Tumor dormancy, oncogene addiction, cellular senescence, and self-renewal programs

Adv Exp Med Biol. 2013;734:91-107. doi: 10.1007/978-1-4614-1445-2_6.

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.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Cycle Checkpoints
  • Cell Differentiation
  • Cellular Senescence*
  • Computational Biology / methods
  • Early Detection of Cancer / methods
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunologic Factors / immunology
  • Immunologic Factors / therapeutic use
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oncogenes*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Transcriptional Activation*
  • Tumor Microenvironment

Substances

  • Biomarkers, Tumor
  • Immunologic Factors
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc