Deletion of the Endothelial Bmx Tyrosine Kinase Decreases Tumor Angiogenesis and Growth

Holopainen, Tanja; López-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D’Amico, Gabriela; Wiener, Zoltán; Andersson, Leif C.; Pihlajaniemi, Taina; Wang, Min; Alitalo, Kari

doi:10.1158/0008-5472.can-11-1070

Cited by 33 publications

(25 citation statements)

References 36 publications

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“…Also, we found significant decreases in the percent of ECs expressing pβ3-(Y759), in the intensity of phospho-BMX (BMX activation) and phospho-p130CAS in ECs, and in vessel surface area in the tumors of RGD-peptide treated mice as compared to controls (Figure 7F, 7H-7K). Phospho-BMX staining of ECs in the xenograft tumors was detected in a population of vessels, consistent with BMX expression in vessels of arterial origin [39, 40]. These data suggest that ECs interact with tumor cells in the perivascular niche through an RGD-peptide-binding integrin and that this interaction promotes BMX and p130CAS activation, thereby enhancing angiogenesis.…”

Section: Resultssupporting

confidence: 62%

“…In ECs co-seeded with CSCs, we found that integrin αvβ3 is necessary for BMX activation and that BMX is necessary for p130CAS activation whereas in ECs seeded in CM/EC+CSC, αvβ3 is not necessary for BMX activation and BMX is not necessary for p130CAS activation. BMX, a cytoplasmic non-receptor tyrosine kinase, can activate signaling pathways that promote migration and angiogenesis as well as other signaling pathways [39, 40, 42–46]; thus, the increased BMX activity downstream of activated integrin αvβ3 in the ECs co-seeded with CSCs could serve to amplify and diversify signaling.…”

Section: Discussionmentioning

confidence: 99%

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Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

et al. 2016

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The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs. It promotes both EC network formation and enhances directed migration toward basic fibroblast growth factor. Activation of αvβ3 and bone marrow tyrosine kinase on chromosome X (BMX) is required for migration stimulated by direct binding but not for migration stimulated by soluble factors. RGD-peptide treatment of mice with established intracerebral GBM xenografts significantly reduced the percentage of Sox2-positive tumor cells and CSCs in close proximity to ECs, decreased integrin αvβ3 and BMX activation and p130CAS phosphorylation in the ECs, and reduced the vessel surface area. These results reveal a previously unrecognized aspect of the regulation of angiogenesis in GBM that can impact therapeutic anti-angiogenic targeting.

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Section: Resultssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

et al. 2016

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“…Heterodimerization of HER4 with HER2 and subsequent downstream signalling, including the PI3K‐AKT pathway, plays a crucial role in heart physiology 103. As described in the previous section, also the ibrutinib‐binding protein BMX was shown to be of importance for the cardiovascular system 53. Thus, there are several possibilities for that ibrutinib's interaction with target proteins other than BTK could cause cardiac dysfunction and atrial fibrillation, and we favour the idea of an off‐BTK target mechanism.…”

Section: Consequences Of Ibrutinib Treatment Not Related To B Cellsmentioning

confidence: 95%

Targets for Ibrutinib Beyond B Cell Malignancies

et al. 2015

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Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

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“…The samples were then mounted in mounting medium containing DAPI (Vector Laboratories). Frozen sections of the ventral skin (10 mm) were cut and stained as previously described (Holopainen et al 2012a).…”

Section: Immunofluorescent Staining and Microscopymentioning

confidence: 99%

Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions

et al. 2014

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Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development.

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Deletion of the Endothelial Bmx Tyrosine Kinase Decreases Tumor Angiogenesis and Growth

Cited by 33 publications

References 36 publications

Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

Targets for Ibrutinib Beyond B Cell Malignancies

Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions

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