The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression.

The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53ß and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53ß and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53ß, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.

HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.

Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.

Exploration, anxiety, and spatial memory in transgenic anophthalmic mice.

Contradictory results are found in the literature concerning the role of vision in the perception of space or in spatial navigation, in part because of the lack of murine models of total blindness used so far. The authors evaluated the spatial abilities of anophthalmic transgenic mice. These mice did not differ qualitatively from their wild-type littermates in general locomotor activity, spontaneous alternation, object exploration, or anxiety, but their level of exploratory activity was generally lower. In the spatial version of the water maze, they displayed persistent thigmotaxic behavior and showed severe spatial learning impairments. However, their performances improved with training, suggesting that they may have acquired a rough representation of the platform position. These results suggest that modalities other than vision enable some degree of spatial processing in proximal and structured spaces but that vision is critical for accurate spatial navigation.

Neural and angiogenic defects in eyes of transgenic mice expressing a dominant-negative FGF receptor in the pigmented cells.

Fibroblast growth factors (FGF) are multipotent cytokines with demonstrated mitogenic, neurotrophic and angiogenic properties. There is evidence that they have multiple functions during and after development of the vertebrate eye. Amongst these, the role of FGF receptor mediated signaling in the retinal pigmented epithelium (RPE) is not yet well understood. FGF-2 is produced in RPE cells and may play a role in photoreceptor development and/or survival in vivo. It may also stimulate growth of melanocytes and angiogenesis in the choroid. To address these questions, we have specifically disrupted FGF signaling by generating lines of transgenic mice expressing dominant-negative FGF receptor 1 (FGFR-1) in the pigmented cells. Histological analysis of the eyes were conducted on hemizygous and homozygous mice at different ages. In homozygotes, eye growth is strongly impaired during embryogenesis leading to massive eye degeneration seen in the early post-natal stages. In hemizygotes, the choroid is thinned and the finger-like junctions between RPE cells and photoreceptors are disrupted. Scanning electron microscopy of the choroid vasculature showed that choriocapillary density, diameter and branching are strongly affected. As mice age, they develop progressive retinal degeneration as evidenced by photoreceptor cell loss. Our results are in agreement with the hypothesis that FGF signaling in the RPE participates in photoreceptor survival in vivo. Our model provides evidence that FGF signaling is also involved in choroidal angiogenesis by a process that could relate to induction of terminal branching.

New insights in the biology of fibroblast growth factor-2.

Fibroblast growth factor (FGF)-2 stimulates endothelial cell proliferation and is a potent angiogenic molecule in vitro and in vivo. In this review, we have focused on recent findings that relate to the mechanism of action and function of FGF-2. FGF-2 is expressed as four different isoforms: one 18 kDa FGF-2 form that is mainly cytoplasmic and three high molecular weight (HMW) FGF-2 forms that are preferentially localized in the nucleus. It has been demonstrated that these different isoforms lead to specific cellular phenotypes when expressed in cells. HMW FGF-2 controls proliferation by a receptor-independent mechanism, whereas 18 kDa FGF-2 stimulates migration by autocrine receptor activation. Intracellularly, HMW FGF-2 may directly associate with molecules that are involved in growth control. The action of FGF-2 at the cell surface may be altered by angiogenic inhibitors. Angiogenic inhibitors may directly interfere with FGF receptor activation or downstream signaling and thus inhibit FGF activity.

[Angiogenesis and neoangiogenesis]. / Angiogenèse et néoangiogenèse.

Angiogenesis, the development of new capillary networks from the normal vasculature, is a fundamental process during embryogenesis. In adulthood, angiogenesis contributes to corpus luteum formation, placental implantation and wound healing and is also required in some pathological conditions such as several intraocular syndromes, growth of solid tumors, and metastasis. Many factors are involved in the regulation of neovascularisation among which FGF-2 (fibroblast growth factor-2) and VEGF (vascular endothelial growth factor) are considered as key inducers. Their biological activity is highly controlled by extracellular matrix components and angiostatic factors. Better understanding of the molecular mechanisms regulating angiogenesis should contribute to the development of new molecules to be used for the treatment of neovascularisation-linked diseases.

[Angiogenesis and cancer]. / Angiogenèse et cancer.

Tumor invasion and dissemination is tightly controlled by angiogenesis. In recent years, a number of angiogenic factors and inhibitors have been identified. However, the molecular mechanisms leading to this phenomenon are still incompletely understood. In this review, we focus on recent developments in the angiogenesis field. We will summarize our present knowledge about the molecular mechanisms involved in angiogenesis and about the factors that control this phenomenon. We will then shortly discuss the pharmacological modulation and the therapeutic and clinical implications for cancer biology.