title: Tumor dormancy, oncogene addiction, cellular senescence, and self-renewal programs.
abstract: Cancers are frequently addicted to initiating oncogenes that elicit aberrant cellular proliferation, self-renewal, and apoptosis. Restoration of oncogenes to normal physiologic regulation can elicit dramatic reversal of the neoplastic phenotype, including reduced proliferation and increased apoptosis of tumor cells (Science 297(5578):63-64, 2002). In some cases, oncogene inactivation is associated with compete elimination of a tumor. However, in other cases, oncogene inactivation induces a conversion of tumor cells to a dormant state that is associated with cellular differentiation and/or loss of the ability to self-replicate. Importantly, this dormant state is reversible, with tumor cells regaining the ability to self-renew upon oncogene reactivation. Thus, understanding the mechanism of oncogene inactivation-induced dormancy may be crucial for predicting therapeutic outcome of targeted therapy. One important mechanistic insight into tumor dormancy is that oncogene addiction might involve regulation of a decision between self-renewal and cellular senescence. Recent evidence suggests that this decision is regulated by multiple mechanisms that include tumor cell-intrinsic, cell-autonomous mechanisms and host-dependent, tumor cell-non-autonomous programs (Mol Cell 4(2):199-207, 1999; Science 297(5578):102-104, 2002; Nature 431(7012):1112-1117, 2004; Proc Natl Acad Sci U S A 104(32):13028-13033, 2007). In particular, the tumor microenvironment, which is known to be critical during tumor initiation (Cancer Cell 7(5):411-423, 2005; J Clin Invest 121(6):2436-2446, 2011), prevention (Nature 410(6832):1107-1111, 2001), and progression (Cytokine Growth Factor Rev 21(1):3-10, 2010), also appears to dictate when oncogene inactivation elicits the permanent loss of self-renewal through induction of cellular senescence (Nat Rev Clin Oncol 8(3):151-160, 2011; Science 313(5795):1960-1964, 2006; N Engl J Med 351(21):2159-21569, 2004). Thus, oncogene addiction may be best modeled as a consequence of the interplay amongst cell-autonomous and host-dependent programs that define when a therapy will result in tumor dormancy.
authors.affiliation: Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305-5151, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Bellovin
authors.forename: Bikul
authors.initials: B
authors.lastname: Das
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D016922:Cellular Senescence; D019295:Computational Biology / Q000379:methods; D055088:Early Detection of Cancer / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D007155:Immunologic Factors; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc