Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells

Farahani, Mosavar; Treweeke, Andrew T.; Toh, Cheng Hock; Till, Kathleen J.; Harris, Robert J.; Cawley, James F.; Zuzel, Mirko; Chen, H

doi:10.1038/sj.leu.2403631

Cited by 65 publications

(58 citation statements)

References 47 publications

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“…However, this conclusion is drawn from our in vitro experiments and our results do not exclude the possibility that inhibition of VEGF might contribute to the cytotoxic effects of sorafenib in vivo. In line with this hypothesis, Farahani et al 34 showed that modulation of VEGFR signalling through CD154 or CD40 signalling had significant effects on VEGF-dependent cell protection, whereas exogenous VEGF did not rescue CLL cells ex vivo. In line with this observation, we showed that exogenous VEGF did not attenuate the cytotoxic effect of sorafenib on CLL cells (Figure 3b).…”

Section: Discussionmentioning

confidence: 61%

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

et al. 2011

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Section: Discussionmentioning

confidence: 61%

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

et al. 2011

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“…48 It has been demonstrated that CD40 engagement by CD154 upregulates production of VEGF in B-CLL cells in an NF-kB-dependent fashion. 47 In turn, VEGF favors the nuclear translocation of NF-kB in malignant B-CLL cells, suggesting the initiation of a positive feedforward loop in which NF-kB activation is amplified by VEGF in an autocrine manner.…”

Section: B-cllmentioning

confidence: 98%

“…46 Vascular endothelial growth factor (VEGF), another factor of the microenvironment, implicated in increased neo-vascularization in B-CLL bone marrow, has been demonstrated recently to be potentially important for the pathogenesis and prognosis of B-CLL. 47 B-CLL cells produce VEGF in vitro. High VEGF levels are found in the serum of patients.…”

Section: B-cllmentioning

confidence: 99%

“…In those cases of B-CLL that are CD154 þ , addition of a neutralizing anti-CD154 mAb resulted in inhibition of NF-kB activity associated with subsequent cell death. 47 Furthermore, survival kinases such as phosphatidylinositol-3 kinase (PI3-K) and Akt/protein kinase B may contribute to NF-kB activation. These pathways are constitutively activated in B-CLL upon CD40 crosslinking, leading to PI3-K-dependent Akt and NF-kB signaling.…”

Section: B-cllmentioning

confidence: 99%

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Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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“…15 VEGF is another important mediator of the antiapoptotic effect of CD40 ligation that is essential for NF-kB activation 16 (Figure 1). Furthermore, proteins such as BIRC5 and MCL1, expressed by prolymphocytes inside the PCs, are involved in VEGF-mediated CLL/SLL cell survival.…”

mentioning

confidence: 99%