Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias
ABSTRACT Antiangiogenic agents block the effects of tumor-derived angiogenic factors (paracrine factors), such as vascular endothelial
growth factor (VEGF), on endothelial cells (EC), inhibiting the growth of solid tumors. However, whether inhibition of angiogenesis
also may play a role in liquid tumors is not well established. We recently have shown that certain leukemias not only produce
VEGF but also selectively express functional VEGF receptors (VEGFRs), such as VEGFR-2 (Flk-1, KDR) and VEGFR1 (Flt1), resulting
in the generation of an autocrine loop. Here, we examined the relative contribution of paracrine (EC-dependent) and autocrine
(EC-independent) VEGF/VEGFR signaling pathways, by using a human leukemia model, where autocrine and paracrine VEGF/VEGFR
loops could be selectively inhibited by neutralizing mAbs specific for murine EC (paracrine pathway) or human tumor (autocrine)
VEGFRs. Blocking either the paracrine or the autocrine VEGF/VEGFR-2 pathway delayed leukemic growth and engraftment in vivo, but failed to cure inoculated mice. Long-term remission with no evidence of disease was achieved only if mice were treated
with mAbs against both murine and human VEGFR-2, whereas mAbs against human or murine VEGFR-1 had no effect on mice survival.
Therefore, effective antiangiogenic therapies to treat VEGF-producing, VEGFR-expressing leukemias may require blocking both
paracrine and autocrine VEGF/VEGFR-2 angiogenic loops to achieve remission and long-term cure.
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ABSTRACT: Acute Myeloid Leukemia is a malignant transformation of hematopoietic tissue, bone marrow infiltration of undifferentiated cells known as blasts that interfere with the production of normal cells. Vascular endothelial growth factor (VEGF) is persistently secreted from myeloid cells and high levels can be detected in patients' serum. Twenty-one AML patients, who were chemotherapy candidates were evaluated in a clinical trial. Serum VEGF was measured by ELISA. VEGFA, VEGFC mRNA and bone marrow MVD were measured in all patients before and after chemotherapy and then all results were analyzed. There were 10 (48%) female and 11(52%) male patients ranged in age from 20 to 60 years, with an average age of 39.5 ±14.1 years. The mean amount of MVD was reduced from 10.8±3.6 before chemotherapy to7.6±3.3 after chemotherapy (P=0.008). VEGF was also reduced from 0.59±0.16 before chemotherapy to 0.24±0.03 after chemotherapy (P=0.005). Gene expression differences for VEGFA mRNA was 4.6±1.4, while it was 120.7±93.2 for VEGFC mRNA, showing the significance only for VEGA mRNA (P=0.02). Regarding reduced angiogenesis, we can conclude that anti-angiogenic preparations can be effective in treatment course of AML in combination with chemotherapy regimen.
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ABSTRACT: Purpose: Tumor-derived vascular endothelial growth factor A (VEGF-A), apart from expediting sufficient vascularization, subsequent tumor growth and metastatic spread, can act on malignant cells themselves provided that VEGF receptors 1 or 2 (VEGF-R1, -R2) are co-expressed. The study goal was to investigate whether such autocrine VEGF-A signaling exists in uveal melanoma (UM). Methods: Primary (MEL-270, OM-431) and metastatic (OMM-2.3, OMM-2.5) UM cells were analyzed for VEGF-A, VEGF-R1, and VEGF-R2 expression by RT-PCR, ELISA (VEGF-A protein) and immuno¬cytochemistry (VEGF receptors). Proliferation of UM cells incubated with neutralizing anti-VEGF-A antibody bevacizumab (≤ 2.5 mg/ml), or VEGF-A (≤ 100 ng/ml) was assessed by BrdU ELISA. It was measured by real-time PCR, whether VEGF-A (100 ng/ml) modulated the expression ratio of VEGF-A itself and its antiangiogenic antagonist pigment epithelium-derived factor (PEDF). Results: All UM cells expressed VEGF-A, VEGF-R1, VEGF-R2 mRNA and protein. In each cell line, the proliferation was stimulated by VEGF-A or inhibited by blocking VEGF-A, or both: Bevacizumab significantly decreased the proliferation in MEL-270 (p=0.005), OMM-2.3 (p=0.001), and OMM-2.5 (p=0.011). Increased VEGF-A signaling significantly raised the proliferation in MEL-270, OM-431 (p<0.001, respectively), and OMM-2.3 (p=0.043) in a dose-dependent manner, but did not significantly change the VEGF-A/PEDF mRNA expression ratio. Conclusions: Autocrine VEGF-A signaling seems to be present in UM sustaining the proliferation of both primary and metastatic UM cells. Apparently, VEGF-A signaling in UM cells does neither retroact on VEGF-A expression in the sense of a feedback loop, nor contribute to an proangiogenic shift of the VEGF-A/PEDF ratio.Investigative ophthalmology & visual science 03/2014; DOI:10.1167/iovs.13-13254 · 3.66 Impact Factor
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ABSTRACT: Understanding the intricate cellular components of the bone marrow microenvironment can lead to the discovery of novel extrinsic factors that are responsible for the initiation and progression of leukemic disease. We have shown that endothelial cells (ECs) provide a fertile niche that allows for the propagation of primitive and aggressive leukemic clones. Activation of the ECs by VEGF-A provides cues that enable leukemic cells to proliferate at higher rates and also increases the adhesion of leukemia to ECs. VEGF-A activated ECs decrease the efficacy of chemotherapeutic agents to target leukemic cells. Inhibiting VEGF-dependent activation of ECs by blocking their signaling through VEGFR2 increases the susceptibility of leukemic cells to chemotherapy. Therefore, the development of drugs that target the activation state of the vascular niche could prove to be an effective adjuvant therapy in combination with chemotherapeutic agents.Experimental Hematology 08/2014; DOI:10.1016/j.exphem.2014.08.003 · 2.81 Impact Factor