p73 overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis

Vikhanskaya, Faina; Bani, Maria Rosa; Borsotti, Patrizia; Ghilardi, Carmen; Ceruti, Roberta; Ghisleni, Gabriele; Marabese, Mirko; Giavazzi, Raffaella; Broggini, Massimo; Taraboletti, Giulia

doi:10.1038/sj.onc.1204896

Cited by 50 publications

(36 citation statements)

References 34 publications

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“…To address this, we analyzed VEGF-A and TGF-β signaling, both altered in p73KO retinas. In agreement with previous publications, 6,7 DDp73-CD31 + cells expressed lower levels of VEGF-A (Figure 4d). The expression of VEGFR1, a decoy of angiogenic signaling, was significantly higher in DDp73-CD31 + , while VEGFR2 expression, the VEGF signaling transducer, was lower (Figure 4d).…”

Section: Resultssupporting

confidence: 93%

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p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

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Section: Resultssupporting

confidence: 93%

“…4 The members of the p53 family (p53, p73 and p63) coordinate cell proliferation, migration and differentiation, and could act as regulators of vascular development. TP73 function in angiogenesis is quite controversial, [5][6][7] and it has never been addressed using developmental models.…”

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confidence: 99%

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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“…This phenotypic change is called the angiogenic switch, a consequence of which is that transformed cells initiate the process of tumor neovascularization. The angiogenic switch results from diminished expression of inhibitors of angiogenesis, augmented expression of inducers of angiogenesis or both of these changes by tumor cells (Vikhanskaya et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

2004

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Human papillomavirus (HPV) 16 is involved in causing cervical cancer. The E6 and E7 proteins of HPV 16 immortalize human keratinocytes and this is due, at least in part, to inactivation of the tumor suppressor proteins p53 and pRB. These tumor suppressor proteins also regulate the expression of pro-and antiangiogenic factors by cells. For this reason, experiments were conducted to determine whether the expression of E6 and E7 in primary keratinocytes alters the phenotype of these cells such that they express diminished levels of antiangiogenic factors and/or increased levels of proangiogenic factors. To avoid variances in experimental observations, pools of human foreskin keratinocytes from multiple sources were infected with recombinant retrovirus expressing HPV 16 E6 and E7 or control retrovirus. Gene array analysis, RT-PCR, ELISAs and Western blotting showed that in cells expressing HPV 16 E6 and E7, expression levels of two potent angiogenesis inhibitors, thrombospondin-1 and maspin, were lower compared to controls. Additionally, major angiogenesis inducers, interleukin-8 and vascular endothelial growth factor (VEGF), were increased relative to controls. VEGF can be produced as multiple splice variants, all of which are required for the formation of patent blood vessels. The expression of HPV 16 E6 and E7 in keratinocytes augmented expression of VEGF 121, 145, 165 and 189. These observations show that HPV 16 E6 and E7 alter the phenotype of primary keratinocytes, diminishing expression of inhibitors and increasing expression of inducers of angiogenesis. This altered phenotype may permit keratinocytes infected by HPV 16 to play a role in the progression of cancer by permitting tumors to acquire a blood supply permissive of growth and spread.

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“…Moreover, increasing evidence suggests that an altered ratio between TAp73 and ΔNp73 isoforms affects tumor progression (10). Contradictory and preliminary evidence has linked p73 to VEGF expression, but not to angiogenesis (12,13).…”

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confidence: 99%

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Amelio

Inoue

Markert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

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Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.

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p73 overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis

Cited by 50 publications

References 34 publications

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

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