The intersection of RB tumor suppressor function, stem cells, metabolism and inflammation

Abstract

The RB tumor suppressor regulates the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most of cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment resistant cancers, it has become increasingly clear that in the majority of cancers somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of the cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene are often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates the G1/S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we demonstrated that RB inactivation enhances pro-inflammatory signaling through stimulation of IL-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling.

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