpha,25(OH)(2)D(3) and lose responsiveness to 24(R),25(OH)(2)D(3), a characteristic of more mature growth zone (GC) chondrocytes. 1alpha,25(OH)(2)D(3) elicits its effects on GC through different signal transduction pathways than those used by 24(R),25(OH)(2)D(3). These studies indicate that 24(R),25(OH)(2)D(3) plays an important role in endochondral ossification by regulating less mature chondrocytes and promoting their maturation in the endochondral lineage.

24,25-Dihydroxyvitamin D 3↗
PubMed2006

Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are the main endogenous ligands of a class of G protein-coupled receptors (Rs). Three subtypes of PACAP/VIP Rs have been identified and named PAC(1)-Rs, VPAC(1)-Rs, and VPAC(2)-Rs. The PAC(1)-R almost exclusively binds PACAP, while the other two subtypes bind with about equal efficiency VIP and PACAP. VIP, PACAP, and their receptors are widely distributed in the body tissues, including the adrenal gland. VIP and PACAP are synthesized in adrenomedullary chromaffin cells, and are released in the adrenal cortex and medulla by VIPergic and PACAPergic nerve fibers. PAC(1)-Rs are almost exclusively present in the adrenal medulla, while VPAC(1)-Rs and VPAC(2)-Rs are expressed in both the adrenal cortex and medulla. Evidence indicates that VIP and PACAP, acting via VPAC(1)-Rs and VPAC(2)-Rs coupled to adenylate cyclase (AC)- and phospholipase C (PLC)-dependent cascades, stimulate aldosterone secretion from zona glomerulosa (ZG) cells. There is also proof that they can also enhance aldosterone secretion indirectly, by eliciting the release from medullary chromaffin cells of catecholamines and adrenocorticotropic hormone (ACTH), which in turn may act on the cortical cells in a paracrine manner. The involvement of VIP and PACAP in the regulation of glucocorticoid secretion from inner adrenocortical cells is doubtful and surely of minor relevance. VIP and PACAP stimulate the synthesis and release of adrenomedullary catecholamines, and all three subtypes of PACAP/VIP Rs mediate this effect, PAC(1)-Rs being coupled to AC, VPAC(1)-Rs to both AC and PLC, and VPAC(2)-Rs only to PLC. A privotal role in the catecholamine secretagogue action of VIP and PACAP is played by Ca(2+). VIP and PACAP may also modulate the growth of the adrenal cortex and medulla. The concentrations attained by VIP and PACAP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their adrenal content is consistent with a local autocrine-paracrine mechanism of action.

Adrenal Glands↗
PubMed2004

Discovering novel phenotype-selective neurotrophic factors to treat neurodegenerative diseases.

Astrocytes and neurons in the central nervous system (CNS) interact functionally to mediate processes as diverse as neuroprotection, neurogenesis and synaptogenesis. Moreover, the interaction can be homotypic, implying that astrocyte-derived secreted molecules affect their adjacent neurons optimally vs remote neurons. Astrocytes produce neurotrophic and extracellular matrix molecules that affect neuronal growth, development and survival, synaptic development, stabilization and functioning, and neurogenesis. This new knowledge offers the opportunity of developing astrocyte-derived, secreted proteins as a new class of therapeutics specifically to treat diseases of the CNS. However, primary astrocytes proliferate slowly in vitro, and when induced to immortalize by genetic manipulation, tend to lose their phenotype. These problems have limited the development of astrocytes as sources of potential drug candidates. We have successfully developed a method to induce spontaneous immortalization of astrocytes. Gene expression analysis, karyotyping and activity profiling data show that these spontaneously immortalized type-1 astrocyte cell lines retain the properties of their primary parents. The method is generic, such that cell lines can be prepared from any region of the CNS. To date, a library of 70 cell lines from four regions of the CNS: ventral mesencephalon, striatum, cerebral cortex and hippocampus, has been created. A phenotype-selective neurotrophic factor for dopaminergic neurons has been discovered from one of the cell lines (VMCL1). This mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20 kD, glycosylated, human secreted protein. Homologs of this protein have been identified in 16 other species including C. elegans. These new developments offer the opportunity of creating a library of astrocyte-derived molecules, and developing the ones with the best therapeutic indices for clinical use.

Animals↗
PubMed2004

Granulocyte colony-stimulating factor receptor signals for beta1-integrin expression and adhesion in bladder cancer.

