p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway

Ghahremani, Morvarid Farhang; Goossens, Steven; Nittner, David; Bisteau, Xavier; Bartunkova, Sonia; Zwolińska, Aleksandra; Hulpiau, Paco; Haigh, Katharina; Haenebalcke, Lieven; Drogat, Benjamin; Jochemsen, Aart G.; Roger, Pierre P.; Marine, Jean–Christophe; Haigh, Jody J.

doi:10.1038/cdd.2013.12

Cited by 92 publications

(95 citation statements)

References 40 publications

(50 reference statements)

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“…19,20 p21 is a well-known downstream target of p53 and is also a negative regulator of VEGF. 21 Intriguingly, the second most common tumors in p21-null mice are of vascular origin. 33 Therefore, the occurrence of hemangiosarcoma is most likely the result of a series of defects in cell cycle regulation and angiogenesis, 34 which ultimately lead to malignant transformation of the endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest a complex cross-talk between the p53 and VEGF signaling pathways to ensure normal vessel homeostasis in the quiescent vasculature. 21 Seventy percent of the Tie2-Cre p53 fl/fl mice developed another tumor type, T-cell lymphoma/leukemia (46.9% of total neoplasms). We expected the development of lymphomas, as the Tie2-Cre is active in both the endothelium and hematopoietic lineages, 40 and the most common tumor type reported in p53-null mice is T-cell lymphomas.…”

Section: Discussionmentioning

confidence: 99%

“…[16][17][18] These findings suggest that alteration in the Trp53 gene could be associated with tumorigenesis of the blood vessel endothelium. In addition, p53 inhibits VEGF expression via SP1, 19 E2F, 20 and p21/ RB-dependent 21 processes. Overall then, we hypothesized that decreased p53 expression and upregulated VEGF levels might act synergistically to transform the vascular endothelium.…”

Section: Introductionmentioning

confidence: 99%

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Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

et al. 2014

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Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

et al. 2014

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“…Normally, this pathway is activated by continued hypoxia and is mechanistically distinct from the classic roles the p21/E2F/Rb pathway plays in cell-cycle regulation. 44 Because in most retinoblastoma tumors the main event is a mutation of the RB1 gene, resulting in an absent or nonfunctional RB1 protein, one of the indirect VEGF repressors may be absent, thereby increasing tumor neovascularization.…”

Section: Expression Of the Neural Stem Cell Marker Sox2mentioning

confidence: 99%

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

Garcia

Gombos²,

Prospero³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context Progression of retinoblastoma is associated with increased tumor angiogenesis. However, a clear relationship between the expression of angiogenic markers in specific regions of the tumor and tumor progression has not been established. This study investigates the association between angiogenic factors in retinoblastomas with choroidal and/or optic nerve invasion (high-risk/invasive retinoblastoma) and expression of Sox2, a stem cell marker. Objective To investigate the association between the expression of angiogenic factors and markers of tumor invasiveness, such as the stem cell marker Sox2, in retinoblastoma tissues. Design Immunohistochemistry was used to evaluate coexpression of the angiogenic growth factors vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), and endoglin (CD105); markers of glial differentiation (vimentin and glial fibrillary acidic protein); and a neural stem cell marker (Sox2). Expression was assessed in nonneoplastic and neoplastic ocular tissues collected from enucleated eyes of patients with retinoblastoma. During qualitative data interpretation, evaluating pathologists were masked to patient grouping. Results Expression of VEGF-A and VEGFR-2 in noninvasive (non–high-risk feature) retinoblastoma tumors was lower than in the invasive, or high-risk feature tumors. Moreover, our data indicate that the tumor cells, and not the surrounding stroma, secrete VEGF-A and that angiogenesis is mostly localized to the iris. Finally, our data showed that the expression of the neural stem cell marker Sox2 is associated with eyes with increased VEGF-A expression and tumor invasiveness. Conclusions Increased expression of angiogenic factors, with a concomitant increase in expression of the stem cell marker Sox2 observed in retinoblastoma tissues, may partially explain the aggressiveness of these tumors. The complex interaction of angiogenic and stem cell–related pathways in these tumors, especially in high-risk feature retinoblastoma, suggests that targeting tumor cells capable of secreting vasculogenic factors, as well as proangiogenic genes and signaling pathways, may be necessary for development of effective antimetastatic retinoblastoma drugs.

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“…In particular this is important for cancer, where p53 mutations are implicated in over 50 % of human malignancies, and defects within its pathways are linked to tumorigenesis [1]. Many of these perturbations are associated with aberrant levels of important anti-proliferative processes such as apoptosis [2] and angiogenesis [3] to which p53 has a well-defined role. Cancer at the cellular level is dynamic, involving both epigenetic and genetic alterations resulting in genomic instability and inducing malignant change [4].…”

Section: Introductionmentioning

confidence: 99%

The Expanded p53 Interactome as a Predictive Model for Cancer Therapy

Hussain

Tian

Mutti

et al. 2015

Genomics Comput Biol

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The tumour suppressor gene TP53 is implicated in the majority of all human cancers, thus pivotal to genomic integrity. Even though over 72,000 PubMed publications are linked with the keyword p53 and this number is continuously increasing, due to the complexity of its interactions we are still far from fully elucidating p53's role in tumorigenesis. Computational methodologies are novel tools to depict and dissect complex disease networks. The Boolean PKT206 p53-DNA damage model has previously demonstrated good predictive capability for p53 wildtype and null tumours in various in silico knockouts. Here, we have expanded PKT206 to generate a more clinically robust representation of p53 dynamics. The new PMH260 model incorporates 260 nodes representing genes, with 980 interactions between them representing inhibitions and activations. Additional biological outputs, including angiogenesis, cell cycle arrest and DNA repair were also amalgamated into the model. Three in silico knockouts of highly connected nodes (p53, MDM2 and FGF2) were generated and logical steady state analysis and dependency relationships determined. 71 % of predictions were considered true from superimposition of human osteosarcoma and HCT116 microarray profiles. In silico knockout analysis revealed 98 potential novel predictions, of which 13 were validated by literature; 83 % of them were overlapping with PKT206. Thus the expanded Boolean PMH260 model offers a promising platform for clinical potential in targeted cancer therapeutics.

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p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway

Cited by 92 publications

References 40 publications

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

The Expanded p53 Interactome as a Predictive Model for Cancer Therapy

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