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Involvement of RB Gene Family in Tumor Angiogenesis

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Involvement of RB Gene Family in Tumor Angiogenesis Oncogene (2006) 25, 5326–5332 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Involvement of RB gene family in tumor angiogenesis C Gabellini, D Del Bufalo and G Zupi Experimental Chemotherapy Laboratory, ‘Regina Elena’ Cancer Institute, Rome, Italy Angiogenesis, the development of new blood vessels from chronic inflammation, tumor progression and metasta- pre-existing vessels, represents a fundamental step in tization (Folkman, 2003). The induction of vasculature tumor progression and metastatization.The induction is required for the growth of the tumor mass, and to of vasculature is required for growth of the tumor mass, ensure an adequate supply of oxygen and metabolites to to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size (Bergers and Benjamin, the tumor beyond a critical size.Tumor angiogenesis is a 2003). Neovascularization is controlled by a balance highly regulated process that is controlled physiologically between several factors promoting or suppressing by the tumor microenvironment and genetically by altera- angiogenesis and the induction of the so-called ‘angio- tion of several oncogenes or tumor suppressor genes.We genic switch’ is determined by proangiogenic factors will focus on recent demonstrations regarding the overcoming the antiangiogenic ones (Folkman, 1995; involvement of the retinoblastoma family proteins (phos- Beck and D’Amore, 1997; Ferrara, 2000; Kerbel, 2000; phorylated retinoblastoma (pRb), p107 and pRb2/p130) Li et al., 2000, Tonini et al., 2003). During the initial at different levels of the angiogenic process.pRb and activation stage, tumor and/or epithelial cells secrete its homologs can regulate the expression of pro- and angiogenic factors such as vascular endothelial growth antiangiogenic factors, such as the vascular endothelial factor (VEGF), basic fibroblast growth factor (bFGF), growth factor, through an E2F-dependent mechanism. platelet-derived growth factor and interleukin-8 (IL-8), Moreover, pRb is able to modulate also the transcriptional which stimulate endothelial cell proliferation, migration activity of several angiogenesis-related factors like HIF-1, and differentiation within the tumor bed (Hanahan, Id2 and Oct-1.pRb2/p130 is required for both differ- 1997; Maisonpierre et al., 1997; Carmeliet and Collen, entiation and mobilization of bone marrow-derived 2000). In later stages, tube formation and vessel matura- endothelial cell precursors and endothelial sprouting from tion lead to vessel remodeling and apoptosis, which neighboring vessels.The involvement of the pRb pathway is regulated by transforming growth factor-b and in the angiogenesis process has also been demonstrated by mesenchymal cells, in the absence of endothelial cell different cellular models expressing viral oncoproteins, proliferation (Pepper et al., 1991; Beck and D’Amore, like human papilloma virus.Moreover, some natural 1997; Taipale and Keski-Oja, 1997). and synthetic compounds demonstrate their antiangio- genetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohisto- chemical evaluation of pRb and/or pRb2/p130 expression Modulation of angiogenesis involving the retinoblastoma/ can represent a useful tool for the characterization of the E2F pathway in tumor and endothelial cells angiogenic phenotype of specific tumor histotypes. Oncogene (2006) 25, 5326–5332. doi:10.1038/sj.onc.1209631 It has been reported that several oncogenes or tumor suppressor genes have a role in angiogenesis, modulat- Keywords: cancer; angiogenesis; retinoblastoma family ing the expression of pro- and anti-angiogenic factors. proteins Activating mutations in Kras and Hras upregulate VEGF expression and downregulate expression of the angiogenesis inhibitor thrombospondin 1 (TSP-1) (Rak et al., 2000; Udagawa et al., 2002; Watnick et al., 2003). Moreover, wild-type p53 protein normally inhibits Introduction tumor angiogenesis by upregulating TSP-1 (Dameron et al., 1994), inducing degradation of hypoxia-inducible Angiogenesis, the development of new blood vessels factor-1a (HIF-1a) (Ravi et al., 2000), suppressing from pre-existing vessels, represents a fundamental step transcription of VEGF and downregulating bFGF- in several physiological and pathological conditions like binding protein expression (Sherif et al., 2001), whereas embryonic development in utero, wound healing, overexpression of antiapoptotic bcl-2 oncogene in- creases tumor angiogenesis upregulating VEGF expres- sion (Del Bufalo et al., 1997; Biroccio et al., 2000) Correspondence: Dr G Zupi, Experimental Chemotherapy Labora- tory, ‘Regina Elena’ Cancer Institute, Via delle Messi d’Oro, 156, and enhancing HIF-1 