OBJECTIVES: To examine the association of granulocyte colony-stimulating factor (G-CSF) and G-CSF receptor (G-CSFR) expression with increased beta1-integrin expression and determine the ability of autocrine G-CSFR signaling to promote bladder cancer cell adhesion by way of beta1-integrin. beta1-integrin is expressed at higher levels in more invasive bladder carcinoma cells and participates in the process of tissue invasion. Cancer cell invasion and metastasis in some ways mimic normal neutrophil behavior. In neutrophils, G-CSF acts through its receptor to enhance adhesion and migration. A significant fraction of bladder carcinoma has been reported to express both G-CSF and G-CSFR. METHODS: We examined bladder carcinoma tissue samples obtained from segmental or radical cystectomy specimens for expression of G-CSF, G-CSFR, and beta1-integrin using reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemical methods. We determined the G-CSFR-mediated beta1-integrin adhesion using a static adhesion assay and the bladder cancer cell line 5637. RESULTS: Eleven of 14 bladder cancer samples expressed G-CSFR. All 11 G-CSFR positive tumors also expressed G-CSF, and the G-CSF/G-CSFR positive tumors had elevated beta1-integrin protein levels. All but one G-CSFR negative tumor demonstrated low beta1-integrin protein levels. In four G-CSF/G-CSFR positive tumors for which distant urothelium was available for examination, G-CSF, G-CSFR, and beta1-integrin expression was also increased. In the 5637 cell line, we demonstrated G-CSFR-mediated upregulation of beta1-integrin-dependent adhesion to fibronectin and laminin. CONCLUSIONS: G-CSF/G-CSFR expression in some bladder cancers appears to be an early event during malignant transformation that increases beta1-integrin expression and adhesion and thereby may promote tissue invasion.

Autocrine Communication↗
PubMed1997

The homeobox gene GBX2, a target of the myb oncogene, mediates autocrine growth and monocyte differentiation.

The homeobox gene GBX2 was identified as a target gene of the v-Myb oncoprotein encoded by the avian myeloblastosis virus (AMV). GBX2 activation by c-Myb requires signal transduction emanating from the cell surface while the leukemogenic AMV v-Myb constitutively induces the GBX2 gene. Mutations in the DNA binding domain of AMV-Myb render it independent of signaling events and concomitantly abrogate the collaboration between Myb and CCAAT Enhancer Binding Proteins (C/EBP), which are involved in granulocyte differentiation. Ectopic expression of GBX2 in growth factor-dependent myeloblasts induces monocytic features and independence from exogenous cytokines, reflecting distinct features of AMV-transformed cells. Our results suggest that Myb or factors it interacts with contribute to hematopoietic lineage choice and differentiation in a signal transduction-dependent fashion.

Animals↗
PubMed1998

An autoregulatory cascade of EGF receptor signaling patterns the Drosophila egg.

Intercellular signaling through the EGF receptor (EGFR) patterns the Drosophila egg. The TGF alpha-like ligand Gurken signals from the oocyte to the receptor in the overlying somatic follicle cells. We show that in the dorsal follicle cells this initial paracrine signaling event triggers an autocrine amplification by two other EGFR ligands, Spitz and Vein. Spitz only becomes an effective ligand in the presence of the multitransmembrane domain protein Rhomboid. Consequent high-level EGFR activation leads to localized expression of the diffusible inhibitor Argos, which alters the profile of signaling. This sequential activation, amplification, and local inhibition of the EGFR forms an autoregulatory cascade that leads to the splitting of an initial single peak of signaling into two, thereby patterning the egg.

Animals↗
PubMed1997

Comparison between vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide levels in neuroblastoma tumour tissues.

Vasoactive intestinal polypeptide (VIP) is reported to exert an autocrine control on neuroblastoma cell tumours: VIP is produced by the tumour and stimulates cell differentiation. This study tested the hypothesis that the parent peptide; the pituitary adenylate cyclase activating polypeptide (PACAP) may have a similar role. It was found that PACAP mRNA and PACAP were expressed in 12/12 tumours; it was also observed that PACAP receptor mRNA and functional PACAP receptors were expressed in 12/12 and 5/9 tumours, respectively. VIP mRNA and VIP were detected in 9/12 tumours. VIP receptor mRNA was expressed in 5/12 tumours and functional VIP receptors were never demonstrated. The tumours having the highest VIP levels also had the highest PACAP contents and were associated with a watery diarrhoea syndrome due to activation of intestinal VIP receptors. As PACAP recognizes the PACAP receptors and the VIP receptors with the same high affinity it may contribute to the syndrome and is a likely candidate for an autocrine control of neuroblastoma cell growth and differentiation.

Autocrine Communication↗
PubMed2001

Homotypic interactions protect chronic lymphocytic leukaemia cells from spontaneous death in vitro.

