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.
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Acknowledgements
The authors would like to acknowledge current members of the Felsher laboratory for critical discussion and previous members who have contributed to characterizing various models of oncogene addiction.
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Bellovin, D.I., Das, B., Felsher, D.W. (2013). Tumor Dormancy, Oncogene Addiction, Cellular Senescence, and Self-Renewal Programs. In: Enderling, H., Almog, N., Hlatky, L. (eds) Systems Biology of Tumor Dormancy. Advances in Experimental Medicine and Biology, vol 734. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1445-2_6
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