Editorial [Hot Topic: The RB-Pathway in Cancer (Executive Editor: Erik Knudsen)]

OVERVIEW The concept that the retinoblastoma arises as a result of two discrete genetic hits in the same tumor suppressor gene has been in existence for greater than 20 years [1-4]. Cloning and analyses of the retinoblastoma tumor suppressor gene (Rb) revealed that this same tumor suppressor is mutated not only in retinoblastoma, but in a litany of other tumor types (e.g. bladder cancer, osteosarcoma, lung cancer and breast cancer) [5-9]. Subsequent studies demonstrated that in many additional tumors, the RB protein can be inactivated by a multitude of mechanisms [10-12]. For example, the E7 protein of human papilloma virus directly binds and inactivates the RB protein in cervical cancer [13, 14]. Additionally, RB is functionally inactivated by deregulated phosphorylation in those tumors which lack the p16ink4a tumor suppressor or harbor excessive CDK4 and cyclin D1 oncogenes [10, 12, 15]. The frequency of functional disruption of the retinoblastoma tumor suppressor in human cancers has precipitated significant efforts to define its modes of action. In general, these studies have been focused on two areas: 1. Defining Physiological/Biochemical Function Analyses of RB function in vitro or in cell culture models have defined the mechanisms through which RB is regulated and those biological processes which are governed by RB. RB action encompasses control of cell cycle, regulation of apoptosis, control of genomic stability, and modulation of differentiation [10, 16-19]. Each process is known to be altered in human cancer, and the influence of RB on each pathway is reviewed in this issue. 2. Delineating Tissue Specific Actions in Tumor Suppression RB and critical interacting factors are conserved in metazoans. As a result, it has been possible to study the functionality of RB in multiple organisms [20-23]. These models have been used to uncover the consequence of RB loss related to organismal development and tumorigenesis, and have revealed that RB likely utilizes distinct mechanisms to suppress tumorigenesis in specific tissues. Corresponding reviews discuss the disparate functions of RB in discrete model organisms, context dependent RB action and implications for tumor suppression. Taken together the body of work described in this issue and additional research, which regrettably due to space constraints could not be included herein, have provided significant insights into the action of RB in cancer. CHALLENGE FOR THE FUTURE Cloning of the Rb tumor suppressor, provided great promise that knowledge of such inhibitors of oncogenic proliferation would represent ideal nodes for the treatment of cancer. The concept that molecules like RB could be used to treat cancer was originally supported by studies demonstrating that reintroduction of functional RB protein into retinoblastoma cell lines could inhibit tumorigenic proliferation [24]. Indeed, today we can readily inhibit the proliferation of virtually any tumor cell type via manipulation of RB function [25-27]. While it is well appreciated that restoring the activity of a factor, such as RB, lost in cancer can be quite difficult, there are now clear instances where restoration of tumor suppressive signaling pathways can be achieved through pharmacological means. This is perhaps best demonstrated in the context of the p53 tumor suppressor [28-30], wherein multiple therapeutic agents have been shown to unleash the nascent p53 activity present in many tumor cells. Such approaches can be similarly applied to the RB pathway, wherein in many instances RB inactivation is achieved not through mutation but through other mechanisms. Unfortunately, RB has apparently failed to receive the level of exploration directed against p53 and other tumor suppressive pathways. Since RB loss occurs in many cancers and modifies the response to a variety of therapeutic agents [31-33], RB status could provide a critical diagnostic/prognostic basis upon with to direct treatment. While this concept is not new and a plethora of studies have evaluated RB status in disease outcome and therapeutic response, testing for RB status is largely confined to retinoblastoma susceptibility and is not yet used as the basis to direct therapy [34-37]. In summary, identification and study of the RB tumor suppressor has provided an essential knowledge basis for delineating endogenous mechanisms that protect against tumor formation. Significant advances in our understanding of RB funtion have unexpectedly revealed that its tumor suppressive activity extends to many disparate cellular pathways and that RB function is often tissue specific. Current challenges remain on how to harness this information and apply this detailed understanding of RB action to the improvement of cancer diagnosis and therapy....