Tumor suppressors: heroes and villains?
Tumor suppressors: heroes and villains?
复制标题
肿瘤抑制因子：英雄和恶棍？
DOI：
10.1007/s10911-011-9227-z
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发表时间：
2011
影响因子：
2.5
通讯作者：
Hinck,Lindsay
中科院分区：
文献类型：
--
作者：
Hinck,Lindsay
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 antitumorigenic 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.Autophagy, specifically macroautophagy in which cytoplasmic constituents are degraded and recycled through the lysosome, is the subject of the first review. This process is activated in response to multiple stresses occurring during tumor progression, including nutrient starvation, the unfolded protein response and hypoxia. Additionally, it is activated in response to cytotoxicity generated by cancer treatment. Consequently, at first glance, it appears that autophagy is villainous, functioning as a survival mechanism by facilitating nutrient recycling that helps cells endure the assaults associated with disease progression and treatment. However, other evidence paints a more complicated picture and supports a valiant role for autophagy in halting disease progression. At least one of the primary autophagy related genes, Becn1, appears to protect cells from genotoxic stress and maintain genome integrity under some conditions. Moreover, there is strong genetic evidence that Becn1 is a tumor suppressor. The gene for Becn1 maps to a tumor susceptibility locus that is mono-allelically deleted in a high percentage of human breast cancers, and its single copy loss in mice results in spontaneous tumor development. Together, these observations put Becn1 in the class of haploinsufficient tumor suppressors whose function may be regulated by cellular context. In this issue, Jayantha Debnath discusses the multifaceted nature of autophagy in breast tumor progression, proposing a model in which the consequences of autophagy depend on tumor type, context and stage. The tumor suppressive functions of autophagy occur during tumor initiation, whereas its oncogenic role emerges at later stages of tumor progression as tumor cells cope with stresses from their microenvironment