Chronic lymphocytic leukaemia (CLL) cells are long-lived in vivo but undergo spontaneous apoptosis when cultured in vitro. Since CLL cells associate intimately with one another at sites of tissue involvement, we examined the hitherto unproven possibility that homotypic interactions between the malignant cells might reduce their propensity to undergo spontaneous cell death. In a series of experiments in which highly pure CLL-cell populations were cultured on a non-adherent surface, cell viability was found to increase markedly with the level of crowding at the bottom of the culture vessel. The effect was observed among unevenly distributed cells within a single culture vessel and did not require direct cell-cell contact. This indicates that cell survival was being regulated in an autocrine fashion by locally acting soluble products. Conditioned medium from crowded CLL cells enhanced the survival of autologous non-crowded cells, indicating that at least some of the autocrine survival factors produced by CLL cells could accumulate in the extracellular environment. In addition, the survival of non-crowded CLL cells was markedly enhanced by co-culturing them with an excess of autologous fixed cells. This protective effect of direct cell-cell contact was mediated by specific surface structures since it was abrogated by pre-treating the fixed cells with neuraminidase. Our results provide the first direct demonstration that the survival of cultured CLL cells is enhanced by homotypic interactions. We speculate that these protective effects may contribute to the accumulation of CLL cells in vivo, and that further elucidation of the underlying mechanisms may lead to novel therapeutic strategies.

Antigens, CD19↗
PubMed2002

Expression of insulin-like growth factors IGF-I and IGF-II, and their receptors during the growth and megakaryocytic differentiation of K562 cells.

Insulin-like growth factors (IGFs) I and II are critical regulators of cell proliferation and differentiation and most of the growth promoting properties of both ligands are mediated by IGF-I receptor (IGF-IR). In the present study we have investigated the role of IGFs in K562 cell line during normal growth and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced megakaryocytic differentiation. Abundant expression of IGF-I, IGF-II and IGF-IR was demonstrated in resting cells and exogenous IGF-I and IGF-II increased 3H-thymidine incorporation in a dose dependent manner. In contrast, we found that basal growth of the cells was inhibited by using anti-IGF-IR mAb. Furthermore, also IGF-I and IGF-II induced DNA synthesis was significantly suppressed by anti-IGF-IR mAb. During megakaryocytic differentiation, expression of IGF-IR increased during first 12h, but after that the expression started to decrease together with IGF-I. Taken together, our data suggest that autocrine production of IGF-I and IGF-II may via IGF-IR play a significant role in the growth and megakaryocytic differentiation of K562 cells.

Animals↗
PubMed2004

Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML.

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.

Acute Disease↗
PubMed2004

Immature B cell malignancies synthesize VEGF, VEGFR-1 (Flt-1) and VEGFR-2 (KDR).

Expression of VEGF and VEGFR support a role for angiogenic pathways in the pathogenesis of some hematological malignances. Our goal was to determine if expression of these angiogenic molecules also extend to childhood precursor B cell acute lymphoblastic leukemia (pre-B ALL). We now show that transcripts of VEGF, and its receptors VEGFR-1 and VEGFR-2 are concomitantly expressed in both ALL cell lines and primary pre-B ALL. Western blot and ELISA consistently detected VEGF protein in the supernatants of the cell lines. Similarly, VEGFR-1 and VEGFR-2 proteins are also detectable by FACS analysis. Interestingly, the expression of the receptors in immature B cells is limited to the intra-cytoplasmic compartment and may suggest either internalization of the receptors or a block in trafficking of the receptor to the surface.

Autocrine Communication↗
PubMed2004

All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells.

B-chronic lymphocytic leukemia (B-CLL) cells have a long survival owing to an alteration in the normal pathways of apoptosis. CLL cells have been found to produce and secrete vascular endothelial growth factor (VEGF). In addition to its major role in angiogenesis, VEGF affects cell survival by interfering with apoptosis. The aim of the present study was to investigate the expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 on B-CLL cells, singly and combined. B-CLL cells were isolated from peripheral blood drawn from patients with CLL. Total VEGF receptor, examined in 13 samples by flow cytometry was present in all cases with mean CD19+/VEGF+ expression of 76% (range 52-92%). Specific receptor expression, examined in 27 samples by immunocytochemical methods, was positive for VEGFR-1 in all 27 patients and for VEGFR-2 and VEGFR-3 in 26 (96%). These findings suggest that the VEGF transduction pathway may be very active in CLL cells, and both its paracrine and autocrine pathways may contribute to their enhanced survival.

Aged↗