Involvement of RB gene family in tumor angiogenesis. Oncogene

Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Oncogene (Impact Factor: 8.46). 09/2006; 25(38):5326-32. DOI: 10.1038/sj.onc.1209631
Source: PubMed


Angiogenesis, the development of new blood vessels from pre-existing vessels, represents a fundamental step in tumor progression and metastatization. The induction of vasculature is required for growth of the tumor mass, to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size. Tumor angiogenesis is a highly regulated process that is controlled physiologically by the tumor microenvironment and genetically by alteration of several oncogenes or tumor suppressor genes. We will focus on recent demonstrations regarding the involvement of the retinoblastoma family proteins (phosphorylated retinoblastoma (pRb), p107 and pRb2/p130) at different levels of the angiogenic process. pRb and its homologs can regulate the expression of pro- and antiangiogenic factors, such as the vascular endothelial growth factor, through an E2F-dependent mechanism. Moreover, pRb is able to modulate also the transcriptional activity of several angiogenesis-related factors like HIF-1, Id2 and Oct-1. pRb2/p130 is required for both differentiation and mobilization of bone marrow-derived endothelial cell precursors and endothelial sprouting from neighboring vessels. The involvement of the pRb pathway in the angiogenesis process has also been demonstrated by different cellular models expressing viral oncoproteins, like human papilloma virus. Moreover, some natural and synthetic compounds demonstrate their antiangiogenetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohistochemical evaluation of pRb and/or pRb2/p130 expression can represent a useful tool for the characterization of the angiogenic phenotype of specific tumor histotypes.

Download full-text


Available from: Chiara Gabellini
  • Source
    • " processes that are particularly relevant to the progression of preexisting tumors . For example , autophagy is induced in hypoxic tumors . The pRb / E2F switch regulates a number of genes important for hypoxia induced autophagy ( Polager et al . , 2008 ; Tracy et al . , 2007 ) . The pRb / E2F switch also regulates genes involved in angiogenesis ( Gabellini et al . , 2006 ) . Loss of pRb could thus alleviate hypoxic stress as tumors grow and also influence the responses to that stress . We have noted above that pRb functions to enforce cellular senescence and the fidelity of mitosis . Increased chromosome instability and loss of senescence responses in the absence of pRb will also facilitate tumor progre"
    [Show abstract] [Hide abstract]
    ABSTRACT: The RB1 gene is the first tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer, the pediatric cancer retinoblastoma. The 25 years of research since its discovery has not only illuminated a general role for RB1 in human cancer, but also its critical importance in normal development. Understanding the molecular function of the RB1 encoded protein, pRb, is a long-standing goal that promises to inform our understanding of cancer, its relationship to normal development, and possible therapeutic strategies to combat this disease. Achieving this goal has been difficult, complicated by the complexity of pRb and related proteins. The goal of this review is to explore the hypothesis that, at its core, the molecular function of pRb is to dynamically regulate the location-specific assembly or disassembly of protein complexes on the DNA in response to the output of various signaling pathways. These protein complexes participate in a variety of molecular processes relevant to DNA including gene transcription, DNA replication, DNA repair, and mitosis. Through regulation of these processes, RB1 plays a uniquely prominent role in normal development and cancer.
    Full-text · Article · Dec 2011 · Current Topics in Developmental Biology
  • Source
    • "For example, the tumor suppressor p53 positively regulates the expression of angiogenic inhibitors and negatively regulates the expression of angiogenic inducers (Volpert et al., 1997). Similarly, pRb family members regulate expression of angiogenic factors to maintain a quiescent environment (Gabellini et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor suppressors negatively regulate angiogenesis, an essential step in tumor progression. Together, HPV 16 E6 and E7 proteins, which target p53 and pRb family members, respectively, for degradation, increase the expression of two angiogenic inducers, VEGF and IL-8, in primary foreskin keratinocytes (HFKs). Conditioned media from such cells are sufficient to alter endothelial cell behavior. Here, the individual contribution of E6 and E7 to angiogenesis was investigated. E7 and, to a lesser extent E6, increased expression of VEGF and IL-8. Nevertheless, neither conditioned media from HPV 16 E6 nor E7-expressing HFKs were sufficient to induce migration of endothelial cells. Conditioned media from HFKs expressing the HPV 16 E6 and the E7 mutant E7C24G, which can target p107 and p130 but not pRb for degradation, contained increased levels of VEGF and IL-8. The results suggest that the mechanism of HPV 16 E7-mediated increased levels of VEGF is pRb-independent.
    Full-text · Article · Feb 2011 · Virology
  • Source
    • "Thus, in class A–B double mutants, exogenous LIN-3 is produced from the hypodermis, leading to the hyper-induction of vulval cell fates and the Muv phenotype (Cui et al., 2006a; Andersen et al., 2008). This link between LIN-35 and growth factor expression in C. elegans correlates with findings in mammals where pRb controls the expression of growth factors including VEGF, thus suggesting a novel mode by which pocket proteins may exert their tumor suppressive effects (Gabellini et al., 2006; Chien et al., 2007). It is also worth noting that additional factors identified through studies of SynMuv mutants (e.g., LIN-9), have been subsequently been linked to cancer in humans (Gagrica et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although now dogma, the idea that nonvertebrate organisms such as yeast, worms, and flies could inform, and in some cases even revolutionize, our understanding of oncogenesis in humans was not immediately obvious. Aided by the conservative nature of evolution and the persistence of a cohort of devoted researchers, the role of model organisms as a key tool in solving the cancer problem has, however, become widely accepted. In this review, we focus on the nematode Caenorhabditis elegans and its diverse and sometimes surprising contributions to our understanding of the tumorigenic process. Specifically, we discuss findings in the worm that address a well-defined set of processes known to be deregulated in cancer cells including cell cycle progression, growth factor signaling, terminal differentiation, apoptosis, the maintenance of genome stability, and developmental mechanisms relevant to invasion and metastasis.
    Preview · Article · May 2010 · Developmental Dynamics
Show more