Dysfunctional Microvasculature as a Consequence of <i>Shb</i> Gene Inactivation Causes Impaired Tumor Growth

Funa, Nina S.; Křı́ž, Vı́tězslav; Zang, Guangxiang; Calounova, Gabriela; Åkerblom, Björn; Mareš, Jaroslav; Larsson, E.A.; Sun, Ying; Betsholtz, Christer; Welsh, Michael

doi:10.1158/0008-5472.can-08-3797

Cited by 30 publications

(63 citation statements)

References 48 publications

(56 reference statements)

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“…Phosphorylation of Y397 at FAK was also investigated and was statistically significantly increased by 15± 4 % (p=0.017, n=7) in wild-type endothelial cells whereas no stimulatory response was recorded in the Shb knockout cells (3± 5 %, p=0.57, n=7). The altered signaling characteristics of Shb deficient lung endothelial cells provide a biochemical explanation for the defects in angiogenesis and vascular permeability previously [10,11] and presently observed.…”

Section: Vegfr-2 Cell Surface Expression and Signalingmentioning

confidence: 59%

“…Shb knockout lung endothelial cells displayed reduced ERK and Akt activities in response to VEGF-A. These differences were more pronounced than those previously noted in liver endothelial cells [10]. In addition, Rac1 activity (GTP-Rac1) was determined after 5 minutes of stimulation with VEGF-A (Fig.…”

Section: Vegfr-2 Cell Surface Expression and Signalingmentioning

confidence: 65%

“…They also suggest the involvement of Shb in this process. Indeed, it is clear from our previous publications [10,11,18] that Shb deficiency has consequences for the structure of adherens junctions in vivo and that this has functional implications. The latter is most clearly demonstrated by the altered physiological response to arterial ligation, in which the vascular permeability was reduced 24 hours after the procedure [11].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported an altered in vivo VE-cadherin staining pattern and ultrastructural abnormalities indicating aberrant properties of adherens junctions as a consequence of Shb deficiency [10,11]. An explanation for these observations is abnormal characteristics of VEGFR-2/VE-cadherin co-localization due to signaling defects since VE-cadherin and VEGFR-2 have been reported to interact and it is likely that such an interaction has implications for junction integrity.…”

Section: Ve-cadherin/vegfr-2 Co-localizationmentioning

confidence: 95%

“…An abnormal endothelial compartment was observed in Shb knockout mice that causes reduced tumor growth [10]. The endothelial ultrastructure and VEcadherin and CD31 staining patterns were less distinct in knockout endothelial cells.…”

Section: Introductionmentioning

confidence: 98%

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Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Zang

Christoffersson

Tian

et al. 2013

Cellular Signalling

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This is an accepted version of a paper published in Cellular Signalling. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the published paper: Zang, G., Christoffersson, G., Tian, G., Harun-Or-Rashid, M., Vågesjö, E. et al. (2013) "Aberrant association between vascular endothelial growth factor receptor-2 and VEcadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells" Cellular Signalling, 25 (1) Access to the published version may require subscription. NOTICE: this is the author's version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. AbstractVascular permeability is a hallmark response to the main angiogenic factor VEGF-A and we have previously described a reduction of this response in Shb knockout mice.

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Section: Vegfr-2 Cell Surface Expression and Signalingmentioning

confidence: 59%

Section: Vegfr-2 Cell Surface Expression and Signalingmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Ve-cadherin/vegfr-2 Co-localizationmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

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Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Zang

Christoffersson

Tian

et al. 2013

Cellular Signalling

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Pericyte dysfunction due to Shb gene deficiency increases B16F10 melanoma lung metastasis

et al. 2020

Intl Journal of Cancer

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Intravasation, vascular dissemination and metastasis of malignant tumor cells require their passage through the vascular wall which is commonly composed of pericytes and endothelial cells. We currently decided to investigate the relative contribution of these cell types to B16F10 melanoma metastasis in mice using an experimental model of host Shb gene (Src homology 2 domain‐containing protein B) inactivation. Conditional inactivation of Shb in endothelial cells using Cdh5‐CreERt2 resulted in decreased tumor growth, reduced vascular leakage, increased hypoxia and no effect on pericyte coverage and lung metastasis. RNAseq of tumor endothelial cells from these mice revealed changes in cellular components such as adherens junctions and focal adhesions by gene ontology analysis that were in line with the observed effects on leakage and junction morphology. Conditional inactivation of Shb in pericytes using Pdgfrb‐CreERt2 resulted in decreased pericyte coverage of small tumor vessels with lumen, increased leakage, aberrant platelet‐derived growth factor receptor B (PDGFRB) signaling and a higher frequency of lung metastasis without concomitant effects on tumor growth or oxygenation. Flow cytometry failed to reveal immune cell alterations that could explain the metastatic phenotype in this genetic model of Shb deficiency. It is concluded that proper pericyte function plays a significant role in suppressing B16F10 lung metastasis.

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Vascular Endothelial Growth Factor-A-Induced Vascular Permeability and Leukocyte Extravasation

Phillipson

Christoffersson

Claesson‐Welsh

et al. 2015

Endothelial Signaling in Development and Disease

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Dysfunctional Microvasculature as a Consequence of Shb Gene Inactivation Causes Impaired Tumor Growth

Abstract: Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2

Cited by 30 publications

References 48 publications

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Pericyte dysfunction due to Shb gene deficiency increases B16F10 melanoma lung metastasis

Vascular Endothelial Growth Factor-A-Induced Vascular Permeability and Leukocyte Extravasation

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