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.

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Available from: Chiara Gabellini,
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    • "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). "
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    • " 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"
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    • "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). "
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