transcriptional activity (Iervolino Rome, 00158 Italy. et al., 2002; Trisciuoglio et al., 2005). In recent years, E-mail: [email protected] there has been experimental evidence demonstrating an Involvement of RB family in angiogenesis C Gabellini et al 5327 involvement of the retinoblastoma (RB) proteins family 2000) and it determines a regression of established in different aspects of the angiogenesis process. The tumor xenografts (Howard et al., 1998). Furthermore, product of the RB susceptibility gene, phosphorylated pRb2/p130 overexpression is able to inhibit angiogen- retinoblastoma (pRb), like the two closely related esis, determining a significant decrease of blood vessel proteins, p107 and pRb2/p130, negatively regulate the density inside tumor grafts. Indeed, pRb2/p130 expres- progression from the G1 to the S phase of the cell cycle. sion reduces VEGF mRNA level and protein expression These proteins are characterized by the presence of a both in vitro and in vivo, downregulating VEGF bipartite pocket structure (A/B domains), which is promoter activity through an indirect mechanism necessary for interaction with E2F transcription factors, (Table 1). A direct transcriptional control of pRb2/ viral oncoproteins and other LXCXE motif-containing p130 has been excluded by the authors because VEGF cellular proteins (Grana et al., 1998; Mulligan and promoter does not contain any responsive site of Jacks, 1998; Classon and Dyson, 2001). All three pocket regulation for pRb2/p130 (Claudio et al., 2001). proteins are substrates of cyclin-dependent kinases pRb2/p130 has also been found to cooperate with (CDKs) and are phosphorylated in a cell cycle- CDK inhibitor p27kip1 to ensure angiogenic homeostasis dependent manner (Grana et al., 1998; Mittnacht, at multiple levels. Mice defective in both pRb2/p130 and 1998): sequential phosphorylation of the pRb protein p27kip1 are not able to form new vessels properly, leading by CDK4/6 and CDK2 leads to dissociation of Rb–E2F to an inability to sustain the growth of tumor xenografts complexes, resulting in the activation of E2F-dependent (Vidal et al., 2005). Nevertheless, p130/pRb2 and p27kip1 transcription and cell cycle progression (Weinberg, are required for endothelial cell differentiation induced 1995; Harbour and Dean, 2000a). In addition to their by VEGF in vitro. Impaired angiogenesis was found role in regulating cell proliferation through the E2F to be associated with defects in the VEGF-induced pathway, pRb family members are able to affect the expansion of myeloid cells and VEGF-induced mobili- chromatin structure and function (Harbour and Dean, zation of both myeloid and endothelial precursors. In 2000b; Nielsen et al., 2001). pRb and its related proteins fact, in addition to endothelial sprouting from neighbor- have overlapping as well as unique cellular functions. ing vessels, the angiogenic switch stimulates bone For example, the RB protein family differs in their marrow-derived precursors to proliferate and induces ability to interact with the various members of the the mobilization of these cells into circulation to reach E2F family. Whereas pRb can interact with E2F1–4, the tumor bed (Lyden et al, 2001; Heissig et al., 2002). both pRb2/p130 and p107 associate with E2F4 and Cyclin E seems to be the fundamental common target E2F5 (Dyson, 1998; Trimarchi and Lees, 2002). In for p130/pRb2 and p27kip1 in the angiogenesis process, general, there is experimental evidence which suggests confirming the involvement of pRb2/p130 in coopera- that pRb2/p130 and p107 are more closely related to tion with p27kip1 in a negative feedback regulatory loop one another than to pRb (Classon and Dyson, 2001). with cyclin E in the modulation of cellular proliferation Through a unique motif in the spacer region, the two (Howard et al., 2000). pRb-related proteins share the ability to bind As described above, hypophosphorylated Rb proteins and directly inhibit the activity of CDK2/cyclin E bind E2F factors and inhibit their transcription activity and CDK2/cyclin A complexes (De Luca et al., 1997; on the promoters of many genes involved in DNA Lacy and Whyte, 1997; Woo et al., 1997; Castano replication and additional cellular functions such as et al., 1998). apoptosis and angiogenesis. Overexpression of E2F1 is Functionally, all RB family members show growth- associated with increased tumor cell invasiveness and suppressive properties. Reconstitution of pRb expres- metastatic progression (Banerjee et al., 2000; Zhang sion in various Rb-defective human cancer cell lines et al., 2000) and E2F1 target genes include several genes determines the suppression of tumorigenicity in nude involved in the angiogenesis process such as bFGF, mice and also correlates with the inhibition of tumor cell fibroblast growth
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