The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis

The retinoblastoma tumor suppressor protein Rb plays a major role in regulating G1/S transition and is a critical regulator of cell proliferation. Rb protein exerts its growth regulatory properties mainly by physically interacting with the transcriptionally active members of the E2F transcription factor family, especially E2Fs 1, 2, and 3. Given its critical role in regulating cell proliferation, it is not surprising that Rb is inactivated in almost all tumors, either through the mutation of Rb gene itself or through the mutations of its upstream regulators including K-Ras and INK4. Recent studies have revealed a significant role for Rb and its downstream effectors, especially E2Fs, in regulating various aspects of tumor progression, angiogenesis, and metastasis. Thus, components of the Rb-E2F pathway have been shown to regulate the expression of genes involved in angiogenesis, including VEGF and VEGFR, genes involved in epithelial-mesenchymal transition including E-cadherin and ZEB proteins, and genes involved in invasion and migration like matrix metalloproteinases. Rb has also been shown to play a major role in the functioning of normal and cancer stem cells; further, Rb and E2F appear to play a regulatory role in the energy metabolism of cancer cells. These findings raise the possibility that mutational events that initiate tumorigenesis by inducing uncontrolled cell proliferation might also contribute to the progression and metastasis of cancers through the mediation of the Rb-E2F transcriptional regulatory pathway. This review highlights these recent studies on tumor promoting functions of the Rb-E2F pathway.