Tumor Suppressors: Heroes and Villains?

Excerpt

Great progress has been made in our understanding of tumor suppressor genes since landmark research by Knudson led to the “two-hit” hypothesis and the subsequent molecular identification of the retinoblastoma gene (Rb1) [1]. Knudson’s 2-hit model, whereby germline mutation of one allele predisposes a tissue to tumor formation upon somatic mutation of the second allele, remains valid for many tumor suppressor genes. However, research in the intervening years has demonstrated that the model does not correctly describe the behavior of all tumor suppressors. For example, not all tumor suppressors must be fully inactivated in order to facilitate tumor initiation and progression. Consequently, there is an increasing appreciation of tumor suppressor genes being haploinsufficient. Moreover, it has become clear that tumor suppressors often function within signaling pathways, where they regulate complex cellular behaviors that impact the function of tissues, organs and, indeed, the entire organism. In these complex settings, so-called tumor suppressors can play a far more nuanced role by exerting either pro- or anti-tumorigenic effects depending on the biological context. In this issue, we tackle some of the complexities of tumor suppression by examining how biological processes (such as autophagy and innate immunity), environmental conditions (the microenvironment, parity, circadian cycles) intrinsic pathways (oncogene-induced senescence) and extrinsic cues (axon guidance molecules) influence the context-dependent action of these important genes. In some settings tumor suppressors play their designated role, heroically keeping rogue cells in check, while in other contexts, they are villains that participate in tumor formation